Ep 2016 21 issue 1 by Hogrefe

Volume 21 / Number 1 / 2016

European Psychologist Editor-in-Chief Peter Frensch Managing Editor Kristen Lavallee Associate Editors Rainer Banse Ulrike Ehlert Katariina Salmela-Aro

Official Organ of the European Federation of Psychologists’ Associations (EFPA)

Special Issue Noninvasive Brain Stimulation

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European Psychologist

Volume 21, No. 1, 2016 OfďŹ cial Organ of the European Federation of Psychologists Associations (EFPA)

Special Issue Noninvasive Brain Stimulation

Editor-in-Chief

Peter A. Frensch, Institute of Psychology, Humboldt-University of Berlin, Rudower Chaussee 18, 12489 Berlin, Germany, Tel. +49 30 2093 4922, Fax +49 30 2093 4910, peter.frensch@psychologie.hu-berlin.de

Managing Editor

Kristen Lavallee, lavallee-psych@hu-berlin.de

Founding Editor / Past Editor-in-Chief

Kurt Pawlik, Hamburg, Germany (Founding Editor) / Alexander Grob, Basel, Switzerland (Past Editor-in-Chief)

Associate Editors

Rainer Banse, Institute for Psychology, Social and Legal Psychology, University of Bonn, Karl-Kaiser-Ring 9, 53111 Bonn, Germany, Tel. +49 228 73 4439, Fax +49 228 73 4229, banse@uni-bonn.de Ulrike Ehlert, Institute of Psychology, University of Zurich, Binzmu¨hlestrasse 14 / Box 26, 8050 Zurich, Switzerland, Tel. +41 44 635 7350, u.ehlert@psychologie.uzh.ch Katariina Salmela-Aro, University of Helsinki, P.O. Box 4, 00014 University of Helsinki, Finland, Tel. +358 9 191 23255, katariina.salmela-aro@helsinki.ﬁ

EFPA News and Views Editor

Eleni Karayianni, Department of Psychology, University of Cyprus, P.O. Box 20537, Nicosia, Cyprus, Tel. +357 2289 2022, Fax +357 2289 5075, eleni.karayianni@efpa.eu

Editorial Board

Louise Arseneault, UK Dermot Barnes-Holmes, Ireland Gisela Bo¨hm, Norway Mark G. Borg, Malta Serge Bre´dart, Belgium Catherine Bungener, France Torkil Clemmensen, Denmark Cesare Cornoldi, Italy Istva´n Czigler, Hungary Ge´ry d’Ydewalle, Belgium Iris M. Engelhard, The Netherlands Michael Eysenck, UK Rocio Fernandez-Ballesteros, Spain Dieter Ferring, Luxembourg Magne Arve Flaten, Norway Alexandra M. Freund, Switzerland Marta Fulop, Hungary

Danute Gailiene, Lithuania John Gruzelier, UK Sami Gu¨lgo¨z, Turkey Vera Hoorens, Belgium Paul Jimenez, Austria Remo Job, Italy Katja Kokko, Finland Gu¨nter Krampen, Germany Anton Ku¨hberger, Austria Ingrid Lunt, UK Petr Macek, Czech Republic Mike Martin, Switzerland Teresa McIntyre, USA Judi Mesman, The Netherlands Klaus Opwis, Switzerland Susana Padeliadu, Greece Ståle Pallesen, Norway

Georgia Panayiotou, Cyprus Sabina Pauen, Germany Marco Perugini, Italy Martin Pinquart, Germany Jose´ M. Prieto, Spain Lea Pulkkinen, Finland Vincent Rogard, France Sandro Rubichi, Italy Ingrid Schoon, UK Rainer Silbereisen, Germany Lennart Sjo¨berg, Sweden Katya Stoycheva, Bulgaria Jan Strelau, Poland Tiia Tulviste, Estonia Jacques Vauclair, France Dieter Wolke, UK Rita Zukauskiene, Lithuania

The Editorial Board of the European Psychologist comprises scientists chosen by the Editor-in-Chief from recommendations sent by the member association of EFPA and other related professional associations, as well as individual experts from particular ﬁelds. The associations contributing to the current editorial board are: Berufsverband O¨sterreichischer Psychologen/innen; Belgian Psychological Society; Cyprus Psychologists’ Association; Unie Psychologickych Asociaci, Czech Republic; Dansk Psykologforening; Union of Estonian Psychologists; Finnish Psychological Association; Fe´de´ration Française des Psychologues et de Psychologie; Socie´te Française de Psychologie; Berufsverband Deutscher Psychologinnen und Psychologen; Magyar Pszicholo´giai Ta´rsasa´g; Psychological Society of Ireland; Associazione Italiana di Pscicologia; Lithuanian Psychological Association; Socie´te´ Luxembourgeoise de Psychologie; Malta Union of Professional Psychologists; Norsk Psykologforening; O¨sterreichische Gesellschaft fu¨r Psychologie; Colegio Oﬁcial de Psicologos; Swiss Psychological Society; Turkish Psychological Association; European Association for Research on Learning and Instruction; European Association of Experimental Social Psychology; European Association of Personality Psychology; European Association of Psychological Assessment; European Health Psychology Society. Publisher

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European Psychologist 2016; Vol. 21(1)

Ó 2016 Hogrefe Publishing

Contents Special Issue: Noninvasive Brain Stimulation (Coordinator: Carlo Miniussi, Guest Editor: Giovanni Galfano) Editorial

A Foreword on the Use of Noninvasive Brain Stimulation in Psychology Carlo Miniussi

Original Articles and Reviews

Application of Transcranial Electric Stimulation (tDCS, tACS, tRNS): From Motor-Evoked Potentials Towards Modulation of Behaviour Walter Paulus, Michael A. Nitsche, and Andrea Antal

EFPA News and Views

Ó 2016 Hogrefe Publishing

tES Stimulation as a Tool to Investigate Cognitive Processes in Healthy Individuals Michal Lavidor

Social Psychology and Noninvasive Electrical Stimulation: A Promising Marriage Paulo S. Boggio, Gabriel G. Reˆgo, Lucas M. Marques, and Thiago L. Costa

Noninvasive Brain Stimulation for the Study of Memory Enhancement in Aging David Bartre´s-Faz and Didac Vidal-Pin˜eiro

Transcranial Electrical Stimulation in Post-Stroke Cognitive Rehabilitation: Where We Are and Where We Are Going Silvia Convento, Cristina Russo, Luca Zigiotto, and Nadia Bolognini

Transcranial Direct Current Stimulation as a Novel Method for Enhancing Aphasia Treatment Effects Jennifer T. Crinion

Transcranial Electrical Stimulation (tES) for the Treatment of Neuropsychiatric Disorders Across Lifespan Carolina Pe´rez, Jorge Leite, Sandra Carvalho, and Felipe Fregni

News and Announcements: From the EFPA Network of National News Correspondents

Meeting Calendar

European Psychologist 2016; Vol. 21(1)

Special Issue: Noninvasive Brain Stimulation

Editorial A Foreword on the Use of Noninvasive Brain Stimulation in Psychology Carlo Miniussi1,2 1

Neuroscience Section, Department of Clinical and Experimental Sciences, University of Brescia, Italy, 2Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy ‘‘After a small shock to the head, you can achieve happiness, a high mark in school, or the record in your preferred video game.’’ I am reading this claim in the newspaper while sitting on the train going to work. I know what they are talking about; this is my field of research! Even so, I find these words persuasive, and I would like to try these shocks. The train has slowed down, a voice announces my stop, and I am back to a daily reality where small shocks have become a significant tool in basic and clinical neuroscience but certainly not to improve the performance of normal people in their everyday activities. In recent years, there has been an exponential rise in the number of studies employing noninvasive brain stimulation (NIBS) as a means of gaining understanding of the neural substrates that underlie behavior and as a co-adjuvant for the clinician in treating brain dysfunctions following psychological, cognitive, and neurological disease. In this context, some studies have even suggested that NIBS may enhance brain function in healthy individuals. These findings have attracted media attention and changed the demands of patients and the public to their clinical advisers. Therefore, it is important to open a discussion regarding the utility, effectiveness, and usability of NIBS in real life, outside the laboratory. Along the same lines, the psychologist should understand these techniques to correctly address their patients’ demands. Upon closer examination, we uncover a scenario different from that depicted by the media when NIBS is used to enhance cognition in normal individuals. In this case, the results are confined only to small improvements obtained in the laboratory, improvements that are essential to establish the role of a brain area in a given experimental task, but that certainly do not improve functionality in healthy individuals. Therefore, it is important to prevent pseudoscience from getting ahead of the actual science, which can be done only by discussing the real data. The aim of this special issue is to provide a realistic picture of the state-of-the-art procedures in the field and highlight how these emerging Ó 2016 Hogrefe Publishing

techniques for noninvasive manipulation of the human brain contribute to the development of the field of psychology. Given these premises, it has also become very important to spread this knowledge outside the experimental laboratories and see, if the use of stimulation techniques as a new experimental and therapeutic tool can be fully included in the armamentarium of the psychologist. This special issue consists of seven papers, all on the use of transcranial stimulation in both healthy and clinical populations. In this framework, the recent advances made due to NIBS methods (Paulus, Nitsche, & Antal, 2016) in the understanding of the ‘‘psychological brain’’ (Boggio, Rêgo, Marques, & Costa, 2016; Lavidor, 2016), and whether the use of these brain stimulation techniques alone or combined with rehabilitation, or psychotherapeutic procedures can lead to performance enhancements in the state of our patients are discussed (Bartrés-Faz & Vidal-Piñeiro, 2016; Convento, Russo, Zigiotto, & Bolognini, 2016; Crinion, 2016; Pérez, Leite, Carvalho, & Fregni, 2016). NIBS includes several methods that can be mainly divided into repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES). These different NIBS techniques affect neuronal states through different means. However, the stimulation of the human brain requires that these methods are able to induce a change in the membrane potential of neurons. Moreover, the manner in which they achieve this result and the intensity of their action differ among the different NIBS techniques. Transcranial magnetic stimulation is primarily a method of neurostimulation that includes the induction of depolarization of neuronal membranes and the initiation of action potentials in the area stimulated by electromagnetic induction. This effect is produced using bulky and expensive machinery. Transcranial electrical stimulation is essentially a method of neuromodulation that uses a smaller and less expensive device. Low-intensity electrical stimulation European Psychologist 2016; Vol. 21(1):1–3 DOI: 10.1027/1016-9040/a000253

Editorial

induces a state change in the membrane potential, thereby altering the ionic fluxes. This alteration can result in hyperpolarization or depolarization of the neuron. Transcranial electrical stimulation does not provide direct induction of action potentials, but rather a variation in the response threshold of stimulated neurons, resulting in a modulation of the response that the neurons can provide. Moreover, tES has been proven to be a safe approach, provided that it is administered by trained personnel and with the appropriate medical device (Fregni et al., 2015; Fertonani, Ferrari, & Miniussi, 2015). While a considerable amount of data is now available to support the safety of electric and magnetic stimulation, we should be aware that some real risks in their usage exist. In particular, TMS should be performed according to current safety guidelines (Rossi, Hallett, Rossini, Pascual-Leone, & Safety of TMS Consensus Group, 2009). Given the prevalence of tES methods among psychologists, this issue will mainly address the developments of tES rather than TMS. The introductory article by Paulus et al. (2016) reports the basic aspects of different tES modalities such as transcranial direct current (tDCS), alternating current (tACS), and random noise (tRNS) stimulation. Descriptions of the mechanisms of action for the different approaches are reported, illustrating how several parameters can change the final induced effects. The background knowledge for understanding the basic aspects of tES methods and how to apply them are described, highlighting the relevant features that should be considered when using tES. This work is followed by a description of the possible application of tES as a tool to investigate cognitive processes in healthy individuals by Lavidor (2016). It has been reported that due to tES properties it is possible to interact with the functioning of a specific brain area and therefore the process performed by that area. Such tES-induced modifications can lead to facilitation or impairment of individual performance. In general, it is not important if the induced effect is facilitation or interference, as the unique feature of tES is its ability to interact transiently with the area of the brain stimulated, thus modifying the activity of that area and allowing evaluation of its function. Instead, the induction of behavioral facilitation is important in the field of neurorehabilitation (see Bartrés-Faz & VidalPiñeiro, 2016; Convento et al., 2016; Crinion, 2016). This approach is expanded and further implemented by Boggio and collaborators (2016), who show how the fields of social neuroscience and psychology have made substantial advances due to the introduction of techniques such as tES, allowing not only the establishment of causal brainbehavior relationships, but also relevance in refining and integrating the theoretical models available to account for different social processes. In particular, it is reported how tES has been used to investigate social pain, social interaction, prejudice, and social decision making. The authors conclude that such applications are highly promising, and they show that tES is indeed an appropriate tool for the further development of this field. The article by Bartrés-Faz and Vidal-Piñeiro (2016) builds an important bridge, showing how it is possible to use NIBS as an adjuvant therapeutic strategy in the management of age-associated memory decline. Indeed, European Psychologist 2016; Vol. 21(1):1–3

an area of research that has a great potential for the future is the possibility to maintain or improve memory in aging human beings, given the impact of age-related cognitive dysfunction on the quality of life. Bartrés-Faz and VidalPiñeiro (2016) summarize currently available evidence of memory enhancement and suggest that the use of NIBS offers an attractive and promising opportunity. However, the most important issue is that its use requires appropriate knowledge coupled with a clear understanding of the neurophysiology and cognitive neuroscience of aging. Only by ensuring that these requirements are in place we can refine the hypothesis and select the best procedures to optimize the effect of NIBS on cognition. Such an approach is a key aspect that should also be underscored when NIBS methods are used in the clinical context, as in post-stroke rehabilitation. Most research efforts thus far have been directed in this field, and the results seem, again, very promising. A clear and up-to-date view of using tES in poststroke patients for cognitive rehabilitation is included in the articles by Convento and collaborators (2016) and Crinion (2016). Both of these reports show the important therapeutic potential offered by this technique and provide some crucial suggestions for the design of future clinical trials. Convento et al. (2016) present the current state-ofthe-art information concerning the use of tES for the improvement of post-stroke visual and cognitive deficits. The evidence supporting the potential of tES to increase neuroplasticity in the adult human brain is reported, and how tES can be used as an adjuvant tool for cognitive rehabilitation is explained. This paper provides a rationalized framework for the important elements that should be considered when using tES. Moreover, it is emphasized that these approaches will not only offer a potentiation of the existing treatments, but will provide novel clues to the factors that may predict a patient’s response via novel characterization of the injured cognitive system. The work by Crinion (2016) discusses the latest studies using tES for enhancing aphasia treatment effects in subacute and chronic post-stroke patients and primary progressive aphasia patients. Importantly, the author shows that before treatment is initiated, patients who are likely to respond to specific tES methods and speech and language therapy should be identified by characterizing the brain state via neuroimaging and specific cognitive evaluations. As for all treatments, in tES, it should not be assumed that one size fits all, and therefore, the final significant effect of training will depend on which cortical areas are targeted by the stimulation and by the training. Therefore, an additional key element is related to the behavioral treatment; applying tES during a non-efficient behavioral intervention will not magnify results that are not present. Therefore, choosing the adequate training task is the most relevant element for treatment success (Crinion, 2016). Finally, the paper by Pérez et al. (2016) shows that tES can be used to reduce symptoms in a variety of neuropsychiatric conditions, such as depression, schizophrenia, anxiety, autism, and craving, making tES an important complement for psychological/psychiatric disorders. The authors highlight once more the importance of many variables that determine the final effect. There are several Ó 2016 Hogrefe Publishing

Editorial

variables, and each one requires full awareness of its importance. For example, one variable is age; the human brain undergoes several anatomical and functional changes across the life span, and these changes should be considered when we define the technical variables of our protocol. Therefore, tES-induced effects are not only different in different pathologies, but may even be different across the life span (Pérez et al., 2016). The main aspect that it is highlighted in this special issue is that NIBS can change cortical excitability; nevertheless, such a change is not directly mapped as a unidirectional change in behavior. Applying an electric field to a nonlinear dynamic system, such as the brain, seems likely to have many nontrivial effects that preclude a simple extrapolation on behavior (Miniussi, Harris, & Ruzzoli, 2013). Therefore, before using these methods, we must have a clear theoretical framework and some methodological knowledge that will allow us to make a clear prediction of the final result. Overall, one key aspect that emerges is that the final result induced by neurostimulation can be defined only by fully considering the state of the neural system. Basically, we should not forget a classic rule of physiology, which states that we cannot consider the effects induced by tES as pure because the effects induced in the area that we plan to stimulate will depend on the state of activation of the area at the time of stimulation. Consequently, researchers should be aware that the effects of tES are proportional to the level of neuronal activation (i.e., activity dependency) during the application of the stimulation. As described above, tES is a neuromodulatory approach, and therefore, it produces a rather subtle modulatory effect on neural activity. Thus, tES is inadequate to directly induce action potentials in neurons unless neurons are already close to the discharge threshold. In such a context, we can claim that tES is more effective in brain networks that are already selectively engaged by a given cognitive task than in networks in a resting state. Theoretical and technical difficulties have been encountered using NIBS to obtain reliable results and appropriate models to frame them, and there is still a long way to go in the field before well-defined shared approaches will be used. However, by virtue of recent discoveries and developments, important foundations have been built, and future work will build upon this solid foundation. I therefore believe that the excellent contributions of this special issue will provide inspiration for important advances in this field.

European Psychologist, 21, 55–64. doi: 10.1027/1016-9040/ a000238 Crinion J. T. (2016). Transcranial direct current stimulation as a novel method for enhancing aphasia treatment effects. European Psychologist, 21, 65–77. doi: 10.1027/10169040/a000254 Fertonani, A., Ferrari, C., & Miniussi, C. (2015). What do you feel if I apply transcranial electric stimulation? Safety, sensations and secondary induced effects. Clinical Neurophysiology, 126, 2181–2188. doi: 10.1016/j.clinph.2015.03.015 Fregni, F., Nitsche, M. A., Loo, C. K., Brunoni, A. R., Marangolo, P., Leite, J., . . . Bikson, M. (2015). Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): Review and recommendations from an expert panel. Clinical Research and Regulatory Affairs, 32, 22–35. doi: 10.3109/10601333.2015.980944 Lavidor, M. (2016). tES stimulation as a tool to investigate cognitive processes in healthy individuals. European Psychologist, 21, 15–29. doi: 10.1027/1016-9040/a000248 Miniussi, C., Harris, J. A., & Ruzzoli, M. (2013). Modelling non-invasive brain stimulation in cognitive neuroscience. Neuroscience & Biobehavioural Reviews, 37, 1702–1712. Paulus, W., Nitsche, M. A., & Antal, A. (2016). Application of transcranial electric stimulation (tDCS, tACS, tRNS): From motor-evoked potentials towards modulation of behaviour. European Psychologist, 21, 4–14. doi: 10.1027/1016-9040/ a000242 Pérez, C., Leite, J., Carvalho, S., & Fregni, F. (2016). Transcranial electrical stimulation (tES) for the treatment of neuropsychiatric disorders across lifespan. European Psychologist, 21, 78–95. doi: 10.1027/1016-9040/a000252 Rossi, S., Hallett, M., Rossini, P. M., & Pascual-Leone, A., Safety of TMS Consensus Group. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology, 120, 2008–2039. About the author Carlo Miniussi is Full Professor of Human Neurophysiology, Department of Clinical and Experimental Sciences, School of Medicine, University of Brescia (Italy) and Head of the Cognitive Neuroscience Section, Saint John of God Clinical Research Centre – IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia (Italy). The core of his research activity is driven by the goal to understand if cortical plasticity can be induced and manipulated by means of noninvasive brain stimulation in healthy and pathological adult brains, to understand the relation between induced synaptic plasticity and cognitive plasticity, and how cognitive plasticity can be sustained by the activity of a functional neuronal network.

References Bartrés-Faz, D., & Vidal-Piñeiro, D. (2016). Noninvasive brain stimulation for the study of memory enhancement in aging. European Psychologist, 21, 41–54. doi: 10.1027/1016-9040/ a000241 Boggio, P. S., Rêgo, G. G., Marques, L. M., & Costa, T. L. (2016). Social Psychology and noninvasive electrical stimulation: A promising marriage. European Psychologist, 21, 30–40. doi: 10.1027/1016-9040/a000247 Convento, S., Russo, C., Zigiotto, L., & Bolognini, N. (2016). Transcranial electrical stimulation in post-stroke cognitive rehabilitation: Where we are and where we are going. Ó 2016 Hogrefe Publishing

Carlo Miniussi Dept of Clinical and Experimental Sciences University of Brescia Viale Europa, 11 25123 Brescia Italy Tel. +39 030 3717-441 Fax +39 030 3717-443 E-mail carlo.miniussi@cognitiveneuroscience.it European Psychologist 2016; Vol. 21(1):1–3

Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

Application of Transcranial Electric Stimulation (tDCS, tACS, tRNS) From Motor-Evoked Potentials Towards Modulation of Behaviour Walter Paulus,1 Michael A. Nitsche,2 and Andrea Antal1 1

Department for Clinical Neurophysiology, University Medical Center Göttingen, Germany, 2 Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany Abstract. Low-intensity transcranial electrical stimulation (tES) techniques are a group of noninvasive brain stimulation approaches, where currents are applied with intensities ranging between 0.4 and 2 mA through the human scalp. The most frequently used tES methods are transcranial direct current (tDCS), alternating current (tACS), and random noise stimulation (tRNS). These methods have been shown to induce changes in cortical excitability and activity during and after the stimulation in a reversible manner. It was observed that while anodal and cathodal tDCS acts on the membrane potentials by depolarizing or hyperpolarizing them, tACS probably modifies cortical oscillations. tRNS, that is a special form of tACS, might act through affecting the signal-to-noise ratio in the brain. Currently, an exponentially increasing number of studies have been published regarding the effects of tES on physiological processes and cognition. The aim of this review is to summarize the basic aspects of tES methods. Keywords: transcranial stimulation, human, direct current, alternating current

During the last 35 years a number of modern, widely used noninvasive electrical brain stimulation (NIBS) techniques have been developed. Low-intensity transcranial electrical stimulation or weak transcranial electrical stimulation (tES) methods are a group of NIBS techniques where currents with low intensities (typically 1–2 mA) are applied through the intact scalp (for a review, see Paulus, 2011). These techniques, though not capable of inducing neuronal firing directly in a resting cell, modulate spontaneous firing rates of cortical neurons and induce changes in cortical excitability which can outlast the duration of the stimulation (Nitsche & Paulus, 2000, 2001). tES methods include transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) and a special form of tACS, transcranial random noise stimulation (tRNS). With regard to the taxonomy, in addition to the physical classification of tES methods based on the current waveform that we are currently using (direct or alternating current) and electrode montage (e.g., motor cortex stimulation), the

European Psychologist 2016; Vol. 21(1):4–14 DOI: 10.1027/1016-9040/a000242

functional characteristics of the stimulation based on the outcome, for example, excitatory versus inhibitory stimulation, are generally used for further differentiation of the methods (Guleyupoglu, Schestatsky, Edwards, Fregni, & Bikson, 2013). Although the number of published reviews is increasing in this field, most of them are focusing on one of the aspects of the stimulation (e.g., tDCS effects on cognition) or giving a general picture related to the physiological effects of the stimulation (e.g., excitation-inhibition). Furthermore, the number of reviews discussing the application of other tES methods, such as tACS and tRNS, is limited. Therefore, we aim to give a basic but not oversimplified introduction to tES methods for students, scientists, and health practitioners, who want to start or have just started using tES methods and require information about elementary taxonomy, terminology, and application of the stimulation. The advantages and disadvantages of different electric stimulation methods are also discussed.

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W. Paulus et al.: Application of Transcranial Electric Stimulation

General Aspects of the Stimulation The mode of application of the stimulation is similar in the case of all low-intensity tES interventions. The current is delivered by a battery-driven stimulator using a pair of rubber electrodes wrapped in a viscose sponge that is soaked in isotonic saline solution. The electrodes may also be fixed with conductive electrode paste. Stimulation is applied over the homogeneous skin without abrasion. Generally, one electrode is defined as the target electrode, which is positioned above the cortical region of interest. The other electrode is usually referred to as the reference, or return electrode (Bikson, Datta, Rahman, & Scaturro, 2010). Usually, the electrode size is between 16 and 35 cm2, however, it can also be reduced to for example, 3.5 cm2 by keeping current density (quotient of the applied intensity and the interfacing electrode surface area) constant. tDCS hereby is able to modulate more focal areas, for example, changing the excitability of small hand muscles (abductor digiti minimi and first dorsal interosseus muscle) differentially (Nitsche et al., 2007). The return electrode is physiologically also active, when placed over another cortical area. To reduce a possibly confounding effect of the return electrode, an extracephalic montage can be used (Moliadze, Antal, & Paulus, 2010b) or the size of the electrode can be increased in order to reduce the current density to subthreshold levels, that is, a current density, which does not elicit physiological or functional effects (Nitsche et al., 2007). Cutaneous sensations, such as itching, tingling, or burning sensations, may occur dose-dependently during the application of tDCS at the electrode-skin interface. For a long time it was widely assumed in the literature that these phenomena associated with the stimulation were mostly restricted only to the initial phase of the intervention (e.g., Fregni & Pascual-Leone, 2007). Only few reports described persistent sensations outlasting the initial phase of the active stimulation (Dundas, Thickbroom, & Mastaglia, 2007) and the presence of similar phenomena after the cessation of sham stimulation (Gandiga, Hummel, & Cohen, 2006). Our studies clearly imply the cutaneous sensations do not disappear completely either during the active or during the sham condition (Ambrus, Paulus, & Antal, 2010; Antal et al., 2008; Poreisz, Boros, Antal, & Paulus, 2007). The application of tRNS and tACS over the scalp induces less sensation compared with tDCS (Ambrus et al., 2010; Fertonani, Ferrari, & Miniussi, 2015). Computer modeling studies suggest that HighDefinition tDCS (HD-tDCS), a variant of tDCS, might represent a significant improvement of the physical focality of the stimulation compared to the conventional design. HDtDCS can be performed via disk-shaped electrodes with 8 mm diameter; the target electrode is surrounded by four return electrodes at for example, 3 cm distance over the primary motor cortex (M1; Datta et al., 2009). Needless to say, the size of the stimulated brain area even with small electrodes is generally clearly larger than the surface of the electrode due to the spreading of the current, in particular cerebrospinal fluid (CSF). The complex cortical geometry combined with the high conductivity of the CSF that covers 2016 Hogrefe Publishing

the cortex gives rise to a very distinctive electric field distribution in the cortex, with a strong component confined to the bottom of sulci under or very near the electrodes and a weaker tangential component that covers large areas of the gyri between the two electrodes (Miranda, Mekonnen, Salvador, & Ruffini, 2013). Any stimulation probably induces not only local but also remote effects (Lang et al., 2005), which are at least partially functional connectivity-driven (Polania, Nitsche, & Paulus, 2011). A standard procedure for quantifying the effects of a tES technique is to measure the amplitude and time course of motor-evoked potentials (MEPs), by using transcranial magnetic stimulation (TMS; Nitsche & Paulus, 2000). Since this is a quite straightforward, efficient, and simple outcome parameter, according to our estimations, about 80% of the tES studies in healthy subjects were done using the motor cortex as a model. In analogy, effects of tES techniques can be assessed at the visual cortex by evaluating changes of TMS intensity thresholds that can elicit phosphenes before and after intervention (e.g., Antal, Kincses, Nitsche, & Paulus, 2003a, 2003b; Antal, Nitsche, & Paulus, 2003), or other physiological parameters (Antal, Kincses, Nitsche, Bartfai, & Paulus, 2004).

Transcranial Direct Current Stimulation (tDCS) Transcranial direct current stimulation (tDCS) is the most widely utilized of the tES techniques. The intensity of the current delivered by tDCS is not sufficiently high to induce action potentials directly in resting cells; tDCS polarizes neuronal membrane potentials and it increases or decreases the spontaneous firing rate of the affected neurons (Creutzfeldt, Fromm, & Kapp, 1962). The anode is defined as the electrode where the current enters the body and the cathode is defined as any electrode where the current exits the body. The conventional tDCS paradigm uses a single current amplitude during the course of stimulation except for one ramp-up and ramp-down period (typically a 10â&#x20AC;&#x201C;30 s linear ramp). Ramp-up and-down periods are introduced in order to minimize the probability of the appearance of sudden skin and visual sensations induced by retinal stimulation after switching on or off the stimulation abruptly. The current flow is not restricted to the area underneath the electrodes, but rather spreads around the vicinity and into the neural tissue between the electrodes (Miranda et al., 2013; Opitz, Paulus, Will, Antunes, & Thielscher, 2015; Ruffini, Fox, Ripolles, Miranda, & Pascual-Leone, 2014). Physiologically, two main effects of tDCS should be discerned. During stimulation, tDCS induces a subthreshold modulation of membrane potentials. Sufficiently long stimulation results in long-term potentiation or depression (LTP- and LTD)-like aftereffects. For the membranepolarizing effects, it has been shown that current flow direction in relation to neuronal orientation determines the effects of stimulation. It seems to be relevant that the electrical field meets the long axis of a neuron to cause effects, European Psychologist 2016; Vol. 21(1):4â&#x20AC;&#x201C;14

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and the orientation of the long axis of the neuron in relation to the electrical field, and not stimulation polarity per se, determines the direction of the effects (Kabakov, Muller, Pascual-Leone, Jensen, & Rotenberg, 2012). Moreover, with regard to a single neuron, current has to flow in and out of the neuron at different areas, and thus each neuron affected by tDCS will experience de- and hyperpolarizing effects at different sub-compartments. The physiologically relatively uniform effect might be caused by compartmental differences of susceptibility for polarization effects. Ion channels and receptors are more densely packed at the soma and axon level of neurons, as compared to dendrites, which might lead to the assumption that these compartments are the most relevant for tDCS effects. Indeed, cell-culture experiments suggest that anodal tDCS hyperpolarizes the membrane potential in the apical dendritic regions and depolarizes it in the somatic region, whereas the cathode has a reversed effect (Radman et al., 2009). However, the situation is more complex in the human brain, where gyration might result in heterogeneous orientation of electrical fields in relation to neurons, and thus result in antagonistic alterations of excitability in single neurons, as proposed by the results of a modeling study (Reato et al., 2013). Nevertheless, the impact of tDCS on excitability alterations at least in the human motor cortex, but also animal cortices, seems to be fairly homogeneous for the target region (Bindman, Lippold, & Redfearn, 1964; Nitsche & Paulus, 2000, 2001). Not only in animal models and modeling studies, but also for the human brain a polarization effect of tDCS on neuronal membranes is suggested because block of voltage-gated ion channels in healthy subjects, which should reduce depolarization, prevents effects of anodal tDCS on excitability (Nitsche, Fricke, et al., 2003). Moreover, the effects of tDCS in human beings seem to be primarily localized intracortically, including corticocortical afferents (Boros, Poreisz, Munchau, Paulus, & Nitsche, 2008). If applied for a few minutes, tDCS induces excitability alterations, which can last for over 1 hr after the end of stimulation (Nitsche, Nitsche, et al., 2003; Nitsche & Paulus, 2001). These excitability alterations probably reflect calcium-dependent plastic changes driven by the glutamatergic system: Previous studies found that NMDA receptor block abolished anodal and cathodal stimulationinduced excitability alterations, whereas an NMDA receptor agonist prolonged, and calcium channel block abolished anodal tDCS-induced facilitation (Nitsche, Fricke, et al., 2003; Nitsche, Liebetanz, et al., 2004). Besides these effects, neuromodulators can also have a complex nonlinear impact on tDCS-induced neuroplasticity. Amphetamine and serotonin boost excitability-enhancing effects of anodal tDCS (Nitsche, Grundey, et al., 2004; Nitsche et al., 2009), whereas the excitability-diminishing effects of cathodal tDCS are prolonged by dopaminergic agents (Kuo, Paulus, & Nitsche, 2008; Monte-Silva et al., 2009; Monte-Silva, Liebetanz, Grundey, Paulus, & Nitsche, 2010). Thus, respective combination of drugs and stimulation might be suited to boost tDCS effects in future studies. In addition to neuronal effects on glutamatergic synapses, it has also been suggested that in the development of the European Psychologist 2016; Vol. 21(1):4–14

aftereffects both glial cells (Ruohonen & Karhu, 2012) and non-synaptic mechanisms may play a role (Ardolino, Bossi, Barbieri, & Priori, 2005). Using tDCS, the current polarity is the main determinant. Polarity-specific physiological aftereffects of tDCS are most consistently observed in the motor domain (see above), where in a medium dose range anodal tDCS leads to an increase of cortical excitability whereas cathodal tDCS decreases it. Similar effects were identified for visual cortex stimulation (e.g., Antal, Kincses, et al., 2004). However, the extent to which anodal and cathodal sources produce net effects on excitation and inhibition might also depend on the macroscopic geometry of the stimulated area (see above), and the state of the target region (see below), and is essentially determined by task performance (Antal, Terney, Poreisz, & Paulus, 2007). According to the antagonistic physiological effects of anodal and cathodal stimulation observed by M1 stimulation, a frequently made assumption is that anodal tDCS should improve, while cathodal tDCS should decrease cognitive abilities. However, the bipolar effects found by M1 stimulation cannot be translated one-to-one to the cognitive domain (Jacobson, Koslowsky, & Lavidor, 2012). Performance-improving effects of anodal tDCS were demonstrated for various cognitive functions including working memory (e.g., Zaehle, Sandmann, Thorne, Jancke, & Herrmann, 2011), executive functions (e.g., Dockery, Hueckel-Weng, Birbaumer, & Plewnia, 2009), declarative memory (e.g., Javadi & Walsh, 2012), and implicit learning (e.g., de Vries et al., 2010), but anodal tDCS also impaired categorization (e.g., Ambrus et al., 2011b) and performance in an episodic memory test (Zwissler et al., 2014). Cathodal tDCS has been shown to decrease performance of working memory (e.g., Berryhill, Wencil, Branch Coslett, & Olson, 2010; Marshall, Molle, Siebner, & Born, 2005), and verbal fluency (Iyer et al., 2005), but enhanced executive functions (Dockery et al., 2009) and complex motion perception (Antal, Nitsche, et al., 2004), improved episodic memory (Zwissler et al., 2014) and led to behavioral improvement (Dockery et al., 2009; Pirulli, Fertonani, & Miniussi, 2014). Several factors may explain this variability in the cognitive domain. Task characteristics such as ‘‘noisiness’’ might be relevant (Antal, Nitsche, et al., 2004). In case of a non-noisy condition, excitability-enhancing stimulation will foster the taskrelevant activation pattern to cross the activation threshold, and therefore improve performance, whereas excitabilitydiminishing stimulation will reduce activation. In contrast, in a ‘‘noisy’’ task, excitability-enhancing stimulation will enhance the probability that pre-activated suboptimal neuronal activation patterns cross the activation threshold, whereas excitability-diminishing stimulation would reduce suboptimal activation patterns to subthreshold level, but keeping the optimal pattern, which should show the strongest activation, supra-threshold. Indeed, respective effects of tDCS have been shown for a random dot protocol (Antal, Nitsche, et al., 2004). In further accordance, it was observed that the effects of tDCS depend on the strength of the signal (the neural activity operational to the task)-to-noise (random neural activity) ratio (Dockery et al., 2009; Miniussi, Harris, & Ruzzoli, 2013). 2016 Hogrefe Publishing

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Recent papers suggest that also in the motor domain the interindividual variability to tDCS is higher, than it was reported previously (López-Alonso, Cheeran, RíoRodríguez, & Fernández-Del-Olmo, 2014; Wiethoff, Hamada, & Rothwell, 2014). Attempts to explain variability include calculation of local skull bone thinnings, which may serve as current pathways independent of the exact positioning of larger electrodes (Opitz et al., 2015). Current density is also an important parameter of tDCS, with larger current densities resulting in stronger effects, at least within certain limits (e.g., Bastani & Jaberzadeh, 2013). Too high current densities can however, result in reverse effects (Batsikadze, Moliadze, Paulus, Kuo, & Nitsche, 2013). Stimulation duration affects the duration and magnitude of the aftereffects. To obtain only acute effects on excitability, which are membrane polarization-driven, but include no synaptic plasticity, 4 s stimulation duration is well suited (Nitsche, Nitsche, et al., 2003; Nitsche & Paulus, 2000). Stimulation for 3 min or longer induces aftereffects. Longer stimulation duration leads to more pronounced changes (Nitsche & Paulus, 2000, 2001); although the relationship is not strictly linear. For example, the application of anodal tDCS for 26 min resulted in inhibitory aftereffects, probably due to calcium overflow (Batsikadze et al., 2013). However, 2 · 13 min anodal tDCS with an interval of 20 min resulted in LTP-like effects, which lasted for more than 24 hr after stimulation, in principal accordance with the rationale of animal experimentation’s protocols to induce late phase LTP (Reymann & Frey, 2007). When combined with a task, repeated application of tDCS can also result in long-lasting effects. For example, the performance improvement caused by anodal tDCS over the M1 in a sequential visual isometric pinch task, which was trained during five consecutive days, was still present 3 months later, compared to sham stimulation (Reis et al., 2009). However, for stimulation of other cortical areas (e.g., visual cortex) different results might be achieved. In a recently published paper, Pirulli et al. (2014) showed that introducing short breaks (2 min) or using different stimulation durations (9 vs. 22 min) during the tDCS over the visual cortex in combination with a learning task did not play any role for the impact on cognitive performance. Timing of stimulation is also an important issue, especially with regard to cognitive neuroscience experiments. It has been reported that anodal tDCS over M1 during execution of a motor sequence-learning task, which involves this area, enhanced performance (Nitsche, Schauenburg, et al., 2003), while anodal tDCS before the execution of the task did not lead to task performance alterations (Kuo, Unger, et al., 2008). Interestingly tDCS of the premotor cortex improved performance only during consolidation, which includes premotor contribution, but not during the initial learning process (Nitsche et al., 2010). In accordance, Stagg et al. (2011) observed that application of tDCS during performance of an explicit sequence-learning task led to modulation of behavior in a polarity-specific manner: relative to sham stimulation, anodal tDCS was associated with faster learning and cathodal tDCS with slower learning. 2016 Hogrefe Publishing

Application of tDCS prior to performance of the sequence-learning task led to slower learning after both anodal and cathodal tDCS. These results suggest that it is relevant to stimulate the respective task-involved area during its task-related activation. This might be especially important for learning processes, in which task-related plasticity might be boosted by tDCS-generated plasticity. Related to this point, the state of the cortex during stimulation is also a determining factor regarding the effects of tDCS (Silvanto, Muggleton, & Walsh, 2008). For example, aftereffects are significantly modulated by cognitive and motor activities, compared to the resting conditions (Antal et al., 2007). Applying a motor task during stimulation a decrease in MEP amplitude independently from the type of the stimulation was observed. Interindividual differences, such as genetic and gender differences, may modulate the effects of tDCS. The brainderived neurotrophic factor (BDNF) has been shown to play a role in the mechanisms of neuroplasticity induction, giving rise to cellular events resulting in LTP and LTD (e.g., Mei, Nagappan, Ke, Sacktor, & Lu, 2011; Schinder & Poo, 2000). In a retrospective analysis Antal and colleagues identified different efficacy of stimulation, when they compared individuals with different alleles of the Val66Met single nucleotide polymorphism of the BDNF gene (Antal et al., 2010): The heterozygotes (Val66Met) reacted stronger to tDCS, independent from stimulation polarity. However, with increased number of the subjects, this effect lost its significance (Chaieb, Antal, Ambrus, & Paulus, 2014). With regard to MEP measurements women seemed to have longer inhibitory aftereffects after cathodal stimulation. However, in the visual cortex cathodally induced excitability effects showed no significant difference between genders whereas in women anodal stimulation heightened cortical excitability significantly when compared to the age-matched male subject group (Chaieb, Antal, & Paulus, 2008; Kuo, Paulus, & Nitsche, 2006). In summary, apart from stimulation parameters, such as polarity, current density, and duration of the stimulation, the state of the subjects or patients before and during stimulation, gender, genetic polymorphisms, time of day, hormonal status, and others may modify the final outcome. Thus the appropriate application of tDCS highly depends on skilled applications. It is thus not surprising that meta-analyses on explorative studies, which take respective factors not systematically into account, will end up with negative results, if studies differ in these parameters.

Transcranial Alternating Current Stimulation (tACS) In transcranial alternating current stimulation (tACS), the externally applied alternating current is assumed to entrain endogenous neural oscillations possibly by increasing the power of oscillations or the phase-locking index between the driving and endogenous oscillations (Ali, Sellers, & Frohlich, 2013; Antal et al., 2008; Cecere, Rees, & Romei, 2015; Helfrich, Schneider, et al., 2014; Neuling, Rach, & European Psychologist 2016; Vol. 21(1):4–14

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Herrmann, 2013). tACS as a method was developed in order to study and better understand the causal relationship between brain oscillations and cognitive functions and as a possible therapeutic tool trying to restore disturbed oscillations in different neurological diseases, such as Parkinson’s disease and schizophrenia. tACS is a form of tES involving application of sinusoidal current across the scalp with a given frequency (Antal et al., 2008; Helfrich, Schneider, et al., 2014; Kar & Krekelberg, 2014; Moliadze, Antal, & Paulus, 2010a; Neuling et al., 2013; Neuling, Rach, Wagner, Wolters, & Herrmann, 2012; Zaehle, Rach, & Herrmann, 2010). tACS lacks the polarity constraint observed by tDCS. During one half cycle of an oscillation, one electrode serves as anode and the other as cathode and current strength increases and decreases following the half sine wave. During the other half cycle, the pattern reverses. In the case of tACS the frequency, intensity, and phase are the major influencing parameters regarding the efficacy of the intervention. tACS can be applied in a wide frequency range such as at conventional EEG frequencies (0.1–80 Hz), or in the socalled ‘‘ripple’’ range (140 Hz, see below) (Moliadze et al., 2010a). As with tDCS, the effects of tACS as revealed by TMS may not correlate with other types of assessments. For example, only a nonsignificant trend toward MEP amplitude inhibition following 10 Hz AC stimulation over M1 was observed in an early study at a low amplitude of 0.4 mA (Antal et al., 2008), while 10 Hz stimulation improved visuomotor implicit learning slightly, using a serial reaction time task. Please note that this dissociation between MEP excitability changes and implicit learning under tACS was also evident, when using higher frequencies (Moliadze et al., 2010a). 140 Hz stimulation induced the largest MEP increase, whereas 250 Hz tACS improved implicit motor learning. In a study using 20 Hz tACS over M1 and placing the return electrode over the parietal cortex, increased corticospinal excitability was observed as compared to the usual contralateral frontal electrode (Feurra, Paulus, Walsh, & Kanai, 2011). On the other side it slowed down voluntary movements using a visuomotor task (Pogosyan, Gaynor, Eusebio, & Brown, 2009) but in parallel it increased beta coherence between scalp-recorded activity and electromyographic activity (EMG) of the first dorsal interosseus muscle. By using low-intensity tACS of 250 lA with 25 and 40 Hz lucid dreaming was facilitated (Voss et al., 2014). Whereas TMS over the occipital cortex can elicit cortical phosphenes, tACS at much lower intensities of up to about 1 mA most likely induces only retinal phosphenes, in particular if at least one of the electrodes is close to the eyes, in a frequency- and intensity-dependent way (Paulus, 2010; Schutter & Hortensius, 2010; Turi et al., 2013). However, tACS can probably influence visual cortical functions at a subthreshold level as shown by modification of TMS-induced phosphene thresholds (Kanai, Paulus, & Walsh, 2010). Cortical contrast-discrimination thresholds were decreased only during 60 Hz tACS, but not during 40 and 80 Hz stimulations (Laczó, Antal, Niebergall, Treue, &

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Paulus, 2012). tACS applied over the parieto-occipital (PO9 and PO10 according to the 10-20 EEG system) electrode positions at the individual alpha frequency range induced an entrainment of the applied oscillatory activity (Zaehle et al., 2010). When the stimulation frequency was fixed at 6 and 10 Hz, tACS impaired performance in the visual detection task (Brignani, Ruzzoli, Mauri, & Miniussi, 2013). tACS applied outside the EEG frequency range (140 Hz and in the low kHz range) increases motor cortical excitability in a similar way as tDCS with 1 mA intensity (Chaieb, Antal, & Paulus, 2011; Moliadze et al., 2010a). Stimulation at 80 Hz remains without an effect, while 250 Hz clearly had a delayed onset and shorter lasting response, compared to the MEP increase observed during and after 140 Hz tACS. The effect of tACS is intensity-dependent, there is some evidence that inhibitory networks respond at lower stimulation intensities than excitatory networks. A trend in a first study (Antal et al., 2008) using a low intensity of 0.4 mA over M1 toward MEP inhibition following 10 Hz AC stimulation was confirmed later with higher frequencies (140 Hz) (Moliadze, Atalay, Antal, & Paulus, 2012). Whereas 0.2 mA intensity had no effect, an intensity of 0.4 mA led to MEP inhibition, 0.6 and 0.8 mA did not provide a significant effect (Moliadze et al., 2012). Again, with 1 mA a significant increase of the MEP amplitudes was obtained. This suggests that stimulation applied at 0.4 mA intensity may inhibit intracortical facilitatory effects on corticospinal motoneurons or the inhibitory circuits are preferentially excited with lower intensities. The effect of tACS also depends on the state of the brain before and during stimulation: It was recently documented that the aftereffects of tACS applied at the individual alpha frequency level may depend on the individual endogenous power (Neuling et al., 2013). Similar results were observed by Cecere et al. (2015): For stimulation at the individual alpha frequency or ± 2 Hz frequency over the occipital cortex during a sound-induced double-flash illusion task, only the individual alpha frequency stimulation improved performance. With regard to higher frequencies, opposing effects at beta and gamma frequencies depending on timing of the administration of tACS during a motor task do exist (Joundi, Jenkinson, Brittain, Aziz, & Brown, 2012). Using a visually driven go-no-go task, stimulation at 20 Hz required a significant slowing of force production in the go task, however, stimulation in no-go trials, where the triggered motor task involved inhibition, led to a major reduction in force generation. In contrast, 70 Hz tACS was ineffective during no-go cues, but increased performance during go trials. When using more than two electrodes, it is possible to manipulate the phase of the stimulation, which refers to the angle of the sinusoid relative to different electrodes, enabling antiphase or in-phase stimulation. Stimulating the left frontal and parietal cortex by 6 Hz tACS in phase, cognitive performance in a delayed letter discrimination task was improved, when stimulating out of phase it was worsened (Polania, Nitsche, Korman, Batsikadze, & Paulus,

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2012). At the temporal cortex using 10 Hz with a DC offset it was found that manipulation of the phase resulted in different auditory detection thresholds (Neuling et al., 2012). Nevertheless, the DC offset used in this study leaves open the possibility of a DC effect. A bilateral 40 Hz stimulation was administered over the visual cortex with a 180 phase difference between hemispheres, while subjects were presented with bistable motion stimuli (Struber, Rach, Trautmann-Lengsfeld, Engel, & Herrmann, 2014). In this task a visual stimulus switches between horizontal and vertical apparent motion thought to indicate interhemispheric gamma coupling. The authors observed that with the increase in interhemispheric gamma band coherence the portion of perceived horizontal motion decreased when the 40 Hz stimulation was applied, but there was no change during 6 Hz stimulation. It was suggested that this is probably related to the functional decoupling of the two hemispheres that resulted in an impaired motion perception. The physiological mechanisms of tACS are less well understood compared to tDCS. Computational network simulation studies combined with in vitro experiments showed the possibility of entraining neural oscillations by applying external electric fields of relatively low amplitudes (minimum estimated cortical electric field of 0.2 mV/mm), if intrinsic frequency was closely matched with the externally applied electric field (Fröhlich & McCormick, 2010; Reato et al., 2010; Schmidt et al., 2014). In human experiments tACS applied in the EEG range is believed to mainly entrain with or synchronize neuronal networks and might enhance the information transfer and speed up processing (e.g., Butts et al., 2007; Helfrich, Knepper, et al., 2014; Helfrich, Schneider, et al., 2014; Struber et al., 2014; Voss et al., 2014; Zaehle et al., 2010). On the other side the repeated modification of the synapse once exposed to an alternating electrical field might also alter the associated biochemical mechanisms, such as accumulation of calcium in the presynaptic nerve terminals leading to short-term synaptic plastic effects (Citri & Malenka, 2008).

Transcranial Random Noise Stimulation (tRNS) tRNS is the noninvasive application of a low-intensity alternating current where the intensity and the frequency of the current vary in a randomized manner. tRNS was developed with the intent to desynchronize pathological cortical rhythms (Terney, Chaieb, Moliadze, Antal, & Paulus, 2008) but additional putative mechanisms, such as stochastic resonance (Stacey & Durand, 2000), may be relevant (see below). The stimulation is biphasic, like with tACS and various forms of noise may be applied. In a typical study during tRNS, a frequency spectrum between 0.1 Hz and 640 Hz (full spectrum) or 101–640 Hz (high-frequency stimulation) is applied. The probability function of the RN current stimulation may follow a Gaussian or bell-shaped curve with zero mean and a variance, for which 99% of all generated current levels are between ± 1 mA. In the frequency domain all coefficients of the random sequence 2016 Hogrefe Publishing

have a similar size (‘‘white noise’’). It was observed that the high-frequency subdivision between 100 and 640 Hz of the whole tRNS spectrum is functionally responsible for alteration of excitability at least in the M1 and clearly superior to low-frequency stimulation (Terney et al., 2008). Although their modes of action might differ, tRNS had an effect comparable to that of anodal tDCS on MEP development over time, that is enhancing the cortical excitability of the targeted cortical area; Terney and colleagues have shown that 10 min of tRNS applied over the M1 with 1 mA intensity can cause excitatory aftereffects lasting up to 1.5 hr, and is capable of improving the performance in the acquisition and early consolidation phase of an implicit motor learning task (Terney et al., 2008). Effects of highfrequency tRNS were also demonstrated by Fertonani, Pirulli, and Miniussi (2011). In this study tRNS was applied to the visual cortices of healthy subjects. A significant enhancement in a visual perceptual learning task was observed. This improvement was significantly higher than the improvement obtained with anodal tDCS. Stimulation of the parietal cortex during the application of a paradigm assessing the ability to discriminate numerosity yielded better and longer lasting improvement (up to 16 weeks posttraining) of the precision of the task compared with cognitive training in the absence of stimulation (Cappelletti et al., 2013). Furthermore, this improvement induced by parietal tRNS was transferred to proficiency in other parietal lobe-based quantity judgments, that is, time and space discrimination. In contrast, application of tRNS to the right DLPFC impaired categorical learning in a prototype distortion task (Ambrus et al., 2011a). With regard to the effect of tRNS on working memory performance, a study showed no effect of stimulation over the DLPFC (Mulquiney, Hoy, Daskalakis, & Fitzgerald, 2011). These results demonstrate that, depending on the learning regime, tRNS can induce long-term enhancement of cognitive and brain functions. The physiological mechanisms of tRNS are not completely clarified yet, it is so far not clear if tRNS may interfere with ongoing network oscillations as mentioned in the original publication (Terney et al., 2008), with homeostatic mechanisms (Fertonani et al., 2011) or induces plastic changes in the brain. One potential effect of tRNS might be improvement of the signal-to-noise ratio in the central nervous system and the sensitization of sensory processing (Miniussi et al., 2013; Moss, Ward, & Sannita, 2004). It was suggested that tRNS may increase synchronization of neural firing through amplification of subthreshold oscillatory activity, which in turn reduces the amount of endogenous noise (Miniussi et al., 2013). Besides this, the effects of tRNS might be associated with repetitive opening of Na+ channels, as it was observed in a study investigating the application of alternating current stimulation to rat hippocampal slices (Schoen & Fromherz, 2008). Indeed, the sodium-channel blocker carbamazepine and the GABA-A agonist lorazepam showed a tendency toward decreasing the efficacy of the stimulation (Chaieb, Antal, & Paulus, 2015). Finally, it is proposed that tRNS might induce long-term hemodynamic changes in the human brain that might be related to neuroplastic reorganization. A recent study reported that the repeated bifrontal application European Psychologist 2016; Vol. 21(1):4–14

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of tRNS for five days enhanced the speed of both calculation- and memory-recall-based arithmetic learning (Snowball et al., 2013). These behavioral improvements were associated with defined hemodynamic responses consistent with more efficient neurovascular coupling within the left DLPFC. Six months later the behavioral and physiological modifications in the stimulated group relative to sham controls were still present.

Conclusion Generally, tES methods seem to be an efficient tool to alter cortical excitability and cognition and behavior. One of the main advantages of tES techniques is that they can not only disrupt, but can also improve definite cortical functions that makes the identification of the involvement of a target area in cognitive processing easier. The performance improvement induced by an ‘‘easy-to-handle’’ stimulator might result in future options to improve functions in everyday life of patients. However, several limitations do apply. Especially, with regard to stimulation of specific areas, a disadvantage of tES is its low focality. This limitation will probably be solved in the near future by modification of stimulation electrodes and protocols. Furthermore, the physiological effects have been most extensively tested for M1. Psychological and behavioral effects show variability between studies, which might be intrinsic to neuromodulatory approaches in general. The main advantage of tACS and tRNS, compared to tDCS, is the direction insensitivity of the stimulation and the higher skin perception threshold during stimulation. However, the more recent methods of tACS and tRNS will not replace tDCS. Each method has advantages and disadvantages mentioned in this review; they may be combined, the parameter space is large and obviously has an indefinitely number of possibilities. Hypothesis-driven approaches based on brain neurophysiology are expected to provide the largest progress in future.

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channels by weak capacitive currents on a silicon chip. Journal of Neurophysiology, 100, 346–357. doi: 10.1152/ jn.90287.2008 Schutter, D. J. L. G., & Hortensius, R. (2010). Retinal origin of phosphenes to transcranial alternating current stimulation. Clinical Neurophysiology, 121, 1080–1084. Silvanto, J., Muggleton, N., & Walsh, V. (2008). State-dependency in brain stimulation studies of perception and cognition. Trends in Cognitive Science, 12, 447–454. doi: 10.1016/j.tics.2008.09.004 Snowball, A., Tachtsidis, I., Popescu, T., Thompson, J., Delazer, M., Zamarian, L., . . . Cohen Kadosh, R. (2013). Long-term enhancement of brain function and cognition using cognitive training and brain stimulation. Current Biology, 23, 987–992. doi: 10.1016/j.cub.2013.04.045 Stacey, W. C., & Durand, D. M. (2000). Stochastic resonance improves signal detection in hippocampal CA1 neurons. Journal of Neurophysiology, 83, 1394–1402. Stagg, C. J., Jayaram, G., Pastor, D., Kincses, Z. T., Matthews, P. M., & Johansen-Berg, H. (2011). Polarity and timingdependent effects of transcranial direct current stimulation in explicit motor learning. Neuropsychologia, 49, 800–804. doi: 10.1016/j.neuropsychologia.2011.02.009 Struber, D., Rach, S., Trautmann-Lengsfeld, S. A., Engel, A. K., & Herrmann, C. S. (2014). Antiphasic 40 Hz oscillatory current stimulation affects bistable motion perception. Brain Topography, 27, 158–171. doi: 10.1007/s10548-013-0294-x Terney, D., Chaieb, L., Moliadze, V., Antal, A., & Paulus, W. (2008). Increasing human brain excitability by transcranial high-frequency random noise stimulation. Journal of Neuroscience, 28, 14147–14155. doi: 10.1523/JNEUROSCI. 4248-08.2008 Turi, Z., Ambrus, G. G., Janacsek, K., Emmert, K., Hahn, L., Paulus, W., & Antal, A. (2013). Both the cutaneous sensation and phosphene perception are modulated in a frequencyspecific manner during transcranial alternating current stimulation. Restorative Neurology and Neuroscience, 31, 275–285. doi: 10.3233/RNN-120297 Voss, U., Holzmann, R., Hobson, A., Paulus, W., KoppeheleGossel, J., Klimke, A., & Nitsche, M. A. (2014). Induction of self awareness in dreams through frontal low current stimulation of gamma activity. Nature Neuroscience, 17, 810–812. doi: 10.1038/nn.3719 Wiethoff, S., Hamada, M., & Rothwell, J. C. (2014). Variability in response to transcranial direct current stimulation of the motor cortex. Brain Stimulation, 7, 468–475. doi: 10.1016/ j.brs.2014.02.003 Zaehle, T., Rach, S., & Herrmann, C. S. (2010). Transcranial alternating current stimulation enhances individual alpha activity in human EEG. PLoS One, 5, e13766. doi: 10.1371/ journal.pone.0013766 Zaehle, T., Sandmann, P., Thorne, J. D., Jancke, L., & Herrmann, C. S. (2011). Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: Combined behavioural and electrophysiological evidence. BMC Neuroscience, 12, 2. doi: 10.1186/14712202-12-2 Zwissler, B., Sperber, C., Aigeldinger, S., Schindler, S., Kissler, J., & Plewnia, C. (2014). Shaping memory accuracy by left prefrontal transcranial direct current stimulation. Journal of Neuroscience, 34, 4022–4026. doi: 10.1523/JNEUROSCI. 5407-13.2014

Received February 19, 2015 Accepted July 10, 2015 Published online March 23, 2016 European Psychologist 2016; Vol. 21(1):4–14

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About the authors

Andrea Antal is a Group Leader at the Department for Clinical Neurophysiology at the University Medical Center Göttingen, Germany. Her research interest is in developing new methods in order to induce and modulate neuroplastic changes in the human brain.

Walter Paulus is director and chair of the Department for Clinical Neurophysiology at the University Medical Center Göttingen, Germany. His research interest is modulation of human cortical neuroplasticity by transcranial stimulation methods and investigation of human cortical physiology by transcranial magnetic stimulation. Michael A. Nitsche is director of the Department of Psychology and Neurosciences at the Leibniz Research Centre for Working Environment and Human Factors in Dortmund, Germany. His main research interest is the physiological Foundation of cognition and behavior, including noninvasive brain stimulation, neuropsychopharmacology, and functional imaging.

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Andrea Antal Department of Clinical Neurophysiology Georg-August University of Göttingen Robert Koch Straße 40 37075 Göttingen Germany Tel. +49 551 398-461 Fax +49 551 398-126 E-mail aantal@gwdg.de

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Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

tES Stimulation as a Tool to Investigate Cognitive Processes in Healthy Individuals Michal Lavidor Department of Psychology, The Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel Abstract. This paper is aimed at providing an introduction to up-to-date noninvasive brain stimulation tools that have been successful in modulating higher-level cognitive functions in healthy individuals. The current review focuses on transcranial electrical stimulation (tES) studies aiming to explore cognitive models from an experimental rather than clinical viewpoint. It focuses primarily on major advances in language, working memory, learning, response inhibition, and other executive functions in healthy individuals, and the use of different methods of electrical brain stimulation such as transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). The final section summarizes the scientific novelty of the reviewed papers and discusses the possible roles of brain stimulation in future experimental research and clinical applications. Keywords: brain stimulation, tDCS, tACS, tRNS, cognitive enhancement

A range of neuroscience tools are used to investigate the human brain during cognitive tasks. Some are based on indirect activation measures (positron emission tomography, PET; functional magnetic resonance imaging, fMRI; nearinfrared spectroscopy, NIRS), and others are based on electrical activity recordings (event-related potential, ERP; electroencephalogram, EEG; and magnetoencephalography, MEG). Although these methods provide excellent spatial and temporal resolution (respectively), they can only reveal correlations between brain regions and cognitive tasks but cannot account for causality. An alternative way to explore cognitive functions is to use transcranial magnetic stimulation (TMS), now a standard laboratory tool for investigating perceptual and cognitive functions (Walsh & Cowey, 1999), or more recent transcranial electrical stimulation (tES) techniques (see Paulus, Nitsche, & Antal, 2016) that have old scientific roots but were only recently developed to allow safe uses. The current review will focus on tES in cognitive research in healthy populations. The interference of tES with brain processes, when coupled with a target cognitive function, can lead to facilitation or impairment of performance, and thus establish a causal link between the stimulated brain region and the cognitive function at hand. The current article discusses how this is 2016 Hogrefe Publishing

done, the ways in which the direction of interference is determined, and presents numerous examples of recent findings obtained with tES methods. The methods can help identify areas that are causally involved in cognitive functions, their interactions, and the specific physiological mechanisms involved (Kuo & Nitsche, 2012). As opposed to tES studies of the motor cortex, cognitive studies using tES are very heterogeneous as many functions and brain areas are included in cognition. Cognition can be defined as the processes an organism uses to organize information. This includes acquiring information (sensation and perception), selecting (attention), communicating (language), representing (understanding) and retaining (memory) information, and using it to guide behavior (reasoning and coordination of motor outputs). There are already several published reviews on cognitive studies using tES, however they typically include clinical (see a review by Berlim, Van den Eynde, & Daskalakis, 2013) or interventional aspects (see a review by Fregni et al., 2014), or focused on specific domains such as memory (see a review by Manenti, Cotelli, Robertson, & Miniussi, 2012). The current review focuses on tES studies aiming to explore cognitive models from an experimental rather than clinical viewpoint. The reviewed studies cover a representative European Psychologist 2016; Vol. 21(1):15â&#x20AC;&#x201C;29 DOI: 10.1027/1016-9040/a000248

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sample of various cognitive domains, and they were selected based on previously successful applications of brain stimulation exploring cognitive functions in healthy individuals. The current review will mainly focus on major advances in functions such as language, working memory, learning, response inhibition, and other executive functions among healthy individuals by using transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). Covering all cognitive functions is beyond the scope of the current paper.

Transcranial Direct Current Stimulation (tDCS) Transcranial direct current stimulation (tDCS) is a noninvasive cortical stimulation technique that applies weak (0.5– 2 mA) electrical currents using surface electrodes. The traditional methodology uses two electrodes, a cathode and an anode, placed over regions of interest on the scalp. The electrodes are placed on the scalp using elastic bands or adaptable caps similar to the ones used for EEG (see a review by Wagner, Valero-Cabre, & Pascual-Leone, 2007). The application of weak, continuous electrical current helps facilitate or inhibit particular areas of the brain, and their associated networks. tDCS induces polarity-dependent cortical activity and excitability enhancements or reductions, which emerge during stimulation, but can persist for 1 hr after stimulation (Nitsche & Paulus, 2000, 2001; Nitsche et al., 2003, 2008). The primary mechanism behind tDCS is thought to be its modulation of the resting membrane potential, which affects spontaneous cortical activity; namely, anodal tDCS causes neural depolarization thus enhancing cortical excitability, and cathodal tDCS causes neural hyperpolarization and hence decreased cortical excitability (Nitsche & Paulus, 2000, 2001). The physiological effects of tDCS were first explored via stimulation of the motor cortex, and have been linked to the neurophysiological mechanisms of long-term potentiation and depression (Liebetanz, 2002; Nitsche et al., 2003; see also Stagg & Nitsche, 2011 for a comprehensive review of the physiological basis of tDCS). In addition, this method affords a highly reliable sham condition (Gandiga, Hummel, & Cohen, 2006). tDCS studies of cognitive functions started after the first motor studies were published, based on the concept that stimulation effects depend on the polarity of the current flow, with brain excitability being usually increased by anodal tDCS and decreased by cathodal tDCS, as was found and replicated in the motor and visual domains. For cognitive domains, the anodal stimulation was found effective in facilitating cognitive functions, however the cathodal tDCS effects on cognition were challenged in a thorough metaanalysis (Jacobson, Koslowsky, & Lavidor, 2012). While there is much evidence supporting the facilitative effect of the anode (Boggio et al., 2009; Flöel, Rösser, Michka, Knecht, & Breitenstein, 2008; Fregni et al., 2005; European Psychologist 2016; Vol. 21(1):15–29

Hsu et al., 2011), the cathodal effects are less consistently documented in the cognitive domain (Jacobson, Koslowsky, & Lavidor, 2012). Although there is some support for the classical inhibitory effects of cathodal stimulation (Berryhill, Wencil, Coslett, & Olson, 2010; Hsu et al., 2011; Ladeira et al., 2011; Penolazzi, Stramaccia, Braga, Mondini, & Galfano, 2014), there are some studies that have reported a null effect (Fregni et al., 2005) or even an opposite one (Antal, Kincses, Nitsche, Bartfai, & Paulus, 2004; Dockery, Hueckel-Weng, Birbaumer, & Plewnia, 2009; Pope & Miall, 2012; Weiss & Lavidor, 2012). Below we present and discuss major tDCS studies in language, working memory, learning, response inhibition, and cognitive control that will demonstrate further polarity effects in cognitive studies.

Language The modern endeavor to understand the basics of language and its neural substrate that began with the seminal work of Broca (1865) and Wernicke (1874) has experienced a recent resurgence with advances in brain stimulation, which provides tools that enable the formulation of strong causal inferences (Silvanto & Pascual-Leone, 2012) in one of the prime brain functions: the language system. To date, several tDCS studies have explored naming, picture naming, and verbal fluency. Naming is a basic, fundamental capacity of the human brain that requires a number of cognitive processes involving the perception of the visual stimuli, the semantic and lexical processing of their features, the selection and retrieval of relevant information, and finally the articulation of a target concept. Several studies have used tDCS to improve performance by employing anodal tDCS. For example, Iyer and colleagues (2005) provided the first direct evidence of a cognitive enhancement in the context of language production by showing that it is possible to transiently change human verbal fluency capacity by electrical stimulation, and showed that this effect depends on intensity. There were no significant effects on performance with 1-mA tDCS over the prefrontal cortex, however, with 2 mA, verbal fluency improved during anodal stimulation. In another study, Sparing, Dafotakis, Meister, Thirugnanasambandam, and Fink (2008) explored whether tDCS could enhance visual picture naming. Fifteen healthy participants performed this task before, during, and after tDCS was applied over the posterior perisylvian region (PPR). This position corresponds to the location of Wernicke’s area, including the posterior part of the left superior temporal gyrus (STG), and has been used in a number of stimulation studies (e.g., Mottaghy et al., 1999). Using a doubleblind, within-subjects design, participants underwent four different 2 mA stimulation sessions: anodal and cathodal stimulation of left PPR as the main target stimulation and anodal stimulation of the homologous region of the right hemisphere and sham stimulation as control conditions. The results showed that participants responded significantly faster following anodal tDCS to the left PPR. 2016 Hogrefe Publishing

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This significant decrease in naming latency was found immediately after the end of anodal tDCS to the left PPR, but was not evident during stimulation. No facilitation effect was observed 5- and 10-min post stimulation. Another successful montage that improved verbal fluency in healthy subjects was employed by Cattaneo, Pisoni, and Papagno (2011), where anodal stimulation of 2 mA was applied for 20 min over Broca’s region (and the reference electrode over the right supraorbitary region). Another major contribution to the study of naming under tDCS was made by Ross, McCoy, Wolk, Coslett, and Olson (2010) who investigated whether stimulation of the anterior temporal lobes (ATL) would be effective in modulating the memory of the proper names of people the participants knew. The results showed that anodal stimulation to the right ATL significantly improved face naming accuracy for people but not for landmarks’, that were presented as control stimuli. The Ross et al. study (2010) is important because it also incorporated a control condition (the landmarks pictures), and implemented a design that provided a selective and specific effect which significantly enhanced the study’s validity. Thus, anodal tDCS produced small yet consistent and significant effects in the studies reviewed above. Interestingly, although different regions of interest were targeted (PPR and the dorsolateral prefrontal cortex, DLPFC), naming/verbal fluency performance improved, suggesting that tDCS can directly affect the neural mechanism that underlies the function (e.g., PPR) or a remote terminal that is a part of the network that underlies the function (e.g., DLPFC). This interpretation seems plausible since picture naming and word generation involve a massive activation of the temporal and frontal regions (Indefrey & Levelt, 2004). To affect naming, it is probably better to use high intensity stimulation (1.5–2 mA), considering that 1 mA stimulation did not affect naming (Iyer et al., 2005). This should be done cautiously, as higher intensities generate stronger subjective sensations, hence increasing the difference between real and sham stimulation (O’Connell et al., 2012).

Working Memory Working memory (WM) is the ability to temporarily hold and manipulate task-relevant information. WM load is considered to be the amount of temporarily stored WM items prior to WM retrieval and is hypothesized to impose higher demands on executive attention as its value increases. Thus, WM tasks that require active maintenance of temporarily stored high-load items are considered to be highly dependent on DLPFC function and executive attention (Kane & Engle, 2002). Most of the transcranial stimulation studies investigating the effects on WM performance stimulated the left DLPFC (Boggio et al., 2006, 2008; Fregni et al., 2005; Mulquiney, Hoy, Daskalakis, & Fitzgerald, 2011; a review by Utz, Dimova, Oppenländer, & Kerkhoff, 2010 and Zaehle, Sandmann, Thorne, Jäncke, & Herrmann, 2016 Hogrefe Publishing

2011; for other stimulation sites, see Sandrini, Fertonani, Cohen, & Miniussi, 2012). One of the first studies looking at working memory was performed by Fregni et al. (2005). They were able to show an improvement in performance on the classic n-back (2-back and 3-back) working memory task with a 1-mA, 10-min stimulation session with the anode over left DLPFC and the cathode on the right supraorbital region. These findings were not replicated when the montage was reversed or when anodal stimulation occurred over the left motor region. A similar protocol was adapted by Ohn et al. (2008), this time with 30 min of stimulation. The improvement was noted both during and after the stimulation sessions. A single study then compared varying stimulation intensities (1 mA vs. 2 mA) and found that with 1-mA anodal stimulation there was a faster reaction time on the n-back test as compared with 2 mA, which challenged the notion that higher currents lead to stronger behavioral effects (Hoy et al., 2013). In a recent study, Andrews, Hoy, Enticott, Daskalakis, and Fitzgerald (2011) reported an interesting result, in which increased digit span (forward, but not backward) was found after anodal tDCS of the left DLPFC, but only when tDCS had been previously delivered concurrently with an n-back working memory test, as compared to tDCS alone or sham tDCS with n-back testing. In other words, using tDCS with a working memory task subsequently increased cognitive control performance as assessed by a different working memory test (the digit span). Research by Zaehle et al. (2011) characterized the effects of tDCS on working memory performance by measuring EEG responses. Anodal tDCS of the left DLPFC resulted in polarity-dependent changes (anodal increases and cathodal decreases) in EEG alpha and theta frequency over occipitotemporal regions, which are thought to reflect hippocampal-dependent learning processes in the brain (Cashdollar, Duncan, & Duzel, 2011). It should be noted that no behavioral effects of anodal or cathodal tDCS versus sham were seen in the Zaehle et al. study (2011), only effects of anodal versus cathodal stimulation. In conclusion, we see that tDCS, even with low intensities and single applications, was found useful in improving performance in laboratory tasks of working memory. Stimulation increased WM performance on different storageand-processing tasks (e.g., n-back speed of performance and accuracy; accuracy in a visual recognition and in a sequential-letter working memory task). The challenge here is to develop stimulation protocols that will generate (safe) long-term modulations (see Park, Seo, Kim, & Ko, 2014) and use ecological memory tasks rather than the artificial n-back.

Learning Flöel and colleagues (2008) examined tDCS effects on learning and acquisition of novel vocabulary. In their European Psychologist 2016; Vol. 21(1):15–29

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experiment, tDCS stimulation was applied over the posterior part of the left perisylvian area in 19 young right-handed individuals, while participants had to acquire a miniature lexicon of 30 novel object names. This study employed a double-blind sham-controlled within-subjects design. Each participant was given anodal, cathodal (each 20 min of 1 mA), and sham sessions in a randomized, counterbalanced manner. The results indicated that with anodal stimulation, participants showed better associative learning compared to sham and cathodal stimulation. Mood ratings, blood pressure, heart rate, discomfort, RTs, and response styles were similar between stimulation conditions. Importantly, transfer of the vocabulary to the participants’ native language was also significantly better after learning under anodal tDCS than under cathodal tDCS or sham. However, no significant difference between the conditions was found for the lexical knowledge test after one week. This study was the first to show that anodal tDCS, when administered to the left hemisphere, significantly improves the acquisition of novel vocabulary in healthy subjects. Another study by Liuzzi et al. (2010) tested the hypothesis that language is embodied in neural circuitry connections between perisylvian language areas and the motor cortex. They examined the functional relevance of the left motor cortex for the learning of a novel action word vocabulary by interfering with neural accessibility in the motor cortex by tDCS. The study utilized a between-subjects, double-blind, sham-controlled, randomized design on 30 young healthy, right-handed volunteers. Along with tDCS (anodal, cathodal, or sham), subjects learned a novel vocabulary of 76 concrete, body-related actions through an associative learning paradigm. Compared to the sham stimulation, cathodal tDCS reduced success rates in vocabulary acquisition, as shown by tests of novel action word translation into the native language. The analysis of learning behavior revealed a specific effect of cathodal tDCS on the ability to associatively pair actions with novel words. These effects were not found in the control conditions where tDCS was applied to the prefrontal cortex or when subjects learned object-related words. This study provided direct evidence that the left motor cortex is causally involved in the acquisition of novel action-related words. In addition, this study stands out thanks to its rigorous methodological design. The inclusion of a target stimulation site alongside a control task clearly addressed the main possible alternative explanation and improved the validity of results. Second, although tDCS is not known for being highly precise in terms of localization, Liuzzi et al. (2010) demonstrated that even when using relatively large electrodes (25 cm2), it is possible to distinguish between close areas, the motor strip, and the frontal cortex. This is in line with recent neuroimaging studies which showed a significant spread of activation following tDCS stimulation at the area underneath the electrode (Holland et al., 2011; Meinzer et al., 2012). Finally, this study demonstrated that cathodal tDCS reduced success rates in vocabulary acquisition, thus providing another venue for tDCS applications in future research.

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Response Inhibition A common feature of human existence is the ability to reverse decisions after they are made but before they are implemented. This cognitive control process, termed response inhibition, allows individuals to recover from potentially harmful situations before it is too late – for example, avoiding touching a hot stove when realizing it is too hot, or not commenting negatively about a coworker who suddenly appears. Cognitive control in general, and response inhibition in particular, are impaired in several neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD; Aron & Poldrack, 2005), and appear to be critically dependent upon intact function of the right Inferior Frontal Gyrus (rIFG; Aron, Robbins, & Poldrack, 2004). Response inhibition can be evaluated by the Stop-Signal Task (SST; Logan & Cowan, 1984). In the SST there are two types of trials: ‘‘go’’ trials and ‘‘stop’’ trials. In the ‘‘go’’ trials, subjects are required to make a simple discrimination task within a prespecified time window; the ‘‘go’’ trials are more frequent, thus setting up a prepotent response tendency. The ‘‘stop’’ trials are less frequent, and require subjects to refrain from making the response when a stop signal is randomly presented following the go signal (Logan & Cowan, 1984). Cognitive control processes, in general, are attributed mainly to the prefrontal cortex (PFC). Response inhibition has been localized more specifically to the right inferior frontal gyrus (rIFG), based on both functional brain imaging and lesion-based approaches (Li et al., 2008; Rubia et al., 2001). Studies employing temporary deactivation using magnetic stimulation over the rIFG have indeed found impaired inhibitory control (Chambers et al., 2006), supporting the potential role of the rIFG in response inhibition. However, although magnetic stimulation was successful in establishing an interference stimulation protocol that impaired cognitive control (Figner et al., 2010), its use also involves some practical limitations such as mobility and subjects’ comfort. Therefore in recent years, we can find teams that employ tDCS to affect SST tasks, as described below. In line with the present review aims, we refer to tES studies that tested healthy (adult). Jacobson, Javitt, and Lavidor (2011) demonstrated that anodal stimulation applied over the rIFG led to significant improvement in the SST performance, but did not modulate response time in the ‘‘go’’ trials (see Figure 1B). In addition, stimulation over rAG, an area which is known not to be involved in the SST (Chambers et al., 2006), did not affect response inhibition (see Figure 1A), demonstrating the regional selectivity of the effect. The Jacobson et al. (2011; see also Stramaccia et al., 2015) results both support theories of brain mechanisms underlying response inhibition, and provide a potential method for behavioral modification. A different research team targeted a different area. Hsu et al. (2011) conducted a tDCS SST study to investigate the functional role of the Pre-SMA in motor inhibition

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Figure 1. (A) Comparison of unilateral simulation conditions of the mean SSRT for 11 subjects. Unilateral AnodalR differed significantly from the sham condition. (B) Comparison of unilateral stimulation conditions of the mean NSRT for 11 subjects. This nonsignificant effect of tDCS on general RT indicates that the Unilateral AnodalR tDCS effect was specific to response inhibition and did not cause general cognitive improvement. (C) The improved inhibition control (SSRT) in the Unilateral AnodalR stimulation compared to sham in the SST plotted for each subject. Shorter SSRT indicates better ability to inhibit responses, which was found in 10 of the 11 subjects. (D) The difference between the power recorded following anodal and sham stimulation conditions presented as percent change [(sham-anodal) · 100/ anodal; mean ± SEM], for each band (Theta, Alpha, Beta, Gamma) and for two clusters representing the rIFG (anode electrode positioning) area (dark gray), and the lOFC (cathode electrode positioning) area (light gray). Asterisk indicates p < .05. (E) Illustration of the 27 recorded channels located over the half front of the head. The different colors refer to the seven different clusters that were divided into 27 channels. (F) T-maps representing the difference in power for each of the four bands (Theta, Alpha, Beta, Gamma) between anodal and sham stimulation conditions. Data for Figures A–C from Jacobson et al. (2012); Data for Figures D–F from Jacobson, Ezra, Berger, and Lavidor (2012). (Li, Huang, Constable, & Sinha, 2006). Three tDCS conditions were employed: Pre-SMA anodal/left cheek cathodal, left cheek anodal/Pre-SMA cathodal, and a control group with no tDCS stimulation. Current intensity was set to 1.5 mA for 10 min. Hsu et al. (2011) found that the effects of inhibitory (cathodal) tDCS replicated previous magnetic stimulation findings by impairing performance on the task. The pattern was similar to magnetic stimulation findings in the sense that there was marked failure to inhibit responses when a stop signal was presented (an elevated noncancelled rate). Additionally, facilitatory effects were observed as a consequence of applying excitatory (anodal) 2016 Hogrefe Publishing

tDCS over the Pre-SMA. Decreased non-cancelled rates suggested improvement in inhibiting responses when a stop signal was presented. This improvement or decrement in non-cancelled rates implies that neuronal excitability was modulated by tDCS, as many studies have suggested (Nitsche & Paulus, 2000). These findings also suggest a critical role for Pre-SMA in suppressing unwanted actions and facilitating desired ones, as seen in a recent microstimulation study (Isoda & Hikosaka, 2007). Whether dealing with the pre-SMA or the right IFG, SST studies clearly suggest that tDCS has potential clinical applications for individuals exhibiting difficulties with European Psychologist 2016; Vol. 21(1):15–29

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inhibitory control. However, further research is required to understand the nature of the neuronal changes following tDCS that enable modification of response inhibition (here as measured by SST performance). Jacobson, Ezra, Berger, and Lavidor (2012) conducted an EEG-tDCS study that suggested a possible neuronal mechanism for tDCS effects in the SST. They found that the right IFG stimulation protocol applied in their behavioral SST study (Jacobson et al., 2011; see Figures 1A–C) generated a significant and selective diminution of the power of theta band (4–7 Hz). The theta diminution was observed in the rIFG area (represented by the anode electrode), but was not found in the left orbitofrontal cortex (lOFC) area (represented by the cathode electrode). A significant effect was only observed in the theta but not in other bands. Since there is evidence that the electrophysiological activity associated with behavioral inhibition is theta band activity (Lansbergen, Schutter, & Kenemans, 2007; Wienbruch, Paul, Bauer, & Kivelitz, 2005), these results may help in accounting for the improvement in behavioral inhibition following tDCS over the rIFG (see Figure 1D–F).

Other Executive Functions In addition to working memory (see above), tDCS has been shown to improve higher-order PFC-supported cognitive functions in different domains such as decision-making (Hecht, Walsh, & Lavidor, 2010), risk-taking (Fecteau, Knoch, et al., 2007; Fecteau, Pascual-Leone, et al., 2007), and probabilistic classification (Kincses, Antal, Nitsche, Bartfai, & Paulus, 2004). We will elaborate here on tDCS studies targeting executive control regulation. Sela, Ivry, and Lavidor (2012) used tDCS to test the hypothesis that a prefrontal cognitive control network is involved in directing semantic decisions required for the comprehension of idioms. A recent conceptualization argues in favor of a broad role of this brain region in figurative language comprehension (Lauro, Tettamanti, Cappa, & Papagno, 2008; Papagno, 2010; see also the metaanalysis by Rapp, Mutschler, & Erb, 2012), and proposed that prefrontal regions are responsible for suppression of alternative interpretations and response monitoring during figurative comprehension. Sela, Ivry, and Lavidor (2012) used a double-blind, sham-controlled design to explore this ‘‘PFC regulation hypothesis.’’ Participants were randomly allocated to one of two stimulation groups (left DLPFC anodal/right DLPFC cathodal or left DLPFC cathodal/right DLPFC anodal). The stimulation lasted 15 min, with an intensity of 1.5 mA. Over a one-week interval, participants were tested twice on a semantic decision task and a control task (a spoonerism task, which assesses phonological awareness; Romani, Ward, & Olson, 1999) after either receiving active or sham stimulation. The semantic decision task required participants to judge the relatedness of an idiom and a target word where the idiom was either predictable or not (predictability is the ability to complete the idiom based on its first words).

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Targets were figuratively related, literally related, or unrelated to the idiom. The results showed that after tDCS stimulation, a general deceleration (around 10%) in reaction times to targets was found. In addition, the neural enhancement of a left lateralized prefrontal network (Left DLPFC anodal/Right DLPFC cathodal) improved performance when participants had to make decisions on figurative targets of highly predictable idioms, whereas the neural enhancement of the opposite network (left DLPFC cathodal/Right DLPFC anodal) improved performance on literal targets of unpredictable idioms (see Figure 2). These effects were quite robust, explaining 28% (figurative targets, left DLPFC) and 23% (literal targets, right DLPFC) of the variance, respectively. The Sela, Ivry, and Lavidor (2012) findings corroborated a hypothesis suggested by Papagno and colleagues (Lauro et al., 2008; Papagno, 2010), and showed how the PFC is involved in selection processes. Sela, Ivry, and Lavidor (2012) posited that the PFC regulates selection processes by implementing a top-down bias based on stimulus characteristics (e.g., idiom predictability). tDCS was also shown to enhance complex problemsolving by anodal tDCS in the left DLPFC. A study by Cerruti and Schlaug (2009) tested whether prefrontal stimulation can enhance performance on the remote associates test (RAT). Typically, in RAT problems, subjects are presented with three words; for example AGE/MILE/SAND, and must find a common linguistic associate that forms a compound noun or a two-word phrase with each cue word-in this case, STONE (STONE-AGE, MILESTONE, and SANDSTONE). This task requires strong executive function capacities, since lateral associations and internal production of many words are needed until a key decision stage is reached where the subject must select or generate a single answer. The Cerruti and Schlaug (2009) findings indicated that stimulating the left DLPFC led to increased fluency when it came to the generation of solutions. Their findings prompt interesting questions regarding the influence of tDCS on cognitive control processing and the role of the left DLPFC in supporting the executive control processes needed to solve verbal insight problems. To describe the underlying neurocognitive processes that may modulate verbal problem-solving, Metuki, Sela, and Lavidor (2012) replicated (with a few methodological modifications) the procedure used by Cerruti and Schlaug (2008). The results indicated that anodal tDCS over the left DLPFC enhanced solution recognition, but did not enhance solution generation for difficult problems (see Figure 3). Metuki et al. argued that these findings support the idea that prefrontal left hemisphere (LH) cognitive control mechanisms modulate linguistic processing and defined the conditions where the facilitation effects were effective and substantial. Both the Cerruti and Schlaug (2008) and the Metuki et al. (2012) studies show how physiological and cognitive hypotheses concerning facilitation effects are constrained by site specification (Cerruti & Schlaug, 2008) and experimental conditions (Metuki et al., 2012).

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Figure 2. (A) Semantic decision task procedure: the trial began with the presentation of a fixation cross for 500 ms. The cross was replaced by an idiom which remained on the screen for 2,000 ms. Participants were instructed to read the idioms silently. The fixation cross reappeared for 750 ms and was followed by the target word for 180 ms. Participants were instructed to indicate whether the idiomatic expression and the target word were related by pressing the right or left mouse key. They were instructed to respond rapidly while maintaining a high level of accuracy. The next trial began after a 2,000 ms interval. (B) Six experimental conditions: two experimental manipulations (2 · 3) were used: idiom predictability with two levels (predictable and unpredictable) and target word type with three levels (figuratively related, literal related, and unrelated). The conditions were a priori defined as prominent, related semantic relations (continuous line), less prominent, related semantic relations (dashed line), or unrelated semantic relations (dashed-dotted line). (C) The main finding in Sela, Ivry, and Lavidor (2012) is reflected in the accuracy change scores (mean ± SE). The threeway interaction revealed that the tDCS effects were limited to specific idiom-target pairings. *p < .05. Data from Sela, Ivry, and Lavidor (2012).

Neural Underpinning of tDCS Effects Performance measures following tDCS should be considered the prime test to evaluate whether a particular set of stimulation parameters (e.g., electrode positions and size, 2016 Hogrefe Publishing

stimulation intensity and duration) can create a transient change in behavior. Neuroimaging and electroencephalography methods can aid in revealing the nature of the changes that occur after anodal or cathodal stimulation. In spite of the noticeable effects of tDCS on cognitive European Psychologist 2016; Vol. 21(1):15–29

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Figure 3. (A) Task procedure: Each trial began with a central fixation cross which was presented for 1,200 ms. The three prime words were then presented simultaneously above, at, and below the center of the screen. The words remained on the screen for 7 s, during which time the participants were asked to solve the problem. After a solution was indicated or the time limit had elapsed, a fixation cross re-appeared for an additional 500 ms, followed by a presentation of the target word for 1,500 ms. Then, the word ‘‘Solution?’’ appeared on the screen, and the participants were instructed to indicate whether the target word was the correct solution to the problem or not. On half of the trials, the target was the correct solution word, and on the other half was an unrelated distractor. In this example, the correct solution followed the three problem words. (B) Solution generation: mean early solution rates and SE, by stimulation condition and item difficulty. *p < .001. (C) Solution generation: mean early solution rates and SE, by stimulation condition and item difficulty. *p < .00. Data from Metuki et al. (2012). functions with prefrontal stimulated brain regions, there have been relatively few studies on neural correlates of these effects, compared to stimulation of the motor cortex (Stagg & Nitsche, 2011). In healthy subjects, modulations of brain networks induced by tDCS on the prefrontal cortex were assessed through fMRI at rest (Holland et al., 2011; Keeser et al., 2011; Peña-Gómez et al., 2012). Holland and colleagues (2011) tested whether tDCS over the left inferior frontal cortex can be used to increase European Psychologist 2016; Vol. 21(1):15–29

spoken picture-naming performance in healthy participants. For all participants, the anode was placed over the left inferior frontal cortex (IFC) and the cathode was placed over the contralateral frontopolar cortex. The results showed a significant effect of left anodal tDCS on naming latency responses when compared to sham responses. The fMRI measures showed that left anodal tDCS significantly reduced activation in the left frontal cortex, including Broca’s area, compared to sham responses. The imaging 2016 Hogrefe Publishing

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data also showed a regionally specific effect. Within the stimulated frontal cortex, not all regions were equally affected; Broca’s area, but not other regions (e.g., precentral or anterior insular cortices) was modulated by anodal tDCS. Holland and colleagues suggested that the reduced activation in Broca’s area might be analogous to the neural priming effects that were seen when utilizing behavioral priming paradigms. A different imaging analysis was applied by Keeser et al. (2011), where healthy subjects underwent real and sham tDCS in random order on separate days. tDCS was applied for 20 min at 2 mA with the anode positioned over the left DLPFC and the cathode over the right supraorbital region. After real tDCS, and compared with sham tDCS, significant changes of regional brain connectivity were found for the default mode network (DMN) and the frontal-parietal networks both close to the primary stimulation site and in connected brain regions. These findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain. Peña-Gómez et al. (2012), in a similar study to Keeser et al. (2011), also scanned brains after active tDCS of the DLPFC and after sham. After active stimulation, functional network connectivity revealed increased synchrony within the focus attention components and reduced synchrony in the DMN components. Exciting results were reported by Stagg et al. (2013) who scanned subjects during application of tDCS to the left DLPFC. They demonstrated increased activation in regions anatomically connected to the DLPFC during anodal tDCS in conjunction with a decreased functional coupling between the left DLPFC and the thalami bilaterally. This finding is interesting because it might provide mechanistic explanations for the behavioral effects of anodal tDCS applied to the left DLPFC in terms of modulating functional connectivity between the DLPFC and thalami.

tACS: Harnessing Oscillatory Brain Activity to Explore and Improve Sensory and Cognitive Functions Another tES method that can be harnessed to investigate and manipulate brain activity is tACS. tACS provides a potentially powerful approach to establish the functional role of neuronal oscillatory activities in the human brain and exploring the functional role of neural oscillations in cognitive tasks by stimulating the brain with biophysically relevant frequencies during task performance. tACS is thought to interact with ongoing rhythms in the cortex in a frequency-dependent manner, thereby interacting with specific functions of the stimulated region (Kanai, Chaieb, Antal, Walsh, & Paulus, 2008; Kanai, Paulus, & Walsh, 2010; Pogosyan, Gaynor, Eusebio, & Brown, 2009; Thut & Miniussi, 2009; Zaehle, Rach, & Herrmann, 2010). Oscillatory activity is believed to play an important role in linking the crosstalk between brain areas (Thut & Miniussi, 2009), and it has been argued that oscillations are particularly instrumental in top-down processing (see 2016 Hogrefe Publishing

a review by Engel, Fries, & Singer, 2001) or in large-scale integration of bottom-up and top-down processes (Varela, Lachaux, Rodriguez, & Martinerie, 2001). Although this technique is still largely unexplored and volume conduction effects are not wholly understood (Feurra et al., 2011; Kanai et al., 2010; Schutter & Hortensius, 2011; Zaghi, Acar, Hultgren, Boggio, & Fregni, 2010), recent studies have demonstrated the efficiency of tACS in a variety of domains. For instance, Kanai et al. (2010) showed that cortical excitability of the visual cortex as measured by the thresholds for magnetic pulse evoked phosphenes exhibited frequency dependency, in that 20 Hz tACS over the visual cortex enhanced the sensitivity of the visual cortex. A recent study demonstrated that stimulation in the alpha (7–12 Hz) and gamma bands (30–100 Hz) over the associative sensory cortex induced positive sensory sensations (Feurra et al., 2011). In a well-cited tACS study, Polanía, Nitsche, Korman, Batsikadze, and Paulus (2012) simultaneously applied tACS at 6 Hz over the left prefrontal and parietal cortices with a relative 0 (‘‘synchronized’’) or 180 (‘‘desynchronized’’) phase difference or a placebo stimulation condition while healthy subjects performed a delayed letter discrimination task. The results showed that induced frontoparietal theta synchronization significantly improved visual memory-matching reaction times as compared to placebo stimulation. In contrast, exogenously induced frontoparietal theta desynchronization deteriorated performance. In another study, Sela, Kilim, and Lavidor (2012) used tACS to investigate the effects of oscillatory prefrontal theta ( 4–7 Hz) stimulation, a frequency involved in regulatory control during decision-making processes that involves risk-taking (Christie & Tata, 2009). To modulate risk-taking they used a well-established paradigm in the realm of risktaking known as the Balloon Analog Risk Task (BART; Lejuez et al., 2002). In this task, participants pump a balloon without knowing when it will explode. The more the pump button is pressed, the more points accumulate while at the same time the risk of losing points with a balloon explosion increases. Subjects are thus pressured to decide whether to adopt risky behavior and keep pumping, or use a more conservative strategy and stop. The results showed a significant effect of left PFC stimulation, whereas right PFC and sham stimulations failed to produce any substantial effect on task performance. More specifically, the increase of sequential losses during theta stimulation over the left PFC suggested that subjects lost the ability to adjust their actions based on the negative feedback given to them explicitly during the task (the balloon exploded and they lost all the points they had earned in that round). In addition, it was suggested that left PFC stimulation interfered with a hypostasized ‘‘left to right theta dependent switch’’ that may be obligatory to switch from an explorative ‘‘risk-taking mode’’ to a ‘‘risk-averse’’ mode. To examine working memory tasks, Jaušovec and Jaušovec (2014) divided 24 healthy young adults into two groups – frontal and parietal – who received theta band tACS with target electrodes placed over left frontal or parietal sites. Each subject was tested on a series of WM tasks (digit span and Corsi block tapping task) under sham and active European Psychologist 2016; Vol. 21(1):15–29

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stimulation in a single-blind design. Parietal tACS significantly increased WM storage capacity, as compared to sham tACS. No such influence was observed for left frontal tACS. Increased WM storage capacity was accompanied by an event-related potential (ERP) P300 latency decrease in the left hemisphere. Jaušovec and Jaušovec (2014) interpreted their results as emphasizing the causal relationship between WM storage capacity and theta frequency oscillations in the left parietal brain area. Recently, an Italian group demonstrated the potential of tACS to improve fluid intelligence (Santarnecchi et al., 2013). In their study, an imperceptible alternating current delivered through the scalp over the left middle frontal gyrus resulted in a frequency-specific shortening of the time required to find the correct solution in a visuospatial abstract reasoning task classically employed to measure fluid intelligence abilities. Crucially, gamma-band stimulation selectively enhanced performance only on more complex trials involving conditional/logical reasoning. In summary, while current number of cognitive studies with tACS are not large, the reported successful studies have led Kuo and Nitsche (2012) to predict that in the near future this method will serve to explore basic questions in other domains of cognition by utilizing the huge amount of the electrophysiological data gathered so far.

tRNS – Stochastic Resonance Transcranial random noise stimulation (tRNS) is a relatively novel tES technique, where a random electrical oscillation spectrum is applied over the cortex. Chaieb et al. (2009), for instance, applied stimulating currents with the 1/f-type power spectrum characteristic of noise measured in the nervous system over the primary motor cortex (M1). The rationale behind this method was the beneficial role played by input noise in sensitizing neuronal systems, which makes it possible to detect weak subthreshold signals. This technique can be used as a sensory prosthesis through a mechanism known as stochastic resonance (Wiesenfeld & Moss, 1995). The fine-tuning of noise in the nervous system may in turn lead to a change in the state of synchrony in oscillating neural networks, affecting local or global processing (e.g., Panagiotaropoulos, Deco, Kapoor, & Logothetis, 2012). In turn, this may provide additional means of cortical stimulation which is not subject to polarity and once optimized, may induce enduring therapeutically relevant aftereffects (Terney, Chaieb, Moliadze, Antal, & Paulus, 2008). Most current studies have explored the motor cortex; hence, little is known about cognitive functions under tRNS. When applied over M1, it was shown to induce facilitation of motor evoked potentials (MEPs), with an effect outlasting the 10-min stimulation duration, with aftereffects lasting up to 90 min post stimulation (Terney et al., 2008). Chaieb et al. (2009) argued that tRNS possesses many advantages over currently used techniques. In particular, tRNS is an oscillatory current and thus does not have the

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polarity constraints of tDCS or the perceptible skin sensations when applied. There have been few cognitive studies with tRNS. Roi Cohen-Kadosh’s group in Oxford reported encouraging findings of improved cognitive training effects when combined with tRNS. In one of their studies, they applied bilateral tRNS over the DLPFC for five consecutive days of tRNS-accompanied arithmetic learning (Snowball et al., 2013). The subjects were healthy young adults with no history of neurological or psychiatric illness, and were randomly divided into a tRNS group (13 subjects) and a sham group (12 subjects). Both the experimenter who assigned participants to the two stimulation groups and the experimenter who administered the stimulation were blinded, and subjects were unaware of the existence of a sham condition. Calculation and drill learning rates were significantly higher for the tRNS group relative to sham controls. Snowball et al. (2013) further tested the groups 6 months after training and reported long-lasting behavioral and physiological modifications in the stimulated group compared to the sham controls for trained and nontrained calculation material. Similar results from the field of numerical cognition were also reported (Cappelletti et al., 2013). In a different cognitive task of face perception, Banissy, Duchaine, Susilo, Rezlescu, and Romanska (2014) reported that 20 min of tRNS of the posterior temporal cortices facilitated facial identity perception compared to the sham condition, but not trustworthiness perception. However, the mechanism governing tRNS and the consistency of its effects remain unclear. Mulquiney et al. (2011) directly compared tRNS and tDCS effects on working memory using the Sternberg WM task, following stimulation over the DLPFC. Their results replicated previous findings with enhanced memory performance following tDCS, but failed to support the hypothesis that tRNS improves WM. This study had some power limitations in that only 12 subjects were tested; however, it is still important due to the direct comparison of tDCS and tRNS in a cognitive function with healthy subjects. Another study that compared tDCS and tRNS with a convincing sample size (N = 107) was reported by Fertonani, Pirulli, and Miniussi (2011) in perceptual learning with stimulation over the primary visual cortex. They observed an improvement in performance when subjects were stimulated with high frequency (hf-tRNS, 100–640 Hz), and some (not significant) improvement with low-frequency tRNS (0.1– 100 Hz), while anodal tDCS reduced performance, and cathodal tDCS did not differ from sham. If we adapt Fertonani et al. (2011) results together with previous similar results with motor cortex stimulation (Terney et al., 2008), the mechanism of action of tRNS might be based on the repeated subthreshold stimulations that prevent homeostasis of the system (Miniussi, Harris, & Ruzzoli, 2013). This effect might potentiate the activity of the neural populations involved in cognitive tasks that facilitate brain plasticity by strengthening synaptic transmission between neurons. Modulation of synaptic transmission efficacy can result in excitability and activity changes in specific cortical

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networks that are activated by the task’s execution, and these changes correlate with cognitive plasticity at the behavioral level.

Summary As the current review shows, the utility of using tES methods (tDCS, tACS, and tRNS) over human brains to temporarily modulate cognitive functions in healthy brains, from language to executive functions, was well demonstrated. The variability in the population being studied, the study protocol, stimulation parameters, montages used, timing and method of testing, all may play a role in these discrepancies. One clear implication of these results is clinical, and the next paragraph considers future developments in this direction. However, the scientific value of tES as tools to explore novel theoretical hypotheses and uncover the neural basis of cognitive functioning should not be underestimated. The cognitive studies described above and others have tackled intriguing questions such as the contribution of the prefrontal cortex and the motor system to language production, learning, and comprehension (e.g., Cerruti & Schlaug, 2009; Iyer et al., 2005; Liuzzi et al., 2010), as well as issues of connectivity (Meinzer et al., 2012), and transcallosal disinhibition (Thiel et al., 2006) using relatively safe, noninvasive methods. Berryhill, Peterson, Jones, and Stephens (2014) published recently several well-supported points that should be considered when designing a tES study with healthy subjects, pointing to the importance of using challenging tasks to keep the subjects sufficiently engaged and motivated. They also argued that the individual differences might modulate stimulation effects (e.g., working memory capacity, or motivational differences, see Sela, Kilim, & Lavidor 2012). Another reservation worth consideration is that effect sizes in tES studies of cognitive functions in healthy adults are relatively modest (between 0.2 and 0.6, see the review by Jacobson et al., 2012). However, considering the complexity and variety of cognitive functions and their neural correlates, it is rather impressive that a short application of weak electrical currents generates consistent changes in cognitive behaviors. The review demonstrated the potential contribution of tDCS to basic cognitive science, where good experimental design with precise control conditions and tasks is required. The review also highlighted the efficiency of tDCS as a cognitive enhancement method, however here we still miss studies that explore higher dose protocols and longer term effects.

Future Directions–tES Use in Clinical Contexts and With Training We saw here that studies with healthy subjects have shown that tES can promote changes in cognitive function after 2016 Hogrefe Publishing

only one session (Kuo & Nitsche, 2012). This area of study may contribute in the future to the investigation of tES applications as an important noninvasive tool for the rehabilitation of cognitive functions. However, the studies so far suggest that the changes in cognitive performance observed after tES stimulation are short lived; this warrants more studies to better explore the development of the application of tES in patients with neurocognitive disorders. Cognitive training has recently become the preferred method to affect brain plasticity. In the last 20 years, controlled cognitive training studies have demonstrated that learning of new cognitive skills and improving existing skills is possible across different populations and ages (see a review by Green & Bavelier, 2008). Successful training has been documented in clinical populations (Schizophrenia: McGurk, Twamley, Sitzer, McHugo, & Mueser, 2007; ADHD: Shalev, Tsal, & Mevorach, 2007). Several brain-imaging studies have recently revealed training-induced plasticity in the healthy human brain (i.e., Erickson et al., 2007; McNab et al., 2009). Facilitation effects of the integration of tDCS with cognitive training are only beginning to be explored (Cohen Kadosh, Soskic, Iuculano, Kanai, & Walsh, 2010; Ditye, Jacobson, Walsh, & Lavidor, 2012; Reis et al., 2009; Snowball et al., 2013). Combining tES protocols with cognitive training holds great promise for future research. It may be used as a tool for enhancing cognitive functions such as memory, language and attention in healthy individuals and in patients. We hereby presented an overview of tES use in cognitive research with healthy subjects. The interest, both academic as of the lay public and the media around the tES, will probably continue to increase, given the promising results that the technique has presented in clinical studies as well (Convento et al., 2016). With the promising results found in various cognitive stimulation studies, further studies, with robust methodologies, should strive to replicate, expand, and optimize the findings, perhaps testing larger, different samples and varying tES parameters such as electrode size, dosage, reference electrode, length of sessions, number of days of application, and more. Such studies are still warranted in order to provide a definite picture regarding tES clinical efficacy.

Acknowledgments This article presents studies that were supported by the Israel Academy of Sciences Grant No. 367/14, and the Israeli Center of Research Excellence (I-CORE) in Cognition (I-CORE Program 51/11).

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Zaghi, S., Acar, M., Hultgren, B., Boggio, (2010). Noninvasive brain stimulation electrical currents: Putative mechanisms and alternating current stimulation. The 285–307.

P. S., & Fregni, F. with low-intensity of action for direct Neuroscientist, 16,

Received November 24, 2014 Accepted August 14, 2015 Published online March 23, 2016 About the author Prof. Michal Lavidor is a professor of Psychology in the Department of Psychology at Bar Ilan University (Israel) and the head of the Cognitive Neuroscience laboratory at the Gonda Brain Research Center at this university. Research in her laboratory focuses on the neural basis of language and includes work on hemisphere-based language processes, visual word recognition, gestures, prosody, and the involvement of executive functions in semantic processing. Lavidor and her team develop noninvasive brain stimulation protocols to enhance interhemispheric cooperation and ultimately improve cognitive functions involved in word and emotion recognition.

Michal Lavidor Department of Psychology The Gonda Multidisciplinary Brain Research Center Bar Ilan University Ramat Gan 52900 Israel Tel. +972 353 18171 Fax +972 353 52184 E-mail michal.lavidor@gmail.com

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Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

Social Psychology and Noninvasive Electrical Stimulation A Promising Marriage Paulo S. Boggio, Gabriel G. Rêgo, Lucas M. Marques, and Thiago L. Costa Social and Cognitive Neuroscience Laboratory and Developmental Disorders Program, Center for Health and Biological Sciences, Mackenzie Presbyterian University, Sao Paulo, Brazil Abstract. Social neuroscience and psychology have made substantial advances in the last few decades. Nonetheless, the field has relied mostly on behavioral, imaging, and other correlational research methods. Here we argue that transcranial direct current stimulation (tDCS) is an effective and relevant technique to be used in this field of research, allowing for the establishment of more causal brain-behavior relationships than can be achieved with most of the techniques used in this field. We review relevant brain stimulation-aided research in the fields of social pain, social interaction, prejudice, and social decision-making, with a special focus on tDCS. Despite the fact that the use of tDCS in Social Neuroscience and Psychology studies is still in its early days, results are promising. As better understanding of the processes behind social cognition becomes increasingly necessary due to political, clinical, and even philosophical demands, the fact that tDCS is arguably rare in Social Neuroscience research is very noteworthy. This review aims at inspiring researchers to employ tDCS in the investigation of issues within Social Neuroscience. We present substantial evidence that tDCS is indeed an appropriate tool for this purpose. Keywords: social neuroscience, social plasticity, neuromodulation, transcranial direct current stimulation

Social neuroscience is a prominent topic in contemporary psychology. Here, we present a review of studies using transcranial direct current stimulation (tDCS) to investigate social cognition. In this review, we aimed to describe how and why the use of tDCS can foster the development of social neuroscience and psychology. This technique allows for the safe and effective direct modulation of ongoing brain activity in human beings and the establishment of causality in brain-behavior relationships that cannot be achieved with imaging or behavioral methods alone. Despite the reduced number of studies using tDCS as a tool to understand social phenomena, we believe that it should be included in the social neuroscience toolkit. We will present recent studies providing preliminary evidence that this technique can help the social psychologist and neuroscientist to foster knowledge on social pain, empathy, social decision-making, and prejudice. One main human characteristic is a social nature, given a high dependence on one’s peers to survive and on their welfare (Brent, Chang, Gariépy, & Platt, 2014; DeVries, European Psychologist 2016; Vol. 21(1):30–40 DOI: 10.1027/1016-9040/a000247

Glasper, & Detillion, 2003). Although clinical studies with brain-lesioned patients have already shed light on some of the structural and functional aspects of the brain related to the processing of social information (e.g., Damasio, Grabowski, Frank, Galaburda, & Damasio, 1994), only in recent decades has the field developed to the point of systematically investigating the intricate neural processing of social information. This was possible due to recent technological advances (e.g., more computational power, new data collection techniques, new statistical methods), as well as the accumulation and interchange of knowledge from diverse areas such as natural and social sciences. An important result of this evolution is the germination of social neuroscience (Lieberman, 2007). Social neuroscience originated by the merging of methods and knowledge from neuroscience, social psychology, and social sciences. Its main objective is to understand the neurobiological bases of social phenomena, aiming to investigate how human beings and other animals perceive themselves, perceive others, and how they interact Ó 2016 Hogrefe Publishing

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(Lieberman, 2007). Although the origin of social neuroscience can be related to studies conducted in the late 20th century that aimed to investigate the biological basis of social processes (e.g., Cacioppo & Berntson, 1992), the major expansion and development of this field occurred in the last 20 years – one of the hallmarks of this expansion was the first social cognitive neuroscience meeting in 2001 (Lieberman, 2007). In the next two sections, we will discuss the relevance of the correlational methods of social neuroscience and argue why and how noninvasive brain stimulation methods are of utmost importance in this field.

Advances Based on fMRI, EEG/ERP, Lesions Before the introduction of the main noninvasive brain stimulation methods used today, most of the research on social cognition relied on behavioral methods, lesions, and/or correlational methods alone. Lesion studies represent some of the first investigations and demonstrations of specific roles of different brain areas in social cognition. Among these, there is no doubt that Phineas Gage is the most popular. After a lesion in the frontal cortex (more specifically, the bilateral prefrontal cortex), Phineas started to struggle with a number of cognitive and behavioral changes. In many textbooks, this case is discussed in terms of personality changes after the brain lesion (see Macmillan, 2008). Nonetheless, it is easy to argue that Phineas Gage was one of the first and most notable case studies of the role of the frontal lobe in social cognition. A lack of inhibitory control, impaired decision-making processes, emotional processing, and compliance with social norms are among the main changes observed in patients with similar lesions. For a long time, lesion studies remained one of the few opportunities to investigate the role of the brain in social cognition until the popularization of electroencephalography (EEG) and other brain imaging techniques during the last two decades of the 20th century (for reviews of lesion studies in social cognition, see Bechara, 2004; Hillis, 2014). EEG has been used to understand social cognition in terms of its dynamics and timing of neural processing. Several event-related potentials (ERP) have been described throughout the last few decades and are significantly correlated with some specific tasks and processes. This technique has led to substantial advances in our understanding of social cognition processes. One of the first studies to use EEG to investigate social cognition evaluated the effects of one week of social isolation in healthy volunteers (Zubek, Bayer, & Shephard, 1969). These authors found no significant changes in subjective stress or intellectual tests but identified a significant decrease in alpha oscillations after the social isolation. This result highlighted one of the strengths of the brain imaging technique: to unveil implicit processes where no directly observable behavior can be identified. As examples of that, many authors have used EEG to study implicit attitudes (e.g., Amodio et al., 2004).

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With limited temporal resolution but higher spatial resolution than EEG, functional magnetic resonance imaging (fMRI) facilitated the understanding of which brain areas are correlated with different types of social cognition demands. The contribution of fMRI to the neuroscience of social cognition has come a long way. Recently, its use as a diagnostic tool for some conditions with clear affective and social deficits has also been investigated. Just, Cherkassky, Buchweitz, Keller, and Mitchell (2014) found that a neurocognitive marker of autism could be identified in fMRI recordings and developed an algorithm that separated autistic patients from controls with 97% accuracy (Just, Cherkassky, Buchweitz, Keller, & Mitchell, 2014). Lesions, EEG, and brain imaging studies have provided relevant discoveries about our social brain. However, several questions can only be answered by directly modulating the brain. In these cases, neuromodulation techniques may be used to probe causality in the brain-behavior relationship. Neuromodulation techniques may be considered a revolution in modern neuroscience. The possibility to noninvasively and transiently interfere with the ongoing brain function using a site-specific technique allows us to understand brain-behavior relationships with another level of causality that cannot be achieved with the imaging of behavioral methods alone. It also represents an alternative to lesion studies because there are several limitations that can easily be overcome in brain stimulation studies. Among these, we highlight the following: (i) a lesion also leads to long-term adaptation and plasticity in other brain areas that might become a confounding factor for research, and (ii) researchers cannot control the place and size of lesions, and it is certainly not possible to implement repeatedmeasures designs comparing patients with and without the lesion (Pascual-Leone, Walsh, & Rothwell, 2000).

Neuromodulation Techniques One of the most popular neuromodulatory techniques is TMS. It allows for the delivery of single or repetitive pulses to relatively superficial and focal (1 cm2) brain areas. For the purpose of this review, it is not important to discuss whether the induced effect is a facilitation or interference because the unique feature of TMS is its ability to interact transiently with the stimulated area of the brain, thus modifying the activity of that area and allowing one to evaluate its function (Miniussi, Harris, & Ruzzolid, 2013). As the TMS technique became popular, it quickly started to play a central role in neuroscience research. From 1997 to 2007, the number of papers grew from less than 500 a year to approximately 2000 a year, and this number keeps growing. In the field of social cognition research and rehabilitation, a growing number of studies with TMS can also be seen. An estimation of the number of publications to mention the terms ‘‘Transcranial Magnetic Stimulation’’ and ‘‘Social’’ per year shows a similar

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Figure 1. Number of publications per year (noncumulative) to mention the terms ‘‘Transcranial Magnetic Stimulation’’ and ‘‘Social,’’ according to the Scopus database (from the first occurrence of both terms in a paper in 1996 to 2014). growing trend, although the overall numbers are still arguably modest (peaking at approximately 250 papers a year, see Figure 1). The impact of TMS in social neuroscience and psychology might be exemplified by the study of Young, Camprodon, Hauser, Pascual-Leone, and Saxe (2010). Authors showed that TMS-induced disruption of the right temporal parietal junction (TPJ) affects moral judgment. In this study, participants had to judge how deserving of punishment were actors who tried to induce harm in innocent people. Participants receiving TMS to the TPJ were less reliable on the actor’s mental states and became more morally permissible (judging failed attempts to induce harm as less deserving of punishment than controls). These results clearly illustrate that TMS can affect social cognition in robust and very specific ways. Therefore, if TMS is very effective in social cognition research, and because there is much more research using TMS than tDCS, why are we presenting a review of tDCS-aided social cognition studies? Similar to TMS, tDCS can allow the researcher to understand the role of one function in one specific area by observing in a repeated-measures design how increased versus decreased excitability of the area might affect behavior. However, when compared to TMS, tDCS did have a set of advantages that justified its use instead of TMS in many cases – particularly its use in the field of psychology outside medical environments. The main advantage is safety. Both procedures are reasonably safe when standard parameters are used, but rTMS can indeed induce seizures, and the field guidelines suggest that it should only be delivered in hospital environments (Rossi, Hallett, Rossini, & Pascual-Leone, 2009). tDCS has no such limitations and is painless, easy to deliver, highly portable, and low in cost (for a recent review, see Filmer, Dux, & Mattingley, 2014). It also has a more reliable placebo control (see Nitsche et al., 2008 for a discussion of this issue). It is associated with moderate and sparse adverse effects (Brunoni et al., 2011). Pain is not commonly

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observed during tDCS, whereas up to 40% of participants receiving TMS report pain, headache, or any other type of discomfort (Anderson et al., 2009; Loo, McFarquhar, & Mitchell, 2008). A study has shown that the discomfort caused by TMS could influence participants’ behavior and be a confounding variable (Abler et al., 2005). Despite the fact that it has not been investigated, TMS-caused discomfort could also be a confounding variable in social cognition studies, and in this case, tDCS would prove to be more reliable once its application was painless. Another tDCS advantage over TMS in social cognition is the easiness of use in social interaction studies with the application of simultaneous stimulation in two or more participants (Knoch et al., 2008). Finally, portability is also an interesting characteristic of tDCS. New studies might employ tDCS coupled with other portable tools (e.g., eyeglass) during social interactions outside the laboratory. However, it is important to note that tDCS has some limitations when compared to TMS that might help to explain why this technique was not used more frequently in the field of social cognition. To understand these limitations, we need to provide a quick explanation of how tDCS works. The most popular tDCS procedure consists of the application of low-intensity current (usually up to 2 mA) via two electrodes (anodal and cathodal) superficially positioned over the scalp. Different electrode sizes have been used, but the main electrode varies from 25 to 35 cm2. The current flows from the anode to the cathode. In general, the brain region below the anodal electrode presents an increase in excitability, while the opposite is observed for the cathodal electrode. This effect is attributed to a change in resting membrane potentials – differently from TMS, tDCS does not induce action potentials. TDCS also seems to induce longer lasting effects by ‘‘LTP-like’’ and ‘‘LTDlike’’ plasticity mechanisms (Stagg & Nitsche, 2011). Many works suggest that anodal tDCS may inhibit GABA (e.g., Nitsche et al., 2004), while cathodal stimulation inhibits glutamate (e.g., Stagg et al., 2009), a fact that can also help to explain the excitatory and inhibitory effects of anodal and cathodal stimulation. Because a detailed explanation of tDCS function and its mechanisms of action is beyond the scope of the present review, we refer to the recent reviews by Stagg and Nitsche (2011), Medeiros et al. (2012), and Filmer et al. (2014). As described above, the electrode sizes were not small; therefore, one of the most crucial limitations is focality. tDCS is known to have a low spatial focality, as it uses large electrodes, and the current might spread beyond the targeted area (although recent current flow models suggest that most of the current density is concentrated below the electrodes and dissipates in between electrodes, see Wagner et al., 2014). In this scenario, targeting very small and specific areas may be challenging or even impossible. Nonetheless, whenever targeting large areas or cognitive processes that are not highly localized, low tDCS focality might be useful.

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Figure 2. Target-areas and the main findings of tDCS studies on social neuroscience.

Another relevant issue is that both anodal and cathodal electrodes have functional effects. Thus, both electrodes will produce significant effects if located anywhere in the head (as is the case in most works in this field). Therefore, electrode placement could produce significant effects that might work as confounding factors (see Nitsche et al., 2008 for a discussion). In many cases, this could not be seen as a limitation. A particular study might benefit by observing how the simultaneous excitation and inhibition of different brain areas affects behavior (as Brunoni, Boggio, Ferrucci, Priori, & Fregni, 2013, for example). However, whenever the functional effects of the reference electrode are unwanted, some solutions are possible. Many studies have employed different electrode sizes of tDCS to minimize these effects (e.g., Fregni et al., 2008). Placing the reference electrode outside the head is a possible solution as well (e.g., Ferrucci et al., 2008). High-definition tDCS is another recent solution that seems to deliver more focal stimulation (see Edwards et al., 2013). Lastly, tDCS has a very limited temporal resolution when compared with TMS. So whenever a high temporal resolution is needed, with very transient (even of the order of milliseconds) periods of stimulation, tDCS is certainly not the most adequate technique. Nonetheless, we argue that tDCS’s safety, ease of use, cost, portability, and robust effects make a case for the more widespread use of this technique in contemporary psychology and neuroscience. In the next sections, we will review some of the most successful studies to use tDCS as a tool in social neuroscience and psychology research. Ó 2016 Hogrefe Publishing

Social Neuroscience and Psychology Studies With Noninvasive Brain Stimulation and tDCS Here, we will review a few relevant topics in social neuroscience research that have employed noninvasive brain stimulation techniques successfully. We will focus on social pain, social interaction, prejudice, and social decisionmaking. Figure 2 depicts the target-areas and the main findings of each study on social neuroscience that are cited along the manuscript.

Social Pain and Touch, Empathy for Pain and Touch Pain is a topic of great interest for social neuroscience and psychology. Typically, it is observed that structures linked to proprioception, conflict detection, attentional control, and decision-making (as somatosensory cortex, anterior cingulate cortex, amygdala, anterior insula, and prefrontal cortex) are involved in pain processing (Lamm, Decety, & Singer, 2011). Interestingly, recent studies demonstrated that these same systems are also involved in the handling of social situations in which some level of suffering (yet no actual physical pain) is occurring (Eisenberger, 2012). This is observed during the visualization of images of painful situations, where the neural underpinnings of empathy for the European Psychologist 2016; Vol. 21(1):30–40

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pain of others can also be observed (Masten, Morelli, & Eisenberger, 2011). Which brain areas and processes are shared by physical pain and social pain is a topic of great relevance in the field today, and some studies using tDCS have helped to elucidate that. In one of the first studies to investigate pain processing using tDCS, Boggio, Zaghi, Lopes, and Fregni (2008) started testing the role of the primary motor cortex (M1), the left primary visual area (V1), and left dorsolateral prefrontal cortex (left DLPFC) in pain processing. The volunteers received anodal tDCS over these structures in separate sessions and received electrical peripheral stimulation (painful and not painful) on their hands. They only found significant results for anodal stimulation over M1 and DLPFC. M1 tDCS increased both somatosensory and pain thresholds, while DLPFC tDCS only increased pain thresholds. The authors discussed these results, highlighting the important influence of both structures (DLPFC and M1) on pain processing and emphasizing a differential role of these structures in pain processing. In this experiment, pain was induced by electrical stimulation. One important debate is about pain induced by observing others in pain. To investigate this issue, the same group conducted a similar study in which the same tDCS conditions were applied, but participants had to judge the unpleasantness of pictures presenting human beings under painful conditions (Boggio, Zaghi, & Fregni, 2009). The results showed a significant decrease in unpleasantness and discomfort assessment during anodal left DLPFC tDCS in relation to sham tDCS, while no other significant effects were found on other conditions. These findings demonstrate that DLPFC is a critical area for the emotional processing of pain. As M1 tDCS did not modulate unpleasantness and discomfort assessment, authors also suggested different pathways for emotional pain and somatosensory perception. In a similar task as Boggio et al. (2009) but with positive and neutral human pictures added, Peña-Gómez, VidalPiñeiro, Clemente, Pascual-Leone, and Bartrés-Faz (2011) found no significant effects for valence assessment of positive and neutral pictures under left DLPFC anodal tDCS in addition to confirming previous findings. Their findings highlight the possible involvement of this structure in the specific processing of negative content and the subsequent emotional regulation of such content. In a similar study, Feeser, Prehn, Kazzer, Mungee, and Bajbouj (2014) investigated the role of the DLPFC in an emotional regulation task (up-regulating and down-regulating the current negative emotion). Anodal tDCS was applied to the right DLPFC with the cathodal electrode over the supraorbital contralateral region. The skin conductance response (SCR) was also recorded. They demonstrated that when up-regulating negative emotions, participants who underwent active tDCS had higher SCR levels and arousal ratings than participants who received sham tDCS. On the other hand, during the down-regulation of negative emotions, smaller SCR levels followed by lower arousal assessments were observed for active compared to sham tDCS. These findings suggest that increased activity in the right DLPFC could be linked to increased cognitive control on emotion regulation (Ochsner, Silvers, & Buhle, 2012). European Psychologist 2016; Vol. 21(1):30–40

Interestingly, not just pain can be modulated via tDCS. Bolognini, Miniussi, Gallo, and Vallar (2013) demonstrated that tDCS is able to modulate touch synesthesia. Bolognini et al. (2013) found that anodal tDCS of the left or right somatosensory cortex induced the manifestation of synesthesia-like effects (being less accurate and slower to identify touch in self when observing incongruent touch in others) in non-synesthetic participants. Additionally, they found a positive correlation between perspective-taking score (a subscale of the Interpersonal Reactivity Index) and the synesthesia-like effect induced by tDCS. The above-mentioned studies show that tDCS can be used to study the neural mechanisms behind understanding others’ somatic sensations, pain perception, judgment of painful situations, and emotion regulation. Another different phenomenon, generally known as social pain, can be characterized as the experience of suffering due to personal losses or rejection and ostracism (Eisenberger, 2012; Lieberman & Eisenberger, 2006; Van Beest, Williams, & Van Dijk, 2011; Williams, 2007). Typically, it is observed that under these conditions, there is a decrease in mood and basic needs levels (belonging, self-esteem, control, and meaning of existence). A recent study by Kelley, Hortensius, and Harmon-Jones (2013) showed that when submitted to right DLPFC anodal tDCS, participants presented higher levels of rumination while being ostracized in the so-called Cyberball (see Williams & Jarvis, 2006 for review). This effect points to the role of the right DLPFC and, particularly, the effects of an imbalance in the interhemispheric activity. It is interesting to observe that rumination is a very common behavior in patients with major depression and that it is accompanied by increased right DLPFC activity and decreased activity of the contralateral homologous structure (Coan & Allen, 2004). Another brain area stimulated by tDCS during ostracism induced by the Cyberball is the ventrolateral prefrontal cortex (VLPFC; Riva, Lauro, DeWall, & Bushman, 2012), which showed that anodal tDCS over the right VLPFC could reduce the discomfort and feelings of pain compared to sham tDCS. More recently, the same group showed that under the same protocol, participants who received active tDCS reported lower levels of aggressiveness after the ostracism task (Riva, Lauro, DeWall, Chester, & Bushman, 2014). A similar effect in aggressive behavior was also achieved with anodal tDCS stimulation over the right DLPFC, which led to diminished levels of self-reported aggressiveness in men (Dambacher et al., 2015). Altogether, these studies provide causal evidence of the role of the prefrontal cortex in emotional control processes and emotion reappraisal (Ochsner et al., 2012). These studies highlight the relevance of tDCS to the study of pain, empathy for pain (see Hétu, Taschereau-Dumouchel, & Jackson, 2012, for a discussion of this issue), and social pain phenomena.

Social Interaction The processing of social information that supports social interaction is a central topic in social neuroscience and Ó 2016 Hogrefe Publishing

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psychology. Among the many processes and abilities subserving social interaction, we highlight three in which tDCS research has provided relevant insights: perception of facial expression, perspective taking, and imitation. Here, we present the main studies using tDCS in the investigation of these abilities. Most of the research using neuromodulation to investigate facial expression perception has focused on elucidating the brain networks involved in emotion detection. A seminal study on this topic used TMS to inhibit the medial prefrontal cortex (Harmer, Thilo, Rothwell, & Goodwin, 2001) while participants viewed faces with angry or happy expressions. This study found that disruption of the medial prefrontal cortex affected only angry face perception. Since that study, others have been conducted supporting the existence of different networks to process specific emotions (e.g., Ferrucci et al., 2012; Nitsche et al., 2012) and the existence of brain processing differences between male and female volunteers in specific emotion perception (Boggio, Rocha, da Silva, & Fregni, 2008). The first study to use tDCS in the investigation of emotional face processing evaluated males and females playing a face expression go-no-go task (Boggio, Rocha, et al., 2008). In this task, photographs of sad, happy, and neutral faces were shown to the participants, and in each block, either sad or happy was specified as the target. The participants were submitted to bilateral tDCS stimulation over the temporal cortex, with the anodal electrode over left and cathodal electrode over the right temporal cortex. The results showed that women made fewer errors with active stimulation compared to the sham when sad faces were the targets. Contrarily, men made more errors in the same condition (sad faces as target) with active stimulation compared to the sham. A possible hypothesis raised by the authors is the existence of different networks subserving sad face perception in women and men. Other studies investigated the involvement of specific brain areas in the processing of facial expressions. The study by Ferrucci et al. (2012) investigated the involvement of the cerebellum and right prefrontal cortex in the perception of negative, positive, and neutral facial expressions. They found that only cerebellar stimulation (for both anodal and cathodal) enhanced the perception of negative (anger and sadness) facial expressions when compared to sham stimulation. Another study by Nitsche et al. (2012) evaluated the involvement of the left and DLPFC cortex in emotional state and emotional face identification. The participants were submitted to tDCS stimulation over the left DLPFC, while the reference electrode was placed over the right frontopolar cortex. The authors found that anodal stimulation over the left DLPFC led to improved positive emotional face recognition. These experiments provide important information about brain structures and their roles in the perception of emotional faces. Nevertheless, the use of tDCS to understand face perception is still at its beginning. New studies are necessary to obtain a deeper comprehension of specific brain structures as well as the neural circuitries underlying face perception. Additionally, new tDCS experiments might help to clarify possible differences between genders with regard Ă&#x201C; 2016 Hogrefe Publishing

to face processing. The construction of affective, social, and cognitive models based on the causal effects promoted by tDCS might help in the investigation of social deficits typically observed in some clinical populations such as autism. In particular, the integration of tDCS with other techniques such as eye tracking systems will possibly answer important questions about the static and dynamic face tracking abnormalities observed in autism and other conditions. As mentioned previously, social interaction also depends on perspective taking, an essential ability related to empathy and consequently to the development and maintenance of positive social connections (Seyfarth & Cheney, 2013). A relevant study investigated the neuromodulation of temporoparietal junction (TPJ) in participantsâ&#x20AC;&#x2122; performance on three social cognition tasks: on a motor imitation task, a spatial perspective-taking task, and a self-referential task. Although neuroimaging studies have shown the involvement of TPJ in abilities related to the execution of these tasks, TPJ tDCS effects were not the same for all tasks. This study showed that anodal TPJ tDCS improved the control of self-other discrimination related to the imitation and perspective-taking tasks, while it did not have any effect on mental attribution ability, as evaluated by the selfreferential task (Santiesteban, Banissy, Catmur, & Bird, 2012). This study helped to clarify the involvement of TPJ in empathy, confirming its main role in the specific function of self-other discrimination. Hogeveen et al. (2014) expanded these findings by testing the effects of anodal tDCS over the right TPJ or right inferior frontal cortex (IFC) on imitative control functions. Interestingly, anodal tDCS of the right IFC improved the ability to inhibit imitation in a task in which it was required but, at the same time, increased the imitation during a social interaction task (which is related to better social interaction). Thus, it seems that IFC is related to imitation control depending on the performing task. With regard to anodal tDCS over TPJ, a positive effect was observed in the ability to inhibit imitation but had no effect on the imitation during the social interaction task. These findings support the notion of a direct role of the IFC in imitative behavior and an indirect role of the TPJ. The possibility of promoting imitative behavior by brain stimulation opens an avenue of investigations on its use as a tool to promote social plasticity. New studies of tDCS on social abilities might point to the future possible clinical use in individuals with developmental disorders that present social cognition impairments such as autism or schizophrenia.

Prejudice The frequency of sexual, social, or racial prejudice in human interactions is significant. Although the frequency of explicit demonstrations of prejudice seems to (arguably) be diminishing in most cultures, implicit prejudice appears to be present in many circumstances and remains a very relevant topic in contemporary neuroscience research (see Kubota, Banaji, & Phelps, 2012, for a discussion of this issue in racial prejudice studies). Among all research tools European Psychologist 2016; Vol. 21(1):30â&#x20AC;&#x201C;40

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in this field, one that is used most is the Implicit Association Test (IAT). It allows for the investigation of interactions between different stimulus categories (e.g., Caucasian and African-American faces and positive and negative valence words) in a fast forced-choice task that unveils biased associations that are frequently not explicitly accessible (Greenwald, McGhee, & Schwartz, 1998). More recently, some groups investigated prejudice and its implicit associations using neuromodulation techniques such as TMS and tDCS. TMS studies showed that inhibiting the left DLPFC function was able to increase the participant’s gender bias (Cattaneo, Mattavelli, Platania, & Papagno, 2011) and religiousness-spirituality bias (Crescentini, Aglioti, Fabbro, & Urgesi, 2014) during IAT. These findings suggest that increased activity in the left DLPFC might be related to decreased inhibitory control, unveiling stereotyped responses. A recent tDCS work has also investigated the role of the left DLPFC in mediating implicit bias in responses to nonsocial stimuli, finding interesting results that are somewhat complementary to those mentioned above. Using an IAT task, Gladwin, den Uyl, and Wiers (2012) found that tDCS of the left DLPFC did not affect the implicit bias processes in the association of insect images and insect names. Taken together with the works of Cattaneo et al. (2011) and Crescentini et al. (2014), these results could be interpreted to suggest that there is something special in the left DLPFC concerning the processing of social (in contrast to nonsocial) bias. In fact, Cattaneo et al. (2011) reviewed evidence from fMRI studies supporting this hypothesis. The studies mentioned in this brief section show that tDCS and TMS can be effective tools in the investigation of the underlying mechanisms of prejudice and implicit social biases. Nonetheless, there are very few investigations of these subjects that employ such techniques. Considering the social burden that is associated with prejudice in our society today, more studies on prejudice employing neuromodulatory techniques are recommended.

Social Decision-Making In the fields of economics and psychology, social decisionmaking is a topic that investigates how a person chooses between alternatives in the context of social interaction (Sanfey, 2007). In the last decade, methods and techniques from neuroscience have been applied to investigate the neurobiological substrates of social decision-making. Despite the fact that most studies combining social decision-making and neuroscience focused on neuroimaging methods, some relevant studies used neuromodulation techniques and handled useful information about the role of different brain areas in decision-making and how controlled and automatic processes interact in the decision-making processes (Loewenstein, Rick, & Cohen, 2008). A relevant research topic in social decision-making is the investigation of the neurobiological underpinnings of fairness perception and compliance with social norms. A pioneer study in this topic was conducted by European Psychologist 2016; Vol. 21(1):30–40

Knoch et al. (2006). They used low-frequency TMS to inhibit the right DLPFC activity while participants played the Ultimatum Game (UG). The UG is a resource-sharing task used to investigate the reaction to unfairness. In this game, two participants are given an initial asset and one of them first proposes a sharing rate and the other participant accepts it (both of them gain the proposed value) or rejects it (both gain nothing). Neuroimaging studies showed increased activity of the anterior insula and right DLPFC in participants facing the unfair proposals. However, it was not clear whether the activity of the DLPFC, an area related to cognitive control, including the top-down control of automatic and prevalent responses, was related to the inhibition of an impulse to reject unfairness or, contrarily, to seek gains independently of quantity. The manipulation of the right DLPFC through TMS showed that the inhibition of this area led to a higher acceptance of unfair proposals, confirming the hypothesis that human beings have an impulse to approach gains and that this temptation would be controlled by the activity of areas related to high-level cognitive control. The seminal study by Knoch et al. (2006) was followed by a study by Knoch and Fehr (2007) in which they applied inhibitory tDCS over the right DLPFC during a UG task. They found similar results using tDCS compared to their previous TMS study (Knoch et al., 2006): enhanced acceptance of unfair proposals due to the inhibition of the right DLPFC activity. Given these similar results, Knoch and Fehr (2007) considered the potential use of tDCS relative to TMS in tasks with simultaneous social interaction, given the previously presented advantages of tDCS. The regular UG task assesses the effect of unfairness on respondents as the proposal’s recipients. Recent experiments have begun to investigate the effects of unfairness when the responder must decide for him/herself (myself condition) or on behalf of a third-party (third-party condition) (Civai, Crescentini, Rustichini, & Rumiati, 2012). Interestingly, inequity aversion was observed in both the myself and third-party conditions. Nevertheless, the MPFC was strongly activated during the myself condition. To test the causal role of the MPFC in personal damage versus general inequity aversion, Civai, Miniussi, and Rumiati (2014) investigated the effect of cathodal tDCS over the MPFC in this modified version of the UG. They found that cathodal tDCS over MPFC led to diminished rejection of unfair proposals in the myself condition. In agreement with previous fMRI experiments, these findings provide evidence that MPFC is related to fairness processing when the self is involved. Another study using tDCS to modulate social decisionmaking was conducted by Ruff, Ugazio, and Fehr (2013). They used a task similar to the UG first used by Spitzer, Fischbacher, Herrnberger, Grön, and Fehr (2007). In this game, two players divide an initial endowment. One player is a proposer and suggests a division rate to a second player, the receiver. The experimenters created two different conditions for this game: a control and a punish condition. In the control condition, the receiver could only accept the proposal passively, similar to a dictator game. In the punish

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condition, the receiver could spend some money to punish the proposer. After the initial endowment, the players received extra money (used by the receivers to punish the proposer in the punishment condition). A neuroimaging study by Spitzer et al. (2007), the first using this task, found that the punishment condition led the proposers to comply with the social norms and share the endowment more fairly, and this behavioral adaptation was related to an enhanced activation of the right DLPFC, left ventrolateral prefrontal cortex, and bilateral orbitofrontal cortex. Ruff et al. (2013) modulated the right DLPFC with anodal and cathodal stimulation to investigate the right DLPFC role on norm compliance. They found that in the punishment condition, the anodal stimulation (compared to sham) led the proposer to transfer more money after punishment, enhancing the norm compliance. In contrast, the cathodal stimulation made the proposers more self-interested and less oriented by social norms of fairness, diminishing the quantity transferred to the receivers. In the control condition (where the receiver could only accept passively), the stimulation acted in a contrary way. During anodal stimulation, proposers shared less with the receiver, while the cathodal stimulation led to fairer sharing. While they found behavioral changes due to the neuromodulation, they did not find any changes in the perception or expectation of social norms. This result suggests that the right DLPFC is involved in a network linked to norm compliance. However, it is not clear why neuromodulation of the right DLPFC acted in contrary ways between the punish and control conditions. A hypothesis raised by Sanfey, Stallen, and Chang (2014) to explain these data suggested that given the role of the right DLPFC in expectation processing as presented in previous studies, the expected norms in the punish and control conditions could be different, with participants expecting that people would offer less money in the control condition and more money in the punishment condition. Nevertheless, the norm expectations for each condition were not evaluated and remain an open question. A suggestion by Sanfey et al. (2014) was that the right DLPFC worked together with other areas such as the anterior cingulate cortex and insula in a network related to compliance. While these two latter areas would be related to a failure in expectancy, the right DLPFC may be related to goal maintenance and the cognitive control to achieve that goal. The above-mentioned studies provide many possibilities for the clinical use of tDCS in neurological or psychiatric disorders in which compliance with social norms is defective (Ruff et al., 2013). Nonetheless, tDCS-aided interventions for social cognition rehabilitation are still in their infancy.

Conclusion and Future Directions The present review argues that our understanding of social neuroscience and psychology would benefit from more research using noninvasive brain stimulation methods.

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Figure 3. Number of publications per year (noncumulative) to mention the terms ‘‘Transcranial Direct Current Stimulation’’ and ‘‘Social,’’ according to the Scopus database (from the first occurrence of both terms in a paper in 2002 to 2014).

More importantly, we argue that tDCS is an effective, safe, and low-cost tool for that purpose. In fact, the present review shows a number of papers that have used tDCS in investigations that have advanced our knowledge of the brain substrate involved in social pain and empathy for pain, implicit associations involved in prejudice-related behavior, social interaction, and social decision-making. Here, we argue that although tDCS is still in its infancy as a tool for social neuroscience and psychology studies, we have passed the point in which researchers should be asking ‘‘if’’ or ‘‘how’’ tDCS might be used for social neuroscience research. We believe that we are now at the point where many researchers are asking ‘‘why not more?’’ or how to do better, and we are certainly among them. Figure 3 (showing the number of publications per year that mentioned the terms ‘‘Transcranial Direct Current Stimulation’’ and ‘‘Social’’) supports that this is a growing trend, although the use of tDCS in the field is still much less popular than TMS (see Figure 1). Regarding future directions, we highlight three main issues in the intersection between Social Neuroscience and tDCS research that are critical for the advancement of the field. First, more studies are needed. As we argued before, this technique needs to be used more frequently in this field. Second, more replication studies are needed, as in every new field. Lastly, more studies with clinical populations should be done. As there is growing evidence for the tDCS potential in neurorehabilitation (Brunoni et al., 2012; Brunoni, Valiengo, et al., 2013) and there are many conditions that strongly impact social cognition with limited choices of treatment (e.g., dementias, traumatic brain injuries, autism spectrum disorder, schizophrenia), it is critical that more investigations are done on the clinical potential of this technique in social rehabilitation. There is a whole avenue of research still to be explored and the promising results showing tDCS can be effective in the treatment of depression (Brunoni, Boggio, et al., 2013) and pain (Mori et al., 2010) justify these investigations.

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Acknowledgments PSB is a CNPq research fellow and is supported by National Council for Scientific and Technological Development (CNPq – 480891/2012-5). LMM is supported by a FAPESP Master grant (FAPESP - 2014/24399-2). TLC is supported by a FAPESP Postdoc grant (FAPESP 2014/11668-5). The authors declare no competing financial interests.

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Gabriel G. Rêgo is a PhD Student at the Social and Cognitive Neuroscience Laboratory at the Mackenzie Presbyterian University, Brazil. His major research interests include Decision-Making, Neuroeconomy, Social Psychology, and Neuromodulation.

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Lucas M. Marques is a Master Student at the Social and Cognitive Neuroscience Laboratory at the Mackenzie Presbyterian University, Brazil. His major research interests include Emotion, Emotion Regulation, Psychophysics, and Neuromodulation.

Thiago L. Costa is a Postdoctoral Research at the Social and Cognitive Neuroscience Laboratory at the Mackenzie Presbyterian University, Brazil. His research mostly focuses on perception, spanning from low-level visual processing and perceptual organization to higher order cognitive processes.

Received February 3, 2015 Accepted June 24, 2015 Published online March 23, 2016 About the authors

Paulo S. Boggio Paulo S. Boggio is a Senior Researcher and Professor of Neuroscience and Behavior, Affiliate Member of the Brazilian Academy of Sciences, CNPq Research Fellow, and Director of the Social and Cognitive Neuroscience Laboratory at the Mackenzie Presbyterian University, Brazil. His research interests include Neuromodulation and Social Cognition.

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Social and Cognitive Neuroscience Laboratory and Developmental Disorders Program Center for Health and Biological Sciences Mackenzie Presbyterian University Rua Piauí, 181, 10° andar Sao Paulo, SP, 01241-001 Brazil Tel. +55 11 2114-8001 Fax +55 11 2114-8563 E-mail boggio@mackenzie.br

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Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

Noninvasive Brain Stimulation for the Study of Memory Enhancement in Aging David Bartrés-Faz1 and Didac Vidal-Piñeiro2 1

Faculty of Medicine, University of Barcelona, Spain, 2Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Norway Abstract. Noninvasive brain stimulation (NIBS) techniques have recently attracted interest due to their potential for transiently improving cognition. This may prove particularly valuable in aging, given the known impact of age-related cognitive dysfunction on quality of life. The present review summarizes the currently available evidence of working and episodic memory enhancements achieved using NIBS in healthy elderly people. The evidence reviewed indicates that research is still at an early stage and that there is a need to define the best procedures for operating and performing multicentre characterization of protocols. However, a limited number of sham-controlled studies have reported improvements in both cognitive domains. Furthermore, evidences of long-term beneficial effects opens up the possibility of using NIBS as an adjuvant therapeutic strategy. However, the relevance of certain variables involved and approaches used remains to be elucidated, including the potential benefits of single versus multiple NIBS sessions, the putative synergistic effects of using NIBS in combination with cognitive training, and the importance of individual differences. Overall, NIBS techniques represent a promising opportunity for psychologists seeking strategies to improve memory functions in the elderly. Nevertheless, their use requires appropriate technical knowledge coupled with a clear understanding of the neurophysiology and cognitive neuroscience of aging. Keywords: aging, memory, improvement, noninvasive brain stimulation

In developed countries, the size of the elderly population is growing rapidly. By 2050, the elderly in these regions are expected to outnumber children by two to one (United Nations, 2013). This substantial increase is due to advances in medicine, public health measures, and rising standards of living (Cohen, 2003). While maturity provides experience and knowledge, aging also entails cognitive and motor decline and is a significant risk factor for several neurodegenerative disorders, especially Alzheimer’s disease (AD; Hebert, Scherr, Bienias, Bennett, & Evans, 2003). Cognitive dysfunction is one of the conditions that negatively impact quality of life in the elderly (Plassman et al., 2008); it is therefore vital to study and develop programs to maintain cognitive function and independence. Ó 2016 Hogrefe Publishing

There is accumulating knowledge about how cognition changes with age. Many aspects of information processing become less efficient (Craik & Salthouse, 2007), a phenomenon which, on a population basis, is particularly marked from the seventh decade of life onwards (Rönnlund, Nyberg, Bäckman, & Nilsson, 2005). Reduced cognitive performance associated with aging is not a homogeneous process; certain functions show substantial decline, while others remain stable throughout the lifetime. Among the cognitive abilities affected by aging, working and episodic memory are perhaps the ones that stand out the most. There is strong evidence that working memory (WM), the process by which information is held and manipulated for very short time intervals, decreases with age (Reuter-Lorenz & European Psychologist 2016; Vol. 21(1):41–54 DOI: 10.1027/1016-9040/a000241

D. Bartrés-Faz & D. Vidal-Piñeiro: Memory Enhancement in Aging

Sylvester, 2005) and is partially responsible for losses in long-term memory. Long-term episodic memory refers to the explicit recollection of events and is also reported to be highly susceptible to age (Zacks, Hasher, & Li, 2000). Vulnerability with advancing age has been demonstrated for the different subprocesses of long-term episodic memory, such as the encoding, storage, and retrieval of information. Memory dysfunctions in the elderly are accompanied by age-related changes in the brain systems that support these cognitive functions. Neuroimaging has revealed that aging in the human brain is characterized by gray matter cortical thinning and loss of volume (Fjell et al., 2009; Good et al., 2001), ventricular expansion (Earnest, Heaton, Wilkinson, & Manke, 1979), decreased density of white matter fibers (Sala et al., 2012), neurotransmitter depletion (Reeves, Bench, & Howard, 2002), and alteration of functional brain networks (Ferreira & Busatto, 2013; Spreng, Wojtowicz, & Grady, 2010). However, age-related changes are not homogeneous, since some regions show steeper declines than others. Specifically, fronto-parietal executive networks, including the dorsolateral prefrontal cortex (PFC) and the superior parietal lobe, which both play a fundamental role in WM processes, are among the regions that suffer the greatest age-related changes (Good et al., 2001). Similarly, the medial temporal lobe is particularly affected by the deleterious effects of age (Fjell, Westlye, et al., 2014; Fjell et al., 2013). Coupled with the PFC, this system includes the hippocampus, the entorhinal cortex, and the parahippocampal cortex and plays an essential role in several phases of long-term episodic memory. As well as encoding, storing, and recalling information, episodic memory includes other processes such as reconsolidation, which involves the reactivation of consolidated memories (usually through a reminder) to a labile state in which these memories can be modified before they restabilize (Schwabe, Nader, & Pruessner, 2014). Finally, the default mode network (DMN) is a set of brain regions which fluctuates synchronically when subjects are at rest and is deactivated during goal-oriented activity. The DMN comprises the prefrontal and posteromedial areas as well as temporal middle and medial areas, and is essential for memory functions. It is particularly vulnerable to the effects of advanced age, in which a progressive reduction in functional connectivity is observed between the main anterior and posteromedial cortical nodes (Andrews-Hanna et al., 2007; Vidal-Piñeiro, Valls-Pedret, et al., 2014) as well as with the hippocampal formation (Salami, Pudas, & Nyberg, 2014). This susceptibility may be related to the network’s central role as a system that subtends lifelong brain plasticity adaptations (Fjell, McEvoy, et al., 2014; Fjell et al., 2009). In summary, memory processing dysfunction is a common, important phenomenon in the elderly and has significant implications for health and for society as a whole. One suitable approach to help to counteract age-related cognitive impairment is the use of cognitive training, which focuses on improving specific cognitive functions through intensive practice of cognitive exercises. Cognitive training is restorative in nature, aiming to reinstate reserve brain capacities or to provide greater resilience against European Psychologist 2016; Vol. 21(1):41–54

neuropathology (Gates & Sachdev, 2014). Although randomized clinical trials are still scarce, meta-analyses and literature reviews indicate that cognitive training can significantly enhance cognitive function in healthy elders in terms of episodic memory, working memory (WM), executive functions (EFs), and processing speed (Gates, Fiatarone Singh, Sachdev, & Valenzuela, 2013; Kelly et al., 2014). The present review focuses on an additional approach which has recently been proposed for enhancing cognitive functions in aging: the use of noninvasive brain stimulation (NIBS) techniques. NIBS is able to obtain potential cognitive benefits in aging as it allows the external induction or modulation of plasticity-enhancing mechanisms. Therefore, it may well be a valid option for tackling age-related cognitive decline (Elder & Taylor, 2014; Gutchess, 2014), either alone or in combination with other tools that aim to enhance adaptive plasticity responses such as cognitive training (Bentwich et al., 2011; Park, Seo, Kim, & Ko, 2014) or physical interventions (Prakash, Voss, Erickson, & Kramer, 2015). Applied in the elderly population, these procedures may help to optimize the usage of preserved functional brain resources that are linked to the maintenance of cognitive performance (Nyberg, Lövdén, Riklund, Lindenberger, & Bäckman, 2012) or may engage compensatory mechanisms (Cabeza, Anderson, Locantore, & McIntosh, 2002) which can moderate impending agerelated or pathology-related brain changes (Bartrés-Faz & Arenaza-Urquijo, 2011). The present review summarizes the available evidence on working and declarative learning/memory enhancements reported with the use of NIBS in healthy elderly individuals (i.e., those without diagnoses of neuropsychiatric conditions). Previous studies have reported improvements in older adults with depression (Moser et al., 2002), in neuro-rehabilitation following stroke, and in neuropsychiatric or neurological conditions (Elder & Taylor, 2014; Flöel, 2014; Kuo, Paulus, & Nitsche, 2014). Findings involving the effects of NIBS on other cognitive domains in healthy older adults, such as language generation (Meinzer, Lindenberg, Antonenko, Flaisch, & Flöel, 2013; Meinzer, Lindenberg, Phan, et al., 2014), naming (Cotelli et al., 2010; Fertonani, Brambilla, Cotelli, & Miniussi, 2014; Ross, McCoy, Coslett, Olson, & Wolk, 2011), inhibitory responses (Harty et al., 2014), and motor learning (Zimerman et al., 2013), are not directly addressed in this review, but references are included when appropriate. Before focusing on the specific studies in this field, a general introduction to the relevant aspects of NIBS is provided. A thorough review of these techniques is beyond the scope of this manuscript, and readers are referred to several excellent articles already published on this topic (Dayan, Censor, Buch, Sandrini, & Cohen, 2013; Hallett, 2007; Stagg & Nitsche, 2011) including the ones published in this issue. Briefly, the NIBS techniques most commonly used in memory studies with older adults are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Other techniques such as transcranial alternating and random noise stimulation (tACS; tRNS) are also widely reported in the neuroscience literature. TMS can Ó 2016 Hogrefe Publishing

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be applied either using single pulses or in a repetitive fashion (repetitive TMS, rTMS) and is based on the principles of electromagnetic induction. A strong and short electric pulse of current passes through a coil placed over the person’s head, inducing a brief changing magnetic field. This in turn causes a secondary electric current in a nearby conducting tissue such as the brain. The effects of the secondary electrical currents can be sufficient to depolarize cortical neurons. The final outcome depends on the characteristics of the stimulation as well as on the functional properties of the targeted area (i.e., degree of activity) when stimulated. In contrast, tDCS uses constant low currents delivered to specific brain areas through a pair of electrodes. This has a neuromodulatory effect, possibly modifying membrane polarization and therefore the neuron firing threshold potential, and changing the cortical excitability in the targeted brain areas (Nitsche & Paulus, 2000). While the effects of NIBS depend on several parameters, it is generally accepted that high-frequency stimulation by TMS ( 5 Hz) and anodal tDCS increase cortical excitability, whereas low-frequency stimulation by TMS ( 1 Hz) and cathodal tDCS leads to cortical inhibition. Additionally, NIBS may produce brain changes in distant but functionally related regions, affecting the activity not only of discrete areas but also of entire brain networks (Bortoletto, Veniero, Thut, & Miniussi, 2015). Critically for cognitive neuro-enhancement, the effects of both tDCS and rTMS can persist after stimulation cessation – the so-called ‘‘after effects.’’ These are considered residual functional brain responses which can last for relatively prolonged periods and are thought to be mediated through the modulation of brain plasticity mechanisms related to long-term potentiation (LPT) and long-term depression-like (LTD) phenomena (Liebetanz, Nitsche, Tergau, & Paulus, 2002; Nitsche et al., 2003). However, it should be noted that it is still not clear how putative LTP/ LTD-like effects induced by NIBS correspond to the changes in brain activity or connectivity observed using functional neuroimaging techniques.

Methods, Search Criteria, and Studies Included Our search was performed using the PubMed database. We included studies available online up to December 15, 2014. The search used the following NIBS keywords: ‘‘Transcranial Magnetic Stimulation or TMS,’’ ‘‘theta-burst stimulation,’’ ‘‘transcranial direct current stimulation or tDCS,’’ ‘‘transcranial alternating current stimulation or tACS,’’ and ‘‘transcranial random noise stimulation or tRNS.’’ Further, we combined these with a term referencing elderly subjects: ‘‘aging,’’ ‘‘ageing,’’ ‘‘old adults,’’ ‘‘older adults,’’ and ‘‘elderly.’’ We reviewed the titles and abstracts from the resulting searches and selected those that referred to cognitive studies. Those that looked at cognitive enhancements associated with NIBS administration were reviewed in full.

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We excluded review reports and studies performed in samples where the age of participants was under 40 years. We also excluded studies of patients and of non-human subjects. Finally, the main review included investigations reporting or hypothesizing changes in brain function or activity associated with NIBS in working and episodic memory functions in the elderly. We identified eight articles that met the review criteria, and these are summarized in Table 1. A brief description of the main findings as well as the interpretation of the observed effects is provided in the next section.

Review of the Use of NIBS NeuroEnhancement Protocols in the Healthy Elderly In what we believe to have been the first published study aiming to improve declarative memory processes in nondemented older individuals (Solé-Padullés et al., 2006) used high-frequency repetitive TMS (rTMS; 5 Hz) over the PFC in a group of participants with subjective cognitive complaints. This investigation included a sham-controlled design with the administration of offline rTMS in the interval between two equivalent face-name associative learning tasks. Increased recognition memory performance was observed only after real stimulation. Further analyses of brain activity by functional magnetic resonance imaging (fMRI) were performed during the encoding task and evidenced greater bilateral prefrontal patterns of brain activity in the group that received real stimulation. Particularly during the baseline (pre-stimulation) encoding task, PFC activity was dominated by left-sided engagement during learning. In contrast, in the second equivalent fMRI session after TMS, areas of the right PFC became more activated. An unusual feature of this study, which may have influenced the results, was the use of a double-cone coil This device is known to be less focal than the more frequently employed figure-of-eight coil which allows dual hemisphere stimulation when positioned over the superior PFC. Therefore, the cognitive improvements observed were interpreted as evidence that rTMS could have intensified the expression of latent compensatory mechanisms by increasing the bilateral recruitment of the frontal cortex. This finding was consistent with the cognitive neuroscience models of aging (Cabeza, 2002). More specifically, the results were also consistent with classical fMRI observations (Cabeza et al., 2002; Reuter-Lorenz et al., 2000) and ‘‘causal mapping’’ rTMS studies. After altering brain activity through online rTMS (Bestmann et al., 2008; Rossi et al., 2004), the presence of a compensatory process was reported in the right hemisphere, while another study (Manenti, Brambilla, Petesi, Miniussi, & Cotelli, 2013) found that elderly with high cognitive performance relied more on the functional integrity of the right PFC when faced with cognitive demands. In a further report, data from the active stimulation group of the study mentioned above (Solé-Padullés et al., 2006)

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Sample

Stimulation type

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24 OA (ma: 72).

Vidal-Piñeiro et al., Brain Stimulation, 2014

Figure-of-eight coil. Single-session stimulation. Intermittent TBS, 80% AMT. Trains every 200 ms during 2 s repeated once every 10 s for a total of 20 repetitions. Total duration 3 min.

Double-cone coil. Single-session stimulation. rTMS 5 Hz, 80% MT. 10 trains lasting 10 s each Total duration 5 min.

Transcranial direct current stimulation (tDCS) studies Flöel et al., 20 OA (ma: 62.1). 1 mA for 20 min. Neurobiology of Aging, 2012

20 OA (ma: 67) pertaining to the active TMS group of the Solé-Padullés et al. (2006) study.

Peña-Gómez et al., PLoS One, 2012

Repetitive transcranial magnetic stimulation studies Solé-Padullés et al., 40 OA (ma: 67). Double-cone coil. Cerebral Cortex, Memory Single-session 2006 complaints stimulation. and low memory rTMS 5 Hz, function. 80% MT. 10 trains lasting 10 s each Total duration 5 min.

Study

Sham-controlled study. Crossover study, counterbalanced: all subjects underwent one sham and one real tDCS session a week apart.

Sham-controlled study. Mixed design: Between group factor: iTBS vs. sham stimulation. Within group factor: memory performance and fMRI activation before vs. after TMS.

Only real rTMS. Mixed design: Between group factor: presence or absence of ApoE e4 allele. Within group factor: memory performance and fMRI activation before vs. after TMS.

Sham-controlled study. Mixed design: Between group factor: real vs. sham TMS. Within group factor: memory performance and fMRI activation before vs. after TMS.

Stimulation design & parameters

Anodal electrode over right temporoparietal. Cathodal electrode over contralateral orbital. Online stimulation.

Left inferior frontal gyrus. Neuronavigated TMS. Offline stimulation.

Prefrontal cortex. Offline stimulation.

Stimulation site & parameters

Visuospatial learning.

Verbal encoding (words) task.

Visual associative (episodic) memory.

Function

Table 1. Summary of studies using NIBS neuro-enhancement protocols on memory function in elders

Object-location learning.

Perceptual vs. semantic encoding (level of processing).

Face-name learning task.

Task

iTBS increased fMRI activation specifically under semantic processing in the stimulation site as well as distally in posterior occipital and cerebellar areas.

No main TMS effects on accuracy or in reaction time on the memory task.

(Continued on next page)

Delayed free recall (1 week) but not learning or immediate recall was significantly better after a tDCS compared to sham.

After rTMS brain activity patterns of ApoE e4 carriers show higher resemblance to those of non-e4 carriers.

Increased brain activity in frontal and parietoocipital areas as measured by fMRI in the real TMS group.

Other results

Equivalent recognition memory improvement for both genetic groups.

Recognition memory improvement following real TMS.

Main result

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40 OA (ma: 69.7)

Park et al., Neuroreport, 2014

2 mA during 30 min per session, performed 5 times a week for 2 weeks. Sham-controlled study. Between group comparison, real tDCS (N = 20) vs. sham (N = 20). Both groups receive computer-assisted cognitive training during stimulation.

Sham-controlled study. Crossover: All subjects stimulated under three conditions: F3, F4, and sham in a counterbalanced order with a washout period of 24 h between sessions.

1.5 mA for 10 min.

25 OA (ma: 63.7)

Stimulation design & parameters

Berryhill & Jones, Neuroscience Letters, 2013

Stimulation type Sham-controlled study. Between group comparison, 4 groups: N = 16 OA and N = 16 young received sham or anodal (N = 8 in each group) stimulation over left/right DLPFC. N = 16 OA and N = 16 young received sham or anodal (N = 8 in each group) over left/right parietal.

Sample

Manenti et al., 32 OA (ma: 67.9); 1.5 mA Frontiers in 32 young (ma: 23.7) for 6 min. Aging Neuroscience, 2013

Study

Table 1. (Continued)

Two tDCS stimulators are used. Anodal tDCS over F3 and F4 and cathode attached on the nondominant arm. Online stimulation.

Anodal electrode (or sham) over F3 or F4, cathodal over contralateral check. Online stimulation.

Anodal electrode over left/right DLPFC or left right parietal. Cathodal electrode over the contralateral orbital. Online stimulation.

Stimulation site & parameters

Visual (symmetrical shapes) and verbal (consonants) WM tasks (2-back).

Presentation of abstract or concrete words to encode for latter recognition.

Task

Main task: Verbal Primary outcome: WM (letters) Working memory. 2-back task. Secondary outcomes: verbal memory, visual memory, attention, motor coordination.

Working memory.

Verbal episodic memory encoding.

Function

Improvements only in the active tDCS group were also observed in an attentional task (digit span).

Other results

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RT and accuracy improvement for the main task in the active tDCS group up to 28 days of completion of the training sessions.

Only highly educated elders benefited from tDCS regardless of the hemisphere stimulated and the type of WM task.

Compared to sham stimulation, faster RT amongst OA under left DLPFC or parietal tDCS. Faster RT for young subjects under both left and right DLPFC or parietal tDCS.

Main result

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Note. AMT: active motor threshold; atDCS: anodal tDCS; DLPFC: dorsolateral prefrontal cortex; F3: left frontal location according to the EEG 10-20 electrode positioning system; F4: right frontal location according to the EEG 10-20 electrode positioning system; fMRI: functional magnetic resonance imaging; Hz: hertz, ms: milliseconds; mA: miliampere; MT: motor threshold; OA: old adult, ma: mean age; RT: reaction times; rTMS: repetitive transcranial magnetic stimulation; TBS: theta-burst stimulation; tDCS: transcranial direct current stimulation; WM: working memory.

Groups that received real tDCS during reconsolidation show reduced forgetting on Day 3 and Day 30. 20 concrete words subject had to memorize on Day 1. Memory reconsolidation plus tDCS on Day 2 (24 hr latter) and memory recall on Day 3 (48 hr after learning session) and Day 30 (after 1 month). Verbal memory reconsolidation. Anodal tDCS to F3 and cathodal to supraorbital. Online stimulation. Sham-controlled study. Between group comparison. Three groups (N = 12) receive tDCS during memory reconsolidation: 1 - Anodal tDCS in the same room as in Day 1. 2 - Sham tDCS in the same room as in Day 1. 3 - Anodal tDCS in a different room and without memory reactivation. 36 OA (ma: 67) Sandrini et al., Frontiers in Aging Neuroscience, 2014

1.5 mA for 10 min.

Main result Task Function Stimulation site & parameters Stimulation design & parameters Stimulation type Sample Study

Table 1. (Continued)

No interaction between tDCS and reconsolidation memory effects.

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Other results

were reanalyzed to determine whether the main genetic risk factor for AD, the apolipoprotein E (APOE) e4 allele, had any effect on brain responses to rTMS (Peña-Gomez et al., 2012). In this sub-analysis, relevant differences appeared at the level of the reorganization of brain networks following brain stimulation in genetic subgroups. Specifically, among the individuals at genetic risk for AD, rTMS resulted in a robust reorganization of brain networks expressed during effortful encoding phases, and affected the functional organization of the DMN regions (investigated as a set of areas showing deactivation during cognitive activity). The most striking observation after TMS was that, despite clearly dissimilar patterns at baseline, the brain network topography was now similar in the group with the genetic risk factor and in the group without it. TMS thus normalized brain connectivity patterns in individuals at genetic risk for AD, a finding borne out by subsequent reports in patients with healthy aging (Meinzer et al., 2013) as well as in patients with mild cognitive impairment (MCI; Meinzer, Lindenberg, Phan, et al., 2014; Petersen, 2011). In these investigations, which focused on word generation tasks, anodal tDCS was able to attenuate the differences in brain activity and connectivity between the intervention and control groups, with few differences being observed between old and young adults or between MCI-affected and healthy older adults following stimulation. Although some previous studies have reported memory improvements in the elderly, others have failed to show any behavioral changes in spite of observing brain activity and connectivity modulation in response to NIBS. This lack of a behavioral impact coupled with a physiological effect of TMS is acknowledged in the literature. Here, when stimulation modulates the remote physiological response in a state-dependent manner but does not disrupt performance it should not be regarded as a null result, as it permits the study of functional relationships between areas that vary under different conditions, while avoiding the complications of interpreting the neural changes in terms of behavioral modulation. Thus, this approach makes it possible to study how the different areas relate to and influence each other under different behavioral states (Feredoes, Heinen, Weiskopf, Ruff, & Driver, 2011). Alternatively, when stimulation is applied offline, changes in physiological correlate without behavioral changes can be interpreted as the engagement of compensatory mechanisms (Ruff et al., 2009). Vidal-Piñeiro, Martin-Trias, et al. (2014) aimed to improve episodic memory during a task that included two levels of encoding (semantic vs. perceptual encoding strategies). For this purpose, TMS was applied over the left inferior frontal gyrus and in the interval between two memory tasks performed within the fMRI. We used intermittent theta-burst stimulation (iTBS), a patterned TMS stimulation that usually leads to excitatory post-effects (Huang, Edwards, Rounis, Bhatia, & Rothwell, 2005). Unexpectedly, iTBS did not lead to memory modulations, but taskdependent modifications in memory networks were observed. Application of iTBS enhanced cortical activity, both locally and in distal connected visual regions, Ó 2016 Hogrefe Publishing

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specifically during deep encoding trials. These findings were interpreted as evidence of a top-down circuit implicated in semantic-based encoding strategies which might be related to the observation of relatively preserved memory in aging when stimuli are semantically encoded (Logan, Sanders, Snyder, Morris, & Buckner, 2002). In another study, facilitation of episodic memory was observed in elderly participants following NIBS (Manenti, Brambilla, Petesi, Ferrari, & Cotelli, 2013). Using tDCS, the authors reported that when the anodal electrode was positioned on the left dorsolateral PFC or on the parietal region, but not in the corresponding areas in the right hemisphere, participants exhibited improved reaction times during a verbal memory recognition task. In a young group, the beneficial effect was found for stimulation of both left and right dorsolateral PFC and the parietal region. The authors interpreted this as evidence of enhanced verbal coded strategies supported by the left hemisphere in the elderly, which improved performance in the system with loss of regional specialization. In contrast, both hemispheres appeared to contribute equally to performance outcomes in young subjects, the left with verbal strategies and the right with visuospatial processes. Therefore, this study linked the cognitive improvement induced by NIBS in old adults to theories of bi-hemispheric compensation and models of dedifferentiation of functional specificity with advancing age (Park & Reuter-Lorenz, 2009). Sandrini and colleagues (2014) recently investigated the effects of tDCS on consolidated memories using a memory reconsolidation paradigm. The concept of reconsolidation highlights the fact that reactivation of consolidated memories through a cue forces the triggered memory into a transiently vulnerable state where it can be strengthened, disrupted, or updated for a short period (Alberini & Ledoux, 2013). Previous reports by the same group (Sandrini, Censor, Mishoe, & Cohen, 2013) using the same paradigm in young individuals showed that rTMS delivered to the DLPFC is able to induce long-lasting memory enhancements if applied during reconsolidation. In their study with elderly participants, 24 hr after the initial learning phase, the authors tested whether anodal tDCS on the left dorsolateral PFC could enhance the effects of reconsolidation of long-term memory performance. They showed that, compared with sham stimulation, active tDCS decreased the ‘‘forgetting rate’’ tested 48 hr and 1 month after the initial memory encoding. However, tDCS induced better long-term memory performance irrespective of whether the subjects underwent a period of memory reconsolidation in the form of a spatial contextual reminder. The ability to reinforce memories after acquisition raises the possibility that NIBS could be applied at different stages of the memory process, not only during external-oriented cognitive tasks. In addition, it might promote the use of NIBS as an adaptable memory enhancement tool when targeting daily routines. The right temporoparietal region is known to be involved in object-location learning. Consequently, Flöel

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and colleagues (2012) applied tDCS to this area while subjects learnt to identify the position of picture buildings in two-dimensional street maps. The authors observed that learning and immediate recall were not affected by tDCS, but that the real stimulation created better long-term (1 week) memory performance compared with sham. The authors suggested that tDCS might have increased hippocampal activity during object-location learning, thereby improving memory performance. The studies of both Sandrini (Sandrini et al., 2014) and Flöel (Flöel et al., 2012) suggest that the effects of tDCS interact with consolidation processes, in accordance with other studies in the literature which report behavioral improvements. For instance, using a complex motor skill learning task over five consecutive days in young individuals, Reis and colleagues (2009) observed benefits induced by anodal tDCS but only when considering offline measures (i.e., improvements between training sessions, reflecting consolidation of the learning period). However, in the specific case of elders this proposal is challenged by the findings of (Zimerman et al., 2013) and the previous study by Hummel (Hummel et al., 2010) which measured the performance of a set of motor skill tasks and motor skill learning, respectively, and reported improvements during online motor skill acquisition. Similarly, using a confrontation-naming task, Fertonani and colleagues (2014) observed greater beneficial online effects for older individuals than for younger ones. Altogether, the findings may be compatible with the interpretation that in young individuals, the fine-tuning of the cerebral systems during task performance would rule out any additional improvement, whereas improvement might be possible in the case of elder participants with ‘‘suboptimal’’ cognitive processing during task performance (Zimerman et al., 2013). Finally, two other studies focusing on the WM domain have used tDCS over the PFC cortex. (Berryhill & Jones, 2012) performed a sham-controlled experiment with anodal tDCS over the dorsolateral PFC (i.e., with the anodal electrode located in either F3 or F4 of the 10-20 EEG system) for 10 min prior to visuospatial and verbal WM tasks. They observed that tDCS improved WM performance on both tasks independently of the stimulation site (left or right PFC), but that this effect was only evident in individuals with high levels of education. The data were interpreted as evidence of the need for bilateral recruitment in order to obtain optimal cognitive performance in the elderly (Cabeza et al., 2002). Better educated individuals were more likely to recruit the PFC bilaterally, leading to better cognitive performance, a pattern that may have been facilitated by the electrode montage used. In the other report of WM, (Park et al., 2014) applied bilateral anodal prefrontal (F3, F4) tDCS during computer-assisted cognitive training. In a sham-controlled study, the authors observed greater improvements in verbal WM and in attention (digit span forward) under real tDCS than in sham stimulation. Notably, the cognitive benefits lasted for almost a month after stimulation.

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Summary of the Use of NIBS NeuroEnhancement Protocols in the Elderly In summary, despite the scarcity of the literature and the heterogeneity of the reports available, a number of promising studies have recorded memory enhancements with the use of NIBS. With regard to the memory paradigms and, stimulation procedures employed and the areas targeted, at least three studies have demonstrated relatively high Hedge’s g (which was calculated in accordance with the published guidelines (Lakens, 2013) and represents an unbiased method for calculating effect sizes that ultimately relies on the means and the standard deviations) effect sizes (> 0.60) for NIBS stimulation over memory functions (Flöel et al., 2012; Sandrini et al., 2014; Solé-Padullés et al., 2006). In addition, these studies were conducted by independent research teams and included sham groups, randomization procedures, and complete reports of the stimulation effects. Therefore, the common sources of possible bias should be minimal, making the available data more robust. In terms of the site of stimulation, most of the review studies targeted the PFC, although parietal executive regions have also been successfully stimulated (i.e., Flöel et al., 2012). These studies were either designed or discussed in view of their potential to mediate successful compensatory responses in the aging brain through putative additional frontal lobe activity recruitments. In addition to reflecting the capacity of NIBS to transiently improve memory functions, the studies reviewed should help further our understanding of the neurobiology of current models of cognitive neuroscience of aging. Notably, NIBS allows inference of brain-cognition causality, a property that makes this technique invaluable for testing aging models such as the Hemispheric Asymmetry Reduction in Older Adults (HAROLD; Cabeza, 2002) which initially emerged in the light of correlational evidence deriving from functional imaging studies. The ability of NIBS techniques to causally study neurocognitive models of aging is not limited to memory functions. For instance, the abovementioned study by Meinzer and colleagues (2013) proved that, compared to young individuals, elders showed right frontal lobe overrecruitment during verbal fluency tasks and that anodal tDCS reductions of brain activity in the right medial frontal gyrus were associated with behavioral improvements. This report indicates that in the case of linguistic functions the increase in right frontal lobe areas (leading to a possible ‘‘hemispheric reduction asymmetry’’ pattern compared to young individuals) is not compensatory but rather counterproductive. Other studies oriented toward neuro-enhancement objectives provided valuable information about the neural changes occurring in specific subgroups of elderly participants. In this vein Berryhill and Jones (2012) observed that beneficial effects on WM performance following tDCS were only observed among highly-educated elders. This result, obtained with NIBS research, may shed further light on the ‘‘cognitive reserve’’(CR) hypothesis, since education is the most common proxy used to reflect CR, and since greater CR is related to more efficient usage European Psychologist 2016; Vol. 21(1):41–54

of brain networks in healthy aging (see Bartrés-Faz & Arenaza-Urquijo, 2011 for a review). While an association between increased excitability and neuro-enhancement is often implicitly assumed, extreme caution should be taken when supposing that increased PFC activity will invariably enhance compensatory mechanisms and improve performance. First, as mentioned above, evidence is now emerging of neural mechanisms underlying the effects of positive stimulation on word generation tasks, in the form of reductions in aberrant hyperactivity both in healthy old adults (Meinzer et al., 2013) and in old adults with MCI (Meinzer, Jähnigen, Copland, et al., 2014). Hence, cognitive enhancement may also be attributed to increased neural efficiency (Kar & Wright, 2014), which may involve a fine-tuning of the neural resources managing inter-network interactions; for instance, facilitating switching between tasks of different levels of difficulty (Meinzer, Lindenberg, Sieg, et al., 2014; Peña-Gómez, Sala-Llonch, et al., 2012). Other explanatory frameworks, such as reduced activity in competitive areas, may also account for the differences in cognition after NIBS (Iuculano & Cohen Kadosh, 2013). Alternatively, improvements caused by NIBS might be driven by conceptually related but nonmutually exclusive cognitive functions in the elderly such as increased inhibitory control, which would highlight the role of top-down processes (Harty et al., 2014). Overall, the use of NIBS to enhance memory functions in aging appears to be promising. Indeed, robust scientific evidence is accumulating, despite being limited to a small number of studies. As Flöel suggested in relation to neurological conditions (Flöel, 2014) a greater number of multicenter studies using standardized procedures will be needed to facilitate comparison. At the same time, efforts must be made to further understand the biological underpinnings of the cognitive effects of stimulation and to take into account how inter- and intra-individual variability in responses to NIBS influence the results of a given study protocol (see below).

Are NIBS-Induced Memory Enhancements Relevant Outside the Laboratory Setting? In the previous section, we reviewed studies that used NIBS in order to improve memory processes in healthy elderly individuals, and briefly interpreted the findings. However, statistically significant findings do not necessary translate into clinically significant results. A central question when assessing the ability of NIBS to induce long-term improvements in memory functions in the elderly is whether the benefits obtained persist beyond the treatment itself. Investigations in young individuals (Meinzer, Jähnigen, Copland, et al., 2014; Reis et al., 2009) and patients (Fridriksson, Richardson, Baker, & Rorden, 2011) have demonstrated that the cognitive and behavioral effects of NIBS can last for months. In healthy elderly individuals, most studies have not tested potential longer-term effects, except for the three studies mentioned above (Flöel et al., 2012; Park et al., 2014; Sandrini et al., 2014) which reported memory Ó 2016 Hogrefe Publishing

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advantages after stimulation lasting from one week to one month. These results suggest that brain stimulation can modulate long-term memory consolidation processes in the elderly, possibly affecting persistent modifications in synaptic connections (Stagg & Nitsche, 2011). A relevant factor when considering the potential positive long-term benefits of NIBS effects is whether it should be delivered in single or repeated sessions. It has been proposed that repetitive stimulation may surpass the transient plasticity modulation obtained with isolated sessions, leading to more robust cerebral changes, such as the durable protein synthesis modulations thought to underlie long-term memory gains. Indeed, studies in young volunteers (Meinzer, Jähnigen, Copland, et al., 2014) and elderly participants (Zimerman et al., 2013) have demonstrated more successful learning of motor learning tasks when tDCS was applied during multiple sessions. Prolonged memory benefits (up to 4 weeks) were also observed after tDCS was applied to patients with AD for five consecutive days (Boggio et al., 2012). Given that the use of repeated NIBS sessions is more costly for the clinician, convincing domain-specific evidence is still needed to demonstrate that the potential benefits over single-session NIBS in the elderly are real. Methodologically, another key question that will need to be addressed is the optimal spacing interval between stimulations. Research into the long-term plasticity phase in animal models has considered brain stimulation training sessions repeated in a relatively tight-spaced period. In parallel, the use of repetitive NIBS sessions in human beings, spaced at intervals of several minutes (i.e., 3–30 min), has obtained greater and more persistent changes in neuroplasticity responses than NIBS applied over more prolonged spacing periods, with the latter appearing to produce more labile and reversible plasticity changes (Goldsworthy, Pitcher, & Ridding, 2014). Therefore, further research should investigate whether frequently applied NIBS sessions result in more durable and stable cognitive benefits than single or more widely spaced sessions. Another relevant issue regarding the implementation of NIBS is the potential for increased benefits if it is applied concomitantly with cognitive interventions. Cognitive training is emerging as a valid method for the control of agerelated cognitive dysfunction (Gates et al., 2013; Kelly et al., 2014). Given that both cognitive training and NIBS can enhance adaptive plasticity mechanisms, one might hypothesize that they may produce synergistic positive effects on cognitive outcomes when applied together (Ditye, Jacobson, Walsh, & Lavidor, 2012). Indeed, among young participants, there is evidence that brain stimulation in combination with cognitive training not only amplifies the benefits of multi-session training regarding the trained task but also improves other conceptually similar untrained cognitive skills (Cappelletti et al., 2013). These results indicate that NIBS may enhance the ecological validity of cognitive training by expanding near transfer effects. The area promises to have many therapeutic applications, and because the limited transfer benefits after cognitive training may be more pronounced in the elderly (Dahlin, Nyberg, Bäckman, & Neely, 2008), it may be particularly interesting for Ó 2016 Hogrefe Publishing

cognitive aging studies. However, while at least three studies have reported the positive adjuvant effects of TMS or tDCS on memory or executive functions in AD (Bentwich et al., 2011; Penolazzi et al., 2014; Rabey et al., 2013), to date only one study (Park et al., 2014) has assessed the combined effect of NIBS with cognitive training in aging. In that study, which involved 10 daily sessions of tDCS and cognitive training, the authors reported that the WM improvements were maintained for up to 28 days after stimulation sessions. However, there was no comparison group (i.e., tDCS without cognitive training), which means that no further conclusions regarding a potential synergistic effect can be drawn. Clearly, future research should address the potential of combining NIBS with cognitive training in memory studies of aging.

The Practical Use of NIBS for the Psychologist: Advantages and Limitations So far we have highlighted the value of NIBS for the investigation of memory functions in aging, including its potential as a therapeutic tool against age-related cognitive dysfunction. In this section, we discuss some of the more practical issues concerning the versatility and limitations of one technique or procedure over another. The aim is to provide guidance for psychologists aiming to initiate clinical research in this field. First, most of the studies (see Table 1) to date have used tDCS rather than TMS. At the time of writing, other promising methods with potential for modulating cognitive functions (including memory processes) in human beings such as transcranial random and alternate current stimulation (Garside, Arizpe, Lau, Goh, & Walsh, 2014; Jaušovec & Jaušovec, 2014) are yet to be applied in the cognitive neuroscience of aging. Beyond the scientific issues, this bias (i.e., the use of tDCS rather than TMS) may be related to practical considerations. Despite the fact that both techniques are relatively safe and cause minimal patient discomfort, tDCS is known to have fewer adverse effects than TMS (Bruononi et al., 2011; Fertonani, Ferrari, & Miniussi, 2015; Rossi, Hallett, Rossini, & Pascual-Leone, 2009). Additionally, tDCS is both more portable and cheaper than TMS and requires less technical skill. It can also be more readily coupled with cognitive testing/learning paradigms. TMS is less portable, particularly if neuronavigation is needed to take advantage of its inherently greater spatial (and temporal) resolution. Additionally, tDCS allows for better placebo stimulation (Davis, Gold, Pascual-Leone, & Bracewell, 2013). TMS pulses produce marked somatic sensations that are difficult to emulate in a placebo; in tDCS, on the other hand, it is possible to switch the current off 10–30 s after sensations associated with the onset of tDCS (i.e., itching or tingling) appear that blur the distinction for the participants between sham and placebo procedures. Yet, at high intensity tDCS, this placebo procedure is much less effective, especially when subjects are not naïve to stimulation; this may potentially induce a bias, particularly in crossover studies (Fertonani et al., 2015; O’Connell et al., 2012). European Psychologist 2016; Vol. 21(1):41–54

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TMS and tDCS can each be applied for long enough to induce brain plasticity responses, and each may enhance the eventual consolidation of long-term memory effects. However, tDCS may again be more suitable for use over relatively extended periods during the learning, consolidation, or retrieval of memory processes, whereas rTMS is usually applied ‘‘offline.’’ For ethical and safety issues it should be stressed that, while both techniques have been shown to be safe, guidelines are only available for TMS (Rossi et al., 2009). Importantly, the techniques are not tailored for specific populations such as pediatric or elderly subjects, as they exhibit particular neurodevelopmental, neurophysiological, and molecular characteristics that may have unforeseen interactions with NIBS effects and side effects (Davis, 2014; Sibille, 2013). Thus, the current recommendation is that caution should be taken, particularly if protocols with high frequencies and/or intensities are used. Protocols should include proper training in the basic technical principles of NIBS, its applicability, and ethical and regulatory issues. An important limitation of the use of NIBS is that significant gaps remain in the mechanistic understanding of the intermediate steps in the cascade of events linking the effects of brain stimulation at a microscopic level with gross changes in behaviour (Bestmann, de Berker, & Bonaiuto, 2015). In the field of cognitive aging, this may even be aggravated by the impact of age on the structure, function, and neurochemical properties of the brain. Knowledge of the basic neurophysiology and cognitive neuroscience of the aging process is not only a basic requirement of further investigation, but will also help with the development of specific hypotheses and with the design of novel stimulation approaches. The aging brain presents highly marked individual differences in terms of atrophy, resilience capacity, and network usage. Although a number of theoretical approaches have been proposed to explain these interindividual differences, the available knowledge of NIBS such as novel methodological approximations and cognitive modeling (Miniussi, Harris, & Ruzzoli, 2013) might allow the refinement of hypotheses and objectives and ultimately optimize the cognitive results achieved with stimulation. In this regard, there is extensive evidence that the effects of NIBS are modulated by several inter- and intra-individual characteristics (Li, Uehara, & Hanakawa, 2015; Maeda, Keenan, Tormos, Topka, & Pascual-Leone, 2000), and that cognitive improvements in one cognitive domain triggered by stimulation may be associated with concomitant interference in other cognitive tasks or measures (Iuculano & Cohen Kadosh, 2013). These aspects should not be seen as limitations of NIBS, but as basic knowledge that will help to define specific methodological procedures in our attempts to target specific regions and determine the optimal parameters for its use. This basic knowledge of the characteristics of the technique, together with theory-based cognitive neuroscience hypotheses of aging, will not only help to predict outcomes, but should ultimately help to optimize the neuro-enhancement properties of brain stimulation in the elderly.

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Conclusions In the present article, we have reviewed the scientific evidence of the ability of NIBS to obtain memory improvements among healthy older adults. We have also described the mechanisms underlying these enhancements proposed in the literature, and have highlighted some approaches that may improve the efficacy of the technique, such as its application across multiple sessions and its concurrent use with learning paradigms or cognitive training strategies. Overall, the use of NIBS to enhance memory among old adults represents a promising approach for both research and clinical psychology. However, the effects of NIBS are likely to be highly dependent on interindividual differences on specific biomarkers, such as neuroimaging-based measures of brain functional and structural integrity, or the presence of particular genetic variations (i.e., APOE, BDNF). Hence, the abovementioned need for harmonized multicentric protocols should also address the issue of inter- and intra-individual variability as a means to identify individuals who can benefit the most from NIBS interventions.

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Park, D. C., & Reuter-Lorenz, P. (2009). The adaptive brain: Aging and neurocognitive scaffolding. Annual Review of Psychology, 60, 173–196. doi: 10.1146/annurev.psych.59. 103006.093656 Park, S.-H., Seo, J.-H., Kim, Y.-H., & Ko, M.-H. (2014). Longterm effects of transcranial direct current stimulation combined with computer-assisted cognitive training in healthy older adults. Neuroreport, 25, 122–126. doi: 10.1097/WNR.0000000000000080 Peña-Gómez, C., Sala-Lonch, R., Junqué, C., Clemente, I. C., Vidal, D., Bargalló, N., . . . Bartrés-Faz, D. (2012). Modulation of large-scale brain networks by transcranial direct current stimulation evidenced by resting-state functional MRI. Brain Stimulation, 5, 252–263. doi: 10.1016/j.brs. 2011.08.006 Peña-Gomez, C., Solé-Padullés, C., Clemente, I. C., Junqué, C., Bargalló, N., Bosch, B., . . . Bartrés-Faz, D. (2012). APOE status modulates the changes in network connectivity induced by brain stimulation in non-demented elders. PloS One, 7, e51833. doi: 10.1371/journal.pone.0051833 Penolazzi, B., Bergamaschi, S., Pastore, M., Villani, D., Sartori, G., & Mondini, S. (2014). Transcranial direct current stimulation and cognitive training in the rehabilitation of Alzheimer disease: A case study. Neuropsychological Rehabilitation, 25, 1–19. doi: 10.1080/09602011.2014.977301 Petersen, R. C. (2011). Clinical practice. Mild cognitive impairment. The New England Journal of Medicine, 364, 2227–2234. doi: 10.1056/NEJMcp0910237 Plassman, B. L., Langa, K. M., Fisher, G. G., Heeringa, S. G., Weir, D. R., Ofstedal, M. B., . . . Wallace, R. B. (2008). Prevalence of cognitive impairment without dementia in the United States. Annals of Internal Medicine, 148, 427–434. Prakash, R. S., Voss, M. W., Erickson, K. I., & Kramer, A. F. (2015). Physical activity and cognitive vitality. Annual Review of Psychology, 66, 769–797. doi: 10.1146/annurevpsych-010814-015249 Rabey, J. M., Dobronevsky, E., Aichenbaum, S., Gonen, O., Marton, R. G., & Khaigrekht, M. (2013). Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: A randomized, double-blind study. Journal of Neural Transmission, 120, 813–819. doi: 10.1007/ s00702-012-0902-z Reeves, S., Bench, C., & Howard, R. (2002). Ageing and the nigrostriatal dopaminergic system. International Journal of Geriatric Psychiatry, 17, 359–370. doi: 10.1002/gps. 606 Reis, J., Schambra, H. M., Cohen, L. G., Buch, E. R., Fritsch, B., Zarahn, E., . . . Krakauer, J. W. (2009). Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proceedings of the National Academy of Sciences of the United States of America, 106, 1590–1595. doi: 10.1073/pnas. 0805413106 Reuter-Lorenz, P. A., Jonides, J., Smith, E. E., Hartley, A., Miller, A., Marshuetz, C., & Koeppe, R. A. (2000). Age differences in the frontal lateralization of verbal and spatial working memory revealed by PET. Journal of Cognitive Neuroscience, 12, 174–187. Reuter-Lorenz, P. A., & Sylvester, C. Y. (2005). The cognitive neuroscience of aging and working memory. In R. Cabeza, L. Nyberg, & D. Park (Eds.), The cognitive neuroscience of aging (pp. 186–217). New York, NY: Oxford University Press. Rönnlund, M., Nyberg, L., Bäckman, L., & Nilsson, L.-G. (2005). Stability, growth, and decline in adult life span development of declarative memory: Cross-sectional and longitudinal data from a population-based study. Psychology and Aging, 20, 3–18. doi: 10.1037/0882-7974.20.1.3 Ó 2016 Hogrefe Publishing

Ross, L. A., McCoy, D., Coslett, H. B., Olson, I. R., & Wolk, D. A. (2011). Improved proper name recall in aging after electrical stimulation of the anterior temporal lobes. Frontiers in Aging Neuroscience, 3, 16. doi: 10.3389/fnagi. 2011.00016 Rossi, S., Hallett, M., Rossini, P. M., & Pascual-Leone, A. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology, 120, 2008–2039. doi: 10.1016/ j.clinph.2009.08.016 Rossi, S., Miniussi, C., Pasqualetti, P., Babiloni, C., Rossini, P. M., & Cappa, S. F. (2004). Age-related functional changes of prefrontal cortex in long-term memory: A repetitive transcranial magnetic stimulation study. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 24, 7939–7944. doi: 10.1523/JNEUROSCI. 0703-04.2004 Ruff, C. C., Blankenburg, F., Bjoertomt, O., Bestmann, S., Weiskopf, N., & Driver, J. (2009). Hemispheric differences in frontal and parietal influences on human occipital cortex: Direct confirmation with concurrent TMS-fMRI. Journal of Cognitive Neuroscience, 21, 1146–1161. doi: 10.1162/ jocn.2009.21097 Sala, S., Agosta, F., Pagani, E., Copetti, M., Comi, G., & Filippi, M. (2012). Microstructural changes and atrophy in brain white matter tracts with aging. Neurobiology of Aging, 33, 488–498.e2. doi: 10.1016/j.neurobiolaging.20.10.04.027 Salami, A., Pudas, S., & Nyberg, L. (2014). Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging. Proceedings of the National Academy of Sciences of the United States of America, 111, 17654–17659. doi: 10.1073/pnas.1410233111 Sandrini, M., Brambilla, M., Manenti, R., Rosini, S., Cohen, L. G., & Cotelli, M. (2014). Noninvasive stimulation of prefrontal cortex strengthens existing episodic memories and reduces forgetting in the elderly. Frontiers in Aging Neuroscience, 6, 289. doi: 10.3389/fnagi.2014.00289 Sandrini, M., Censor, N., Mishoe, J., & Cohen, L. G. (2013). Causal role of prefrontal cortex in strengthening of episodic memories through reconsolidation. Current Biology: CB, 23, 2181–2184. doi: 10.1016/j.cub.2013.08.045 Schwabe, L., Nader, K., & Pruessner, J. C. (2014). Reconsolidation of human memory: Brain mechanisms and clinical relevance. Biological Psychiatry, 76, 274–280. doi: 10.1016/ j.biopsych.2014.03.008 Sibille, E. (2013). Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brainrelated disorders. Dialogues in Clinical Neuroscience, 15, 53–65. Solé-Padullés, C., Bartrés-Faz, D., Junqué, C., Clemente, I. C., Molinuevo, J. L., Bargalló, N., . . . Valls-Solé, J. (2006). Repetitive transcranial magnetic stimulation effects on brain function and cognition among elders with memory dysfunction. A randomized sham-controlled study. Cerebral Cortex, 16, 1487–1493. doi: 10.1093/cercor/bhj083 Spreng, R. N., Wojtowicz, M., & Grady, C. L. (2010). Reliable differences in brain activity between young and old adults: A quantitative meta-analysis across multiple cognitive domains. Neuroscience and Biobehavioral Reviews, 34, 1178–1194. doi: 10.1016/j.neubiorev.2010.01.009 Stagg, C. J., & Nitsche, M. A. (2011). Physiological basis of transcranial direct current stimulation. The Neuroscientist: A Review Journal Bringing Neurobiology, Neurology and Psychiatry, 17, 37–53. doi: 10.1177/1073858410386614 United Nations. (2013). World Population Prospects The 2012 Revision (Publication No. ESA/P/WP.228). Retrieved from http://esa.un.org/unpd/wpp/Publications/) European Psychologist 2016; Vol. 21(1):41–54

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Vidal-Piñeiro, D., Martin-Trias, P., Arenaza-Urquijo, E. M., Sala-Llonch, R., Clemente, I. C., Mena-Sánchez, I., . . . Bartrés-Faz, D. (2014). Task-dependent activity and connectivity predict episodic memory network-based responses to brain stimulation in healthy aging. Brain Stimulation, 7, 287–296. doi: 10.1016/j.brs.2013.12.016 Vidal-Piñeiro, D., Valls-Pedret, C., Fernández-Cabello, S., Arenaza-Urquijo, E. M., Sala-Llonch, R., Solana, E., . . . Bartrés-Faz, D. (2014). Decreased Default Mode Network connectivity correlates with age-associated structural and cognitive changes. Frontiers in Aging Neuroscience, 6, 256. doi: 10.3389/fnagi.2014.00256 Zacks, R. T., Hasher, L., & Li, K. Z. H. (2000). Human memory. In F. I. M. Craik & T. A. Salthouse (Eds.), The handbook of aging and cognition (2nd ed., pp. 293–357). Mahwah, NJ: Erlbaum. Zimerman, M., Nitsch, M., Giraux, P., Gerloff, C., Cohen, L. G., & Hummel, F. C. (2013). Neuroenhancement of the aging brain: Restoring skill acquisition in old subjects. Annals of Neurology, 73, 10–15. doi: 10.1002/ana.23761

Received February 6, 2015 Accepted July 10, 2015 Published online March 23, 2016

Didac Vidal-Piñeiro undertook his doctorate studies at the University of Barcelona and has recently moved to University of Oslo as a postdoctoral researcher. His research is focused in the cognitive neuroscience of aging field and has expertise in the use and analyses of several structural and functional MRI techniques as well as in the application of noninvasive brain stimulation techniques such as tDCS and TMS.

David Bartrés-Faz Department of Psychiatry & Clinical Psychobiology Faculty of Medicine University of Barcelona Casanova, 141 08036 Barcelona Spain Tel. +34 9340 3929 5 Fax +34 9340 3529 4 E-mail dbartres@ub.edu

About the authors David Bartrés-Faz is Associate Professor at the Faculty of Medicine, University of Barcelona. His research interests have been focused on the study of cognitive and neuroimaging correlates of aging and boundaries with dementia, applying noninvasive brain stimulation techniques to modulate brain networks.

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Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

Transcranial Electrical Stimulation in Post-Stroke Cognitive Rehabilitation Where We Are and Where We Are Going Silvia Convento,1 Cristina Russo,1 Luca Zigiotto,1,2 and Nadia Bolognini1,2,3 1

Department of Psychology, University of Milano Bicocca, Milan, Italy, Laboratory of Neuropsychology, IRCCS Istituto Auxologico Italiano, Milan, Italy, 3 NeuroMi â&#x20AC;&#x201C; Milan Center for Neuroscience, Milan, Italy

Abstract. Cognitive rehabilitation is an important area of neurological rehabilitation, which aims at the treatment of cognitive disorders due to acquired brain damage of different etiology, including stroke. Although the importance of cognitive rehabilitation for stroke survivors is well recognized, available cognitive treatments for neuropsychological disorders, such as spatial neglect, hemianopia, apraxia, and working memory, are overall still unsatisfactory. The growing body of evidence supporting the potential of the transcranial Electrical Stimulation (tES) as tool for interacting with neuroplasticity in the human brain, in turn for enhancing perceptual and cognitive functions, has obvious implications for the translation of this noninvasive brain stimulation technique into clinical settings, in particular for the development of tES as adjuvant tool for cognitive rehabilitation. The present review aims at presenting the current state of art concerning the use of tES for the improvement of post-stroke visual and cognitive deficits (except for aphasia and memory disorders), showing the therapeutic promises of this technique and offering some suggestions for the design of future clinical trials. Although this line of research is still in infancy, as compared to the progresses made in the last years in other neurorehabilitation domains, current findings appear very encouraging, supporting the development of tES for the treatment of post-stroke cognitive impairments. Keywords: cognitive rehabilitation, stroke, tDCS

Cognitive rehabilitation refers to the rehabilitation of neuropsychological disorders of cognitive functions, including disorders of language, spatial perception, attention, memory, calculation, praxis, and visual perception, which represent frequent consequences of acquired brain damage, in particular of stroke (Stuss, Winocur, & Robertson, 2008). Post-stroke cognitive impairments cause persistent disability for many individuals that results in a loss of independence, disruption in normal activities and social relationships, and they may represent an obstacle to physical rehabilitation; consequently, they represent a major issue for health system and a financial problem for society

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in terms of need for assistance. Reducing this burden requires the development of effective cognitive rehabilitation strategies. The clinical relevance of post-stroke cognitive rehabilitation is well recognized (Cicerone et al., 2005; Stuss et al., 2008). Nevertheless, the majority of the available treatments seems unsatisfactory: after completing the rehabilitation route, most patients still exhibit some degree of cognitive impairment, showing a little transfer of benefits to daily living (e.g., Bowen, Hazelton, Pollock, & Lincoln, 2013; das Nair & Lincoln, 2007; Pollock et al., 2011; West, Bowen, Hesketh, & Vail, 2008). As consequence, there is a growing need to find out novel

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rehabilitation approaches, or to optimize those available. In this context, transcranial Electrical Stimulation (tES) has attracted the attention of neuropsychologists as potential therapeutic tool for the treatment of post-stroke cognitive deficits (Miniussi & Vallar, 2011). The clinical interest in tES is supported, first of all, by its feature of being a neuromodulator technique that can noninvasively modulate and interact with neuroplasticity (e.g., Brunoni et al., 2012; Paulus, 2011). Neuroplasticity refers to the adaptive capacity of the central nervous system to continuously acquire new skills and shape its structure and functions in response to environmental demands; it is at the basis of learning in normal conditions, as well as it represents the main mechanism guiding recovery after brain injury (e.g., Nahum, Lee, & Merzenich, 2013; Nudo, 2003; Pascual-Leone, Amedi, Fregni, & Merabet, 2005). Second, an increasing amount of evidence documents the usefulness of tES for improving different cognitive functions in healthy human beings, including language, attention, learning, sensory processing, creativity, decision making, and even social abilities (Cohen Kadosh, 2014; Vallar & Bolognini, 2011). Starting from this evidence, and considering the promising results obtained in other domains of neurological rehabilitation, such as the treatment of motor disorders and chronic pain (Brunoni et al., 2012), tES is now under investigation as an instrument for promoting the recovery of cognitive impairments in stroke patients. By inducing long-lasting (excitatory or inhibitory) changes in cortical excitability (Paulus, 2011), tES can be used to drive the neural restoration of the impaired cognitive function, to strengthen compensatory mechanisms that may substitute the lost function, and to suppress maladaptive plasticity hampering recovery (Bliss & Cooke, 2011; Fregni & Pascual-Leone, 2007). So far, language disorders have attracted the greatest effort for the translation of tES in rehabilitation. Instead, the exploitation of tES to treat other post-stroke cognitive impairments is still in its infancy, with clinical evidence limited to a few preliminary, ‘‘proof-of-concept’’ studies, primarily exploring short-living effects of a single application of tES in small clinical samples. Clinical trials still lag behind: the effects of multiple tES sessions, their interaction with specific behavioral rehabilitation procedures, and the long-term retaining of performance improvements have been scarcely addressed. So far, transcranial Direct Current Stimulation (tDCS) has been the main tES method used in cognitive rehabilitation. TDCS consists in the delivery of a homogeneous direct current field of small intensity ( 1–2 mA) directly to the head. The stimulation is delivered transcranially by a battery-driven current stimulator through a pair of electrodes positioned on the scalp. Basically, neurons respond to tDCS by altering their firing rates. In fact, tDCS can induce bidirectional, polarity-dependent changes in cortical excitability: anodal tDCS has been shown to increase cortical excitability (increasing spontaneous neuronal firing rates), while cathodal tDCS has the opposite effect (for reviews of technical and safety aspects of tDCS see: Brunoni et al., 2011, 2012; Miniussi et al., 2008; Nitsche et al., 2008; Paulus, 2011). European Psychologist 2016; Vol. 21(1):55–64

The aim of the present review is to offer an overview of the current state of art of the research concerning the use of tDCS in post-stroke cognitive rehabilitation, with the exception of aphasia and memory disorders (see in this issue, the reviews by Crinion et al. and Bartrés-Faz et al.), highlighting its clinical potentiality and discussing the main issues that need to be taken into account for improving this field of research.

TES in Cognitive Rehabilitation: State of Art Unilateral Spatial Neglect Unilateral Spatial Neglect (USN) is the most frequent and disabling neuropsychological syndrome caused by lesions to the right hemisphere. USN comprises different, dissociable deficits, but the main clinical feature is the patients’ inability to report sensory events occurring in the left side of space, contralateral to the side of the cerebral lesion, and to perform actions in that portion of space (Vallar & Bolognini, 2014). Left USN is recognized as a significant disabling deficit, which may persist chronically and is associated with poor outcome measures on functional activities, in turn posing considerable obstacles to successful rehabilitation (Di Monaco et al., 2011). The theoretical framework that has guided the use of tES in USN rehabilitation refers to the seminal model of hemispheric competition (‘‘rivalry’’) originally proposed by Kinsbourne. Accordingly, USN is interpreted as the result of ‘‘imbalance in opponent systems that control for lateral orientation and action’’ (Kinsbourne, 1987, pp. 69). Under normal conditions both parietal cortices exert reciprocal inter-hemispheric inhibition. A damage to the right parietal cortex causes a breakdown of such physiological dynamic inhibitory balance between the two hemispheres; the result is a pathological overactivation of the left-hemisphere disinhibition, which aggravates the bias to attend to the right side, and hence to neglect the left side (Hesse, Sparing, & Fink, 2011). In this framework, tDCS has been used with the aim of counteracting such poststroke inter-hemispheric imbalance, either by up-regulating the excitability of the damaged parietal cortex or by downregulating the hyperactivation of in the contralesional, intact hemisphere (Hesse et al., 2011; Vallar & Bolognini, 2014). Sparing and colleagues (2009) tested the value of these two approaches. Ten patients with chronic left USN (time post-onset: 2.9 months) due to a right-hemisphere lesion received a single application of anodal tDCS (1 mA, 10 min) to the right posterior parietal cortex (PPC), of cathodal tDCS to the left PPC, and of sham tDCS. Both the inhibitory-cathodal tDCS of the unaffected (left) PPC and the excitatory-anodal tDCS of the affected (right) PPC reduced symptoms of visuospatial neglect, as assessed by means of a visual detection task and a line bisection task. Importantly, the lesion size negatively correlated with the Ó 2016 Hogrefe Publishing

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magnitude of tDCS-induced improvement, in particular following cathodal tDCS of the unaffected hemisphere (Sparing et al., 2009). Similarly, an improvement in cancellation tasks was obtained in 15 subacute (time post-onset: 46 days) patients with left USN, by stimulating the ipsilesional PPC with anodal tDCS (2 mA, 20 min) (Ko, Han, Park, Seo, & Kim, 2008). More recently, the effects of bi-hemispheric (also called ‘‘dual-mode’’) tDCS over the parietal cortices (1 mA, 20 min; anode over the ipsilesional PPC, cathode over the contralesional PPC) were assessed in 10 chronic stroke patients (time post-onset: 27.8 months; Sunwoo et al., 2013). Bi-hemispheric tDCS allows to simultaneously excite one hemisphere and inhibit the other, by applying the anode over a given area of one hemisphere and the cathode over the homologous area of the contralateral hemisphere (e.g., Bolognini et al., 2011; Vines, Cerruti, & Schlaug, 2008). Compared to sham and anodal tDCS of the right PPC, the bi-hemispheric stimulation brought about a greater reduction of the rightward bias in the line bisection task. Instead, no improvement was observed at the star cancellation test. Then, in a double-blind, sham-controlled, single case study (Brem, Unterburger, Speight, & Jäncke, 2014), the bi-hemispheric parietal tDCS (1 mA, 20 min) was combined with a cognitive therapy for USN (i.e., training of saccades toward the left hemi-space and of visual exploration, reading combined with optokinetic stimulation). A patient with a subacute ischemic stroke of the right posterior cerebral artery (time post-onset: 23 days) suffering from left USN, hemianopia, and hemiparesis underwent daily sessions of the therapy for 4 weeks; at the second week, sham tDCS was added to the therapy, while real tDCS was introduced at the third week. After real tDCS, covert attention allocation toward the left hemi-space (measured through the ‘‘Posner paradigm’’) and alertness significantly improved, while for line bisection and copying only a qualitative improvement was observed, as compared to sham tDCS. Again, star cancellation performance did not vary with tDCS. Improvements in covert attention and alertness were maintained at the follow-up assessments, namely at 1 week and at 3 months after the end of the treatment, whereas improvements in paper-pencil tasks were transient, returning to baseline levels at follow-ups. Activities of daily living (ADLs) improved only at the 3-month follow-up (Brem et al., 2014). Taken together, current results are very promising, encouraging further investigations of tES for USN rehabilitation. The anodal tDCS over the damaged parietal cortex and the cathodal tDCS of the intact parietal cortex appear both effective for improving neglect symptoms either at standard clinical tests or at experimental tasks; at least for the bisection task, an advantage of the bi-hemispheric stimulation was shown. Noteworthy, hitherto the effects of tDCS were assessed only with respect to extra-personal visuospatial deficits of the USN syndrome, while the chance of modulating even personal neglect, nonvisual (tactile, auditory) disorders, and other deficits frequently associated to

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this syndrome (e.g., extinction to bilateral stimulation, anosognosia) still needs to be addressed.

Visual Field Loss Unilateral post-chiasmatic lesions determine a contralesional loss of part of the field of view on the same side in both eyes. Visual field loss greatly affects patient’s quality of life, including difficulties in driving, reading, and navigation (Goodwin, 2014). Spontaneous recovery is quite rare and usually incomplete (Zhang, Kedar, Lynn, Newman, & Biousse, 2006). There are three therapeutic approaches for visual field loss: restorative training, optical aids, and compensatory training (Goodwin, 2014). The Vision Restoration Therapy (VRT) is a restorative approach that aims at reducing the visual field loss through repetitive and intensive stimulation of the socalled transition zone, an area of residual vision bordering the blind and the intact visual fields, which it is thought to be only partially deafferented, hence reversibly damaged (Kasten, Wüst, Behrens-Baumann, & Sabel, 1998; Sabel & Kasten, 2000). VRT has been shown to lead to an extension of visual field borders of nearly 5° after 6 months of treatment (Kasten, Wüst, Behrens-Baumann, & Sabel, 1998). A randomized, double-blind, demonstration-of-concept study tested the adjuvant effects of tDCS on the VRT in 12 patients with chronic (time post-onset: 30 months) unilateral post-chiasmatic visual field loss (homonymous hemianopia or quadrantanopia) (Plow, Obretenova, Fregni, Pascual-Leone, & Merabet, 2012). During VRT, anodal or sham tDCS (2 mA, 30 min) was delivered over the occipital pole to target both affected and unaffected hemispheres; 1-hr training sessions were carried out three times per week for 3 months. Anodal tDCS induced a greater expansion of the visual field ( 4°), as compared to sham tDCS (namely, VRT alone, visual field expansion ﬃ0.7°), along with a larger increase in stimulus detection accuracy in the blind hemifield. After the 3-month treatment, patients who received real tDCS showed greater benefits even at vision-related ADLs, in particular visuo-motor activities, while no amelioration was found for quality of life (QOL) measures. The improvement at the ADLs was maintained at the last evaluation, 6 months after the end of the treatment. Intriguingly, only patients stimulated with sham (but not real) tDCS subjectively reported a visual field change (Plow, Obretenova, Fregni, et al., 2012). Such mismatch between changes in objective measures and patients’ own subjective impressions of improvement could be due to a placebo effect or, as suggested by the authors, to methodological issues (e.g., small sample size). Furthermore, anodal tDCS accelerated the recovery of stimulus detection within the first month of VRT, while the shift in the visual field border was only evident after 3 months of treatment (Plow, Obretenova, Jackson, & Merabet, 2012). TDCS-induced improvements in visual field outcomes did not generalize to contrast sensitivity and reading performance, suggesting that the adjuvant use of occipital stimulation is effective in modulating

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VRT-specific outcomes, but measures testing the generalizability of the benefits induced by the training (Plow, Obretenova, Jackson, et al., 2012). In a single case study in a patient with chronic poststroke hemianopia (time post-onset: 72 months), the same research group showed that the visual field expansion by the 3-month VRT plus anodal occipital tDCS was associated to an increase of perilesional occipital activity, around the anode area, as measured with fMRI (Halko et al., 2011). Finally, a double-blind, sham-controlled study in 12 patients with occipital ischemic lesions (time post-onset: 18.4 months) and homonymous visual field defects (hemianopia, quadrantanopia, or paracentral scotoma) showed an increase of visual motion sensitivity in the unaffected hemifield after anodal tDCS (1.5 mA, 20 min) applied over the primary visual cortex on five consecutive days; the improvement was maintained up to 4 weeks, at the time of the last follow-up (Olma et al., 2013). Such amelioration of visual motion perception in the intact hemifield could reflect the reactivation of residual intact neurons in the visual system, which may act as a compensational strategy for damaged visual functions of stroke-related neuronal loss (Olma et al., 2013). However, no clues about the amelioration of visual deficits, nor about the impact of tDCS-induced ipsilesional visual improvement on them, are reported in this work, leaving the clinical relevance of the results uncertain. In conclusion, tDCS appears a valuable tool for optimizing and increasing the effects of VRT. TDCS not only augments the visual recovery brought about by VRT, but it seems also useful for shortening the duration of this therapy: a visual field expansion emerges when the VRT is reduced by one fourth of its standard duration if tDCS is combined to it. Future research should verify if other visual rehabilitation approaches, as, for instance, training for hemianopic dyslexia or oculomotor exploration, can benefit from concurrent tDCS.

Apraxia Limb apraxia is a cognitive-motor disorder, usually due to a left-hemisphere lesion, involving a loss or impaired ability to conceptualize or program motor sequences to perform purposeful limb movements, typically with the upper limbs, in the absence of sensory or motor deficits (Heilman & Rothi, 1993). Limb apraxia impairs the ability of managing activities of daily living and has an adverse influence on physical and language therapies (West et al., 2008). Treatments involve both restorative and compensatory approaches, such as the ‘‘rehabilitation of gesture execution’’ method (Smania et al., 2006) or teaching patients internal and external strategies (i.e., oral and written verbalizations) that can compensate the apraxic deficit during execution of everyday activities (Cantagallo, Maini, & Rumiati, 2012). In a recent double-blind, sham-controlled study in six patients with a left-hemisphere lesion (time post-onset: 12.5 months), we have explored the effect of anodal tDCS (2 mA, 10 min) applied over the left PPC, and over the right motor cortex (M1) on ideomotor apraxia (Bolognini European Psychologist 2016; Vol. 21(1):55–64

et al., 2015). Ideomotor apraxia is characterized by deficits in properly performing tool-use pantomimes and communicative gestures; this impairment is typically identified by asking patients to perform movements on verbal command or to imitate intransitive, symbolic, and nonsymbolic gestures (Barbieri & De Renzi, 1988; Wheaton & Hallett, 2007). Compared to sham tDCS, anodal tDCS of both the contralesional M1 and of the ipsilesional PPC reduced the time required to perform skilled movements with the left, ipsilesional (unimpaired) hand, at the Jebsen Hand Function Test. However, only the left parietal stimulation was able to reduce the planning time required for imitating gestures, and to improve the accuracy of intransitive gesture imitation, at a standard clinical test (see also, Convento, Bolognini, Fusaro, Lollo, & Vallar, 2014). Importantly, the improvement of imitation performance brought about by left parietal tDCS was influenced by the size of the parietal lobe damage: the larger the parietal damage, the smaller the improvement (Bolognini et al., 2015). A sham-controlled, clinical trial explored the effects of anodal tDCS (Marangolo et al., 2011) of the left inferior frontal cortex (IFC) on the recovery of apraxia of speech, an oral motor speech disorder affecting the ability to translate speech plans into motor plans (Wertz, Lapointe, & Rosenbek, 1984). Three non-fluent aphasic patients with severe apraxia of speech (time post-onset: 22 months) were treated; noteworthy, they had a left-hemisphere lesion, but none of them had damage to the IFC where the tDCS anode was positioned. Every patient received five daily sessions of anodal tDCS (20 min, 1 mA) and of sham tDCS, which were delivered during language training for articulatory difficulties. Anodal tDCS augmented the traininginduced improvement of articulatory gestures for the correct production of syllables and words, as compared to sham tDCS. At the three follow-up assessments (1 week, 1 and 2 months post-treatment) patients showed retention of the achieved improvement only for anodal tDCS, which did not show any decrement in response accuracy, suggesting a long-term recovery of the patients’ articulatory disturbances (Marangolo et al., 2011). Similarly results (Marangolo et al., 2013) were obtained by applying a bi-hemispheric frontal tDCS (anode over the left IFC, and cathode over the right IFC; 20 min, 2 mA) during a language therapy in eight patients with chronic apraxia of speech (time post-onset: 29 months). These studies support the view that apraxic disorders can be improved by stimulating with tDCS the left frontal-parietal network involved in the representation of motor programs and their conversion into motor acts (e.g., Convento et al., 2014; Heilman & Rothi, 1993). The beneficial tDCS effect (nearly a mean 20% of improvement of imitation accuracy) in ideomotor limb apraxia induced by 10 min of stimulation encourages clinical trials testing the long-term effects of multiple tDCS applications (Bolognini et al., 2015).

Dysexecutive Syndrome Patients with frontal lobe damage usually suffer from the so-called dysexecutive syndrome, which resembles Ó 2016 Hogrefe Publishing

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different cognitive impairments including deficits of working memory, reasoning and problem solving, cognitive flexibility, as well as behavioral disinhibition and general cognitive decline (Elliott, 2003). These impairments all point to a breakdown of a series of coordination processes that takes place in a distributed network of cortical and subcortical frontal structures (Elliott, 2003). Within this network, the dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal region (VLPFC) represent core structures for implementing complex cognitive functions; in particular, the DLPFC is crucial for working memory, arousal, and attention, and for behavioral control (D’Esposito et al., 1998; Miller & Cohen, 2001). The neuromodulation of this area was shown to improve working memory in healthy subjects (Fregni et al., 2005) and patients with Parkinson’s disease (Boggio et al., 2006). Jo and colleagues (2009) explored the effect of anodal tDCS (2 mA, 30 min) of the left, contralesional, DLPFC on verbal working memory disorders in 10 patients with a right-hemisphere lesion (time post-onset: 2.4 months). Only the Mini-Mental Status Examination, digit and visual span tests were used to screen cognitive functions. Just one application of anodal tDCS improved patients’ performance at a working memory task, as compared to sham tDCS (Jo et al., 2009). Instead, Kang, Baek, Kim, and Paik (2009) explored the usefulness of the anodal stimulation (2 mA, 20 min) of the left DLPFC on attention, which was assessed with a Go/ No-Go task. In this study, 10 chronic (time post-onset: 18 months) patients with heterogeneous brain lesions (unilateral left- or right-hemisphere lesion, or bilateral), suffering from post-stroke cognitive decline (Mini-Mental Status Examination score 25), were tested. One application of anodal tDCS improved patients’ response accuracy in the Go/No-Go task, whereas sham stimulation did not; such improvement emerged 1 hr after tDCS, and it was maintained at the follow-up 3 hrs post-stimulation. Changes in reaction times were comparable for the two stimulations. Unfortunately, the authors did not look for differences in the individual responses to tDCS, notwithstanding the heterogeneity of the brain lesions in their sample. Bueno, Brunoni, Boggio, Bensenor, and Fregni (2011) reported a marked improvement of mood, as well as of memory and executive functions, after 10 sessions of anodal tDCS (2 mA, 30 min) of the left DLPFC in a single case study. The patient was a 48-year-old woman who suffered from an ischemic stroke affecting the left basal ganglia and the left insula; she presented with a mild right hemiparesis and post-stroke depressive symptoms (including psychomotor retardation, apathy, and malaise), which emerged 3 months after stroke. The above evidence, together with results from studies in healthy subjects about tDCS effects on other frontal functions, such as on decision-making behavior (Fecteau et al., 2007), planning ability (Dockery, Hueckel-Weng, Birbaumer, & Plewnia, 2009), vigilance (Nelson, McKinley, Golob, Warm, & Parasuraman, 2014), and multitasking performance (Filmer, Mattingley, & Dux, 2013), strongly supports the potential of tDCS for the treatment of post-stroke dysexecutive disorders, as well as for other neurological conditions Ó 2016 Hogrefe Publishing

in which the functioning of the frontal areas is compromised, as, for instance, Traumatic Brain Injury. Given the involvement of the DLPFC in different cognitive and emotional functions, it will be important to further explore whether the stimulation of this area can also affect different clinical outcomes, beyond the specific primary impairment under investigation.

Disorders of Body Representation Body representation disorders are frequently observed after stroke, and they also required clinical attention in the rehabilitation setting. Although there is no evidence about the use of tES for their treatment, some clues come from the study of Phantom Limb Syndrome (PLS). The amputation of a limb may induce the sensation that the amputated or missing limb is still attached to the body (phantom limb awareness), as well as specific sensory and kinesthetic sensations (phantom sensations), including pain referred to the absent limb (Flor, Nikolajsen, & Jensen, 2006; Hunter, Katz, & Davis, 2003). PLS has been interpreted as the result of the reorganization of the neural network involved in body representation and awareness (Berlucchi & Aglioti, 1997; Flor et al., 2006). While the reorganization of sensorimotor cortical areas plays a major role in the development of phantom limb pain (Flor et al., 2006), the phenomenological experience of having a phantom limb seems to be associated to an abnormally increased excitability of the deafferented PPC, likely due to a release of parietal neurons from inhibitory control (Kew et al., 1994). Support to this hypothesis has been recently provided by using tDCS: the cathodal stimulation (2 mA, 15 min) of this area may induce a short-living (up to 90 min) reduction of the intensity of non-painful phantom sensation, as assessed in a group of seven patients with unilateral lower or upper limb amputation (Bolognini, Olgiati, Maravita, Ferraro, & Fregni, 2013). This evidence not only supports the existence of a relationship between the level of excitability of the PPC and the emergence of phantom sensation, but it also opens up new opportunities for the use of tDCS in disorders of body representation considering that PPC lesions can cause both negative (e.g., disownership of body parts) and positive symptoms (e.g., supernumerary limbs, autoscopic phenomena) related to a derangement of corporeal awareness (e.g., Berlucchi & Aglioti, 1997; Bolognini, Convento, Rossetti, & Merabet, 2013; Vallar & Ronchi, 2009).

Upcoming Directions Defining the state of art of tES in cognitive rehabilitation, and discussing its efficacy, is quite trivial, considering the paucity of evidence in this field, which is mostly related to studies conducted in small samples of patients, using heterogeneous approaches and different outcome measures. Most importantly, the majority of such works features themselves as pilot experiments, testing the efficacy of a single European Psychologist 2016; Vol. 21(1):55–64

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application of tDCS, hence not addressing the issue of the long-term maintenance of the cognitive gains, or their generalization to activities of daily living and functional independence. It is evident that future research is needed to determine the clinical relevance of tES in post-stroke cognitive rehabilitation. However, after recognizing these limitations, some considerations can be put forward, also in light of the progresses made in the last years in other neurorehabilitation domains (e.g., Brunoni et al., 2012; Sandrini & Cohen, 2013). In some studies, the choice of the stimulation mode (e.g., anodal vs. cathodal) and the target area was guided by classical anatomo-functional models of neuropsychological syndromes, such as the model of limb apraxia put forward at the beginning of the 20th century by Liepmann (1977), and the model of ‘‘inter-hemispheric rivalry’’ proposed by Kinsbourne (1987) for USN; in these cases, tES not only has corroborated such neurological, brain-based models of cognitive functions, but it has also highlighted their validity in neurorehabilitation. The choice of the tES protocol has been also based on neuroimaging findings in healthy subjects evidencing that a specific cerebral region is involved in a given cognitive function, hence following modular paradigms, in which complex cognitive functions are thought to be mediated by independent brain areas. Future studies will need to take into account the increasing number of evidence suggesting that most cognitive functions are mediated by widely distributed areas functioning in parallel (Fuster, 2000; Sporns, 2014), as well as recent interpretation of neuropsychological syndromes in terms of a breakdown of functional connectivity in cortical networks (He et al., 2007). In light of this, a challenging advance could be the use of tES to stimulate the connections between areas, rather than a single area, in order to produce changes in brain connectivity that may affect the processing in the impaired cognitive network (Luft, Pereda, Banissy, & Bhattacharya, 2014). Another important step will be the identification of the factors that may predict the patient’s response to tES. For instance, Jung, Lim, Kang, Sohn, and Paik (2011) showed that the severity of the language disorder can foresee responders versus nonresponders to the combined use of tDCS and speech therapy: the minor the language impairment, the greater the benefits by tDCS (Jung et al., 2011). Moreover, it was observed that the time elapsed from stroke is not related to the improvement of apraxic functions brought about by tDCS in chronic patients (Bolognini et al., 2015). Nevertheless, it may play a major role in acute and subacute stages, when the patient’s clinical condition is typically more instable. With respect to the lesion profile, while the overall size of the lesion may reduce the behavioral benefit brought about by parietal tDCS in USN (Sparing et al., 2009), it seems that, more than the lesion volume, it is the extension of the damage affecting the area targeted by tDCS that may predict its efficacy. Indeed, apraxic patients with extensive left parietal lesions show a smaller improvement by left parietal tDCS, while the volume of their lesion is less relevant in determining their behavioral outcome (Bolognini et al., 2015).

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It is worth mentioning that cognitive rehabilitation is typically driven by the characteristics of the neuropsychological symptoms identified by special batteries of tests designed to measure cognitive functioning following brain injury. However, the implementation of tES in cognitive rehabilitation will probably require to go beyond the neuropsychological assessment, looking for neurophysiological markers of either altered cognitive functioning or of functional integrity in the stroke brain; the chance of tracking local and network changes associated with tES enhancement will be also valuable for refining tES protocols (e.g., Romero Lauro et al., 2014; Veniero, Bortoletto, & Miniussi, 2014). Generalization of the treatment effects represents the key goal of any rehabilitation approach; so far, the transfer of tES improvement of cognitive disorders to activities of daily living has been addressed by few studies (Brem et al., 2014; Plow, Obretenova, Fregni, et al., 2012; Plow, Obretenova, Jackson, et al., 2012). On the other hand, given that tES lacks spatial focality (e.g., Brunoni et al., 2012; Wagner et al., 2007), and considering that a given area may be involved in different cognitive processes, it is advisable to measure not only tES effect on the cognitive deficit under investigation, but also on other related cognitive processes. A few examples follow. We have recently shown that anodal tDCS of the left parietal cortex improves ideomotor apraxic functions, but not phonemic fluency, which also involves left-hemisphere activity (Bolognini et al., 2015). Conversely, a study exploring the effect of the combined use of motor cortex stimulation and bilateral robotic training on hemiparesis found an unexpected improvement of language functions (Hesse et al., 2007); Marangolo and coworkers (2011) showed that the anodal tDCS of the left IFC improved the targeted deficit, namely speech apraxia, but it also increased oral production in two out of three patients, and written naming and word writing under dictation in one patient. Another critical issue is ‘‘when’’ tES should be used in cognitive rehabilitation. So far, tDCS was primarily used in patients in a chronic stage of illness, and to a lesser extent in subacute patients; for both, its efficacy was overall confirmed as reviewed above. Hypothetically, neuromodulatory approaches may also be useful to strengthen the reorganization of the neural circuits subtending spontaneous recovery, or to prevent the insurgence of maladaptive plastic phenomena, in the acute post-stroke stage. The issue of the time of the tDCS use in cognitive rehabilitation is also of interest considering the difficulty to engage patients in high demanding cognitive therapies in the acute and subacute phases, as early after stroke there is an important decrease of attentional resources (Loetscher & Lincoln, 2013; Stapleton, Ashburn, & Stack, 2001). An impairment of attention itself may represent a main obstacle for cognitive treatment, even in chronic patients. Hence, the amelioration of attentional abilities should represent a therapeutic priority. In some cases, tES could represent the only affordable way to improve attention, since it does not require an active involvement of the patient in the therapy. Additionally, tES could be used for reducing the time

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required for beginning a specific, intensive, cognitive intervention later on, in turn increasing the patient’s response to the subsequent training. On the other hand, evidence from post-stroke motor rehabilitation indicates that tDCS is overall effective in the chronic (more than 3 months from stroke onset) and subacute (less than 3 months from stroke) phases of stroke, while being ineffective in acute patients (within the first 3 days of symptom onset, see for a review, Marquez, van Vliet, McElduff, Lagopoulos, & Parsons, 2015). Given the limited number of studies in neuropsychological research, with the majority of them not controlling for the effect of the time elapsed from stroke on the patients’ response to tDCS, any prediction of the clinical (and likely different) utility of tDCS in the different stages of illness (acute, subacute, chronic) remains purely speculative for cognitive rehabilitation. Finally, most of the current studies have primarily assessed the therapeutic effects of tES delivered alone, without coupling it with any behavioral training. This is of course a necessary starting point for the determination of the area to stimulate, and how to stimulate it (i.e., anodal, cathodal, bi-hemispheric). But it is important to consider that the use of tES as surrogate of cognitive trainings is likely suboptimal, as tES may activate neural circuits in an unspecific way. Rather, the future research should focus on the possibility of coupling tES-specific cognitive training in order to achieve additive clinical improvements (Miniussi & Vallar, 2011). The rationale of this approach, as originally proposed by Bolognini, Pascual-Leone, and Fregni (2009) for motor rehabilitation, is that practice of a cognitive task may be more effective in using the (surviving) neural mechanisms subserving training-dependent plastic changes, if pertinent areas of the cortex are facilitated by neuromodulation. Given that both strategies, learning and cortical stimulation, share similar mechanisms of action for inducing neuroplasticity, their combination might be more beneficial than their use alone (Bolognini et al., 2009). Importantly, this approach implies to know which are the mechanisms activated by the cognitive therapy in order to be able to target, and in turn strengthen, them with tES. Cognitive rehabilitation involves two essential processes: the restoration of functions damaged by stroke, which implies a neuronal reorganization (or plasticity) in a task-specific neuronal architecture that takes place during learning or relearning within a damaged cognitive system, and the development of compensatory strategies to learn how to do things differently when functions cannot be restored to pre-injury level. This last case implies a cognitive reorganization since the patient uses a different set of cognitive processes to perform the same task either because a new cognitive procedure has been learned or because of increased demands on normal cognitive processes (Munoz-Cespedes, Rios-Lago, Paul, & Maestu, 2005; Price, Mummery, Moore, Frackowiak, & Friston, 1999). Obviously, these two processes require a differential use of tES: if the goal is to restore an impaired cognitive function, the plastic processes involved in the recovery of such function should be identified and primed by tES. Instead, cognitive reorganization may require using tES to facilitate Ó 2016 Hogrefe Publishing

the acquisition of a new strategy, likely by stimulating a system spared by the lesion. Additionally, the combined use of tES and cognitive training requires a careful consideration of dosage parameters, among which current intensity, duration of stimulation, and its timing with respect to the training (Brunoni et al., 2012; Fregni et al., 2015). Indeed, the cognitive effects of tDCS are dependent on the current intensity, and there is evidence for timing-dependent plasticity regulation in the human (motor) cortex (Brunoni et al., 2012). Such factors represent a source of variability and, importantly, may result in a deterioration of performance. Therefore, the long-term effects of multiple applications of tDCS, their interaction with specific learning stages during a cognitive therapy, the optimal parameters of stimulation, including safety issues (Brunoni et al., 2011), still remain to be addressed in cognitive rehabilitation.

Conclusions The evidence reviewed above fosters a further, in-depth, exploration of tES to confirm the usefulness of this neuromodulatory tool for the treatment of different cognitive impairments in stroke patients. This line of research will not only enrich cognitive therapies, where there is a pressing need for their betterment, but it will also offer novel clues on the plastic changes featuring injured cognitive systems, the mechanisms underpinning their post-stroke recovery, and clues on how to interact with them in order to drive the enhancement of cognitive functioning after brain injury.

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S. Convento et al.: Transcranial Electrical Stimulation in Stroke Rehabilitation

Silvia Convento is currently a postdoctoral fellow at the Baylor College of Medicine, Houston, TX, USA. She uses noninvasive brain stimulation techniques to study neural mechanisms of multisensory integration.

Vines, B. W., Cerruti, C., & Schlaug, G. (2008). Dualhemisphere tDCS facilitates greater improvements for healthy subjects’ non-dominant hand compared to unihemisphere stimulation. BMC Neuroscience, 9, 103. Wagner, T., Fregni, F., Fecteau, S., Grodzinsky, A., Zahn, M., & Pascual-Leone, A. (2007). Transcranial direct current stimulation: A computer-based human model study. Neuroimage, 35, 1113–1124. Wertz, R. T., Lapointe, L. L., & Rosenbek, J. C. (1984). Apraxia of speech in adults: The disorders and its management. Orlando, FL: Grune and Stratton. West, C., Bowen, A., Hesketh, A., & Vail, A. (2008). Interventions for motor apraxia following stroke. Cochrane Database of Systematic Reviews, 1, CD004132. Wheaton, L. A., & Hallett, M. (2007). Ideomotor apraxia: A review. Journal of Neurological Sciences, 260, 1–10. Zhang, X., Kedar, S., Lynn, M. J., Newman, N. J., & Biousse, V. (2006). Natural history of homonymous hemianopia. Neurology, 66, 901–905.

Luca Zigiotto is a student at the Specialization School in Neuropsychology, University of Milano Bicocca, Milan, Italy. His research interests include the rehabilitation of post-stroke cognitive and motor disorders with behavioural approaches and noninvasive brain stimulation.

Received November 30, 2014 Accepted March 13, 2015 Published online March 23, 2016 About the authors Nadia Bolognini is Assistant Professor of Psychobiology and Physiological Psychology at the Department of Psychology of the University of Milano Bicocca and Senior Researcher at the Laboratory of Neuropsychology, IRCSS Istituto Auxologico Italiano. Dr. Bolognini is leading a research group investigating the cognitive and neural architecture of multisensory perception in the healthy and injured human brain and the therapeutic applications of noninvasive brain stimulation (i.e., rehabilitation of post-stroke cognitive and motor disorders, neuropathic pain).

Nadia Bolognini Department of Psychology University of Milano Bicocca Piazza dell’Ateneo Nuovo 1 Building U6 20126 Milano Italy Tel. +39 02 6448-3922 Fax +39 02 6448-3706 E-mail nadia.bolognini@unimib.it

Cristina Russo is a PhD student in Experimental Psychology, Linguistic and Cognitive Neuroscience at the University of Milano Bicocca. Her research interests include investigating motor learning in healthy and stroke patients by means of noninvasive brain stimulation and the use of crossmodal illusions in post-stroke rehabilitation.

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Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

Transcranial Direct Current Stimulation as a Novel Method for Enhancing Aphasia Treatment Effects Jennifer T. Crinion Institute of Cognitive Neuroscience, University College London, UK Abstract. Neuromodulation is an exciting area of development. Currently, there is significant interest in academia, industry, and clinical practice where an effective and acceptable transcranial direct current stimulation (tDCS) kit for use in clinical rehabilitation would offer much benefit to patients’ treatment. In this review, I discuss the latest group studies investigating current tDCS methods for enhancing aphasia treatment effects in post-stroke (sub-acute and chronic) and primary progressive aphasia (PPA) patient populations. This field is still new, and many more investigations with larger samples of patients are needed. Nevertheless, in the studies completed to date, on-line tDCS paired with language rehabilitation was feasible, safe, well tolerated, and sham controlled. Results on the effectiveness of tDCS at boosting recovery outcomes are preliminary but promising with a number of themes emerging. I highlight some of these themes and future directions toward identifying those patients who are likely to respond to specific tDCS and behavioral therapies. This would provide an empirical basis from which to investigate specific aphasia interventions in future multicenter clinical trials and could greatly improve the quality of aphasia treatment for stroke and PPA patients. Keywords: aphasia, PPA, stroke, tDCS, treatment

Being able to communicate is something most of us take for granted. But when a person has aphasia (acquired language disorder), most commonly caused by stroke, this becomes a source of profound frustration and anxiety for them and their families. While some people do recover, many do not. Aphasia is an unpleasant disorder, with a high social cost (Lam & Wodchis, 2010). Patients with impoverished speech are more likely to withdraw socially and suffer from depression (Northcott & Hilari, 2011). Speech and language disorders are the most feared outcome by patients at risk of stroke (Samsa et al., 1998). Indeed, aphasia is the second most common major impairment after stroke, with a prevalence of 250,000 in the UK and 1 million in the USA. Speech and language therapy (SALT) is effective at treating aphasia. The recent Cochrane review (Brady, Kelly, Godwin, & Enderby, 2012) concluded ‘‘Significant differences [SALT vs. no SALT] were evident in measures of 2016 Hogrefe Publishing

spoken language.’’ Treatment of aphasia can also improve post-stroke depression (Ayerbe, Ayis, Rudd, Heuschmann, & Wolfe, 2011). Importantly, therapy-driven gains can be made at any point after stroke, not just the early phase (Moss & Nicholas, 2006). As such, SALT works (Brady et al., 2012), but the big issue is making sure aphasic patients with language impairments have access to the correct therapies. Indeed, aphasia may respond to therapy many months and years after the stroke occurs, but a very large dose is required to improve. Meta-analysis studies show that aphasic patients need to complete around 100 hr of behavioral therapy to significantly improve their real-world communicative outcomes (Bhogal, Teasell, & Speechley, 2003). Unfortunately, provision of SALT is far below that needed to provide optimal rehabilitation (Code & Heron, 2003) and the majority of patients do not get the correct dose (Code, 2003; Code & Heron, 2003). Depressingly, European Psychologist 2016; Vol. 21(1):65–77 DOI: 10.1027/1016-9040/a000254

J. T. Crinion: tDCS Adjunct to Aphasia Treatment

most patients in the UK get around 10 hr total therapy input from the national healthcare service – NHS (Code, 2003). This is very disabling and frustrating for patients and their families. It can impair patient’s participation and compliance with rehabilitation programs for associated disabilities (Hilari, 2011; Hilari, Needle, & Harrison, 2012; Jette, Warren, & Wirtalla, 2005). This is unacceptable and healthcare commissioners need to address this growing unmet need urgently. However, it is not economically feasible to solve this unmet need by massively increasing the amount of SALT face-to-face time. To address how the treatment of aphasia might be made more effective, researchers are now investigating using an emerging, safe, low-cost brain stimulation method called transcranial direct current stimulation (tDCS). The aim is to test whether tDCS paired with SALT is an effective and acceptable method to boost aphasic patients’ language functioning. Research to date has primarily assessed whether aphasic stroke patients can improve their spoken language function with targeted and sustained computer delivered practice (Palmer et al., 2012) in combination with tDCS brain stimulation technology. For a more general overview and background to this topic, readers are directed to de Aguiar, Paolazzi, and Miceli’s (2015) recent review paper of the role of brain stimulation parameters, aphasia behavioral treatment, and patient characteristics. In contrast, this review focuses on detailing the recent on-line tDCS studies enhancing aphasia treatment effects in both post-stroke and primary progressive aphasia (PPA) patient populations. Only the latest group studies (minimum six patients) that have used on-line tDCS as an adjunct to SALT in aphasia treatment have been included. It begins with studies of (1) chronic aphasia post-stroke as this is where we have most evidence to date. Studies are discussed according to which brain region was targeted with tDCS – (a) left hemisphere peri-lesional cortices, (b) right hemisphere language cortices, and (c) dual/ bi-hemisphere stimulation. The next two sections cover studies in (2) sub-acute post-stroke aphasia and (3) primary progressive aphasia (PPA). The final section highlights emerging themes and future directions for brain stimulation as a novel therapeutic intervention in aphasia treatment.

online with specific synaptic activation may be necessary. Indeed, there is a precedent for combining on-line tDCS with anomia (word-finding problems) treatment with positive results. The hypothesis underlying this approach is that tDCS itself will not produce any lasting changes in language function; instead, it temporarily creates a state that optimizes learning or, in the case of aphasic patients, relearning and rehabilitation. Consistent with this hypothesis, longer-term consolidation of these learning/relearning processes requires pairing of tDCS with training (co-stimulation) to promote Hebbian learning (Reis et al., 2009). This, in turn, could enable the short-lasting gain observed from a single session of tDCS paired with training to accumulate with repeated sessions and eventually lead to a permanent improvement in function. Supporting behavioral evidence comes from facilitatory effects observed in multiple-exposure tDCS studies of healthy participants learning new information and associations (e.g., de Vries et al., 2010; Fiori et al., 2011; Floël, Rosser, Miichka, Knecht, & Breitenstein, 2008). Specifically for language learning, anodal stimulation applied to left Broca’s area online during the acquisition phase of an artificial grammar enhanced subjects’ performance at detecting syntactic violations along with an increased use of rule-based decision making (de Vries et al., 2010). Similarly, anodal stimulation applied to left Wernicke’s area during acquisition of an artificial lexicon increased the rate and overall success of language learning compared to sham stimulation (Floël et al., 2008). In aphasic patients it is hoped that tDCS could lead to additional improvements in language function, on top of the main effect of SALT by boosting natural learning processes and lead to better recovery outcomes. Interestingly, most tDCS studies in chronic aphasic stroke patients have focused on the treatment of speech production (see Table 1). This approach has been influenced, at least in part, by the favorable behavioral effects of mass practice seen in anomia behavioral training studies that can be easily combined with tDCS. However, not only the behavioral task but also the cortical area being targeted by tDCS will have an impact on the efficacy of the intervention. With this in mind, I will discuss these studies, according to which hemisphere was targeted during stimulation.

Chronic Aphasia (Post-Stroke)

Targeting Left Hemisphere, Peri-Lesional Cortices

In one of the earliest group studies of tDCS and aphasia, Monti et al. (2008) found that a single session of off-line cathodal (but not anodal) stimulation over the left frontotemporal areas leads to a transient improvement of naming abilities in eight nonfluent aphasic patients. However, a more recent study that applied tDCS offline, that is, in isolation or not concurrently with SALT found no effect on chronic aphasic patients’ language function (Volpato et al., 2013). A negative result such as this can never confirm or refute the hypothesis that off-line tDCS is inefficient. Nevertheless, it may be argued that, in post-stroke chronic aphasic patients, simultaneously coupling tDCS

In relatively well-recovered aphasic patients, as in normal individuals, successful speech production has been correlated with brain activity in the peri-lesional left hemisphere (Fridriksson, Bonilha, Baker, Moser, & Rorden, 2010; Fridriksson, Richardson, Fillmore, & Cai, 2012). This suggests that excitatory tDCS delivered to the patient’s structurally intact, residual language cortices may be a mechanism to facilitate activity in these peri-lesional regions and thereby boost speech recovery. Preliminary results suggest that this is indeed the case. Five tDCS group studies (see Table 1, study numbers 1, 2, 6, 8, 9) adopted this approach.

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Lesion location

Lee et al. (2013)

4 – L-temporal 4 – L FT

tDCS type

A, S Crossover Randomized, Sham controlled, 1 week WO

Design

41.1 months (14–84) 100.25 (9–312)

51.9 months (8–180)

32.8 months (7–84)

84.2 months (14–260)

4.6 years (1.3–10)

58.4 months (10–150)

A, Dual

A, S Crossover, Sham controlled, 14 days WO Crossover, A-CS Randomized, A-HD 7 day WO

Crossover, Randomized, 1 day WO

Crossover, A, S Randomized, Sham controlled, 1 week WO A, C, S Crossover, Randomized, Sham controlled, 1 week WO Crossover, A, S Randomized, Sham controlled, 6 days WO

A, S Crossover Randomized, Sham controlled, 3 weeks WO C, S Crossover, 52.4 Randomized, months (6.0–180.6) Sham controlled, 1 week WO

64.6 months (10–242)

PS mean (range)

20 min, CS-1 mA, HD-2 mA***, L posterior

A: 2 mA for 30 min L IFG, Dual: 30 min for 2 mA LIFG & 2 mA RIFG** 1 mA for 20 min, Broca’s, Wernicke’s

1 mA for 20 min, Wernicke’s area, Broca’s area

1 mA for 20 min, twice per day. R TP

15 min picture naming & reading paragraphs

Naming – nouns and verbs

Naming

Melodic intonation training

Word-retrieval training

Computerized Spoken WPM

Therapy task 8%

tDCS effect

83%*

2.5% slower

281 ms faster

Bx effect

2 weeks post-treatment

1 hr following the last (5th) ctDCS

3 weeks post-treatment

1 week post-treatment

Duration of effect

Naming reaction time was faster after Dual (3.92 s) but ns after A (0.86 s).

CS-8.8% (4.38 words), HD-11.3% (5.63 words)

39%

28.7% faster

25%

1 week post-treatment

Naming accuracy improved, Nouns: W:21%, Nouns: 10%, 4 weeks Nouns: W (31%) > B (12) Verbs: B:29% Verbs 13% post-treatment S (10), Verbs: B (42%) > W (15) S (13).

Speech fluency rate 10.9% faster improved, Anodal ( 10.9%) > Sham (+2.5%). Cohen’s d-1.98 Increased naming accuracy 6% A (89%) > S (83%) = C (84%).

174 ms faster Naming reaction time was faster for treated items, A ( 456 ms) > S ( 281 ms). Naming accuracy improved, 2% C (4%) > S (2%).

Naming accuracy improved for treated items, A (14%) > S (6%)

Results

10 Conversation Increased speech coherence (5 · 2 weeks) therapy with SALT B (64%) > W (30%) = S (25%). 5 Computerized Improved naming: RT & Spoken WPM accuracy (treated items only)

2 mA for 20 min, R Broca’s

1.2 mA for 20 min, R posterior IFG (F8)

Exposure (days)

1 mA for 20 min, L posterior cortex

1 mA for 20 min, L frontal-precentral

tDCS parameters

Notes. PS = time post-stroke; tDCS effect = this value is net of the sham or behavioral alone condition; Calculation was: tDCS + Behavioral intervention Behavioral effect alone; WO = washout time between interventions; Bx effect = behavioral effect; L = left; R = right; TP = temporo-parietal; FTP = fronto-temporo-parietal; FT = fronto-temporal; IFG = inferior frontal gyrus; A = anodal stimulation; C = cathodal stimulation; S = sham stimulation; Dual = Anodal and Cathodal concurrently; WPM = word-to-picture matching; SALT = speech and language therapy; K-WAB = Korean version of Western aphasia battery; NA = not assessed; ns = nonsignificant difference/change; NR = not reported; CS = conventional tDCS; HD = high-definition tDCS. *This effect is large due to the fact that patients started off at a baseline level of 0% naming success on items subsequently treated until they reached a naming accuracy of at least 80%. **The authors reported, ‘‘the right tDCS electrode was only switched on for 5 s’’. ***1 mA in each of the four electrodes with a maximum total of 2 mA.

Richardson 8 et al. (2015)

Fiori et al. (2013)

12 1 – L frontal 5 – L TP 1 – L FT 5 – L FTP 7 2 – L FT 2 – L FTP 1 – L temporal – insula 1 – L temporal 1 – L TP 11 L MCA 9 infarct 2 hemorrhage

Floël et al. (2011)

Marangolo 8 et al. (2014)

Vines et al. (2011)

10 1 – L frontal 1 – L TP 3 – L FT 2 – L FTP 3 –L subcortical 6 All had left frontal damage

Kang et al. (2011)

Baker et al. (2010)

10 3 – L frontal 4 – L TP 1 – L FP 1 – L FTP 1 – L temporal Fridriksson 8 All had posterior et al. (2011) cortical or subcortical lesions

Authors

No.

Table 1. Group studies of tDCS delivered concurrently with aphasia therapy in chronic aphasic stroke patients (min. 6 patients)

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Using a repeated intervention protocol in chronic aphasic patients that spanned several days, they applied anodal tDCS to patients’ remaining structurally intact cortex in the lesioned left hemisphere during speech production training. Studies 6 and 8 are the latest papers by two groups who have published additional papers using similar protocols/ data so I will not refer to their earlier papers here. In the first treatment study (Table 1, study 1), 10 aphasic speakers were trained for five consecutive days using a spoken word-to-picture matching task. During training they received 20 min of anodal (1 mA) or sham stimulation delivered to left frontal and precentral cortex (Baker, Rorden, & Fridriksson, 2010). To ensure the active (anode) electrode was placed over structurally intact cortex, tDCS positioning was guided using a priori functional MRI results for each individual from an overt naming experiment. Patients’ naming accuracy improved significantly following both interventions. Behavioral training alone (sham tDCS) resulted in a 6% improvement in naming. After anodal tDCS paired with behavioral training, there was a 14% improvement in naming, that is, tDCS had an additive effect of 8% on top of the behavioral training alone. Importantly, naming improvements were retained for at least 1 week after training. Consistent with the behavioral rehabilitation literature, the naming improvements were restricted to trained items only. In a second study by this group (Table 1, study 2), the same treatment paradigm was used in eight mild fluent aphasic patients with lesions restricted to left posterior cortical and subcortical regions. This time, anodal stimulation was applied to viable left posterior peri-lesional cortex, again determined by results from an fMRI naming study (Fridriksson, Richardson, Baker, & Rorden, 2011). These patients had good naming accuracy but were slow to respond. So the primary outcome measure used was a change in naming reaction time. Anodal stimulation resulted in faster naming responses compared to sham stimulation. This naming improvement persisted for at least 3 weeks. Again, the facilitatory effect of anodal stimulation was restricted to the treated items only. In another naming study (Table 1, study 6), Fiori et al. (2013) trained seven nonfluent aphasic patients to name 102 nouns and 102 verbs they could comprehend but not accurately produce. Naming practice was paired with 1 mA of anodal tDCS applied to left Wernicke’s area, left Broca’s area, and with sham stimulation of the same region. Overall, patients improved naming accuracy in response to the behavioral training (12% sham) after five days of intervention. The authors further discuss how patients were much more accurate in noun naming after anodal left temporal stimulation (Wernicke’s-31%, Broca’s-12%, Sham-10%) and in verb naming after anodal left frontal stimulation (Wernicke’s-15%, Broca’s-42%, Sham-13%). Importantly, these gains were maintained 4 weeks after tDCS. However, considering it was a small study and all of their patients had left-hemisphere damage involving the temporal lobe to some degree, it is not clear how many patients actually had structurally intact cortex underneath the anode electrode for each intervention. No MRI data was used to ensure the active electrode was placed over functionally viable cortex. Therefore, the European Psychologist 2016; Vol. 21(1):65–77

authors’ claims that better recovery observed after left temporal and frontal stimulation, respectively, for nouns and verbs, could be directly related to differential activation of these areas needs further investigation. The same criticism about tDCS electrode positioning can be applied to Marangolo et al.’s study (2014) (Table 1, study 8). Here, the authors extended their speech training approach to look at the differential effects of frontal versus temporal tDCS on conversational therapy outcomes. However, out of the eight patients, only four had preserved frontal cortices, the rest having both temporal and frontal damage. It was perhaps not surprising then that only frontal tDCS had an additive effect resulting in a significant improvement in the patients’ speech coherence directly after treatment compared to behavioral training alone. These studies highlight a crucial point: behavioral change following tDCS combined with training depends on which cortical areas are targeted. One tDCS electrode montage does not fit all patients with the same behavioral profile. tDCS effects cannot be predicted without precise anatomy of individual patient’s lesion and careful positioning of electrodes to ensure tDCS is delivered to structurally intact cortices for each patient. Fridriksson and colleagues (2012) suggest acquiring additional fMRI data as a tool to define individual cortical targets for brain stimulation. However, there is a lot of individual variability in fMRI results; it depends on task used, statistical threshold, whether you predict an increase or decrease in the BOLD signal relative to rest or the control condition. In addition, an fMRI scan as a requirement for entry into tDCS treatment studies significantly limits the number of patients that can be investigated, along with impacting its future application and translational potential. Whether the intended cortical area is functionally viable for an individual will depend on their anatomical lesion – gray and white matter damage. An alternative approach would be to acquire a highresolution structural brain scan for each patient to ensure the targeted anatomical region for stimulation is intact. Response variability to the interventions (behavioral alone and with tDCS) could then be investigated by modeling the anatomical variability in the lesion damage. Advances in detailed anatomical models for language function derived from volumetric brain MRI scans are underway (Hope, Seghier, Leff, & Price, 2013). It is hoped that this approach will help in developing stratified treatments, optimizing individual patient’s treatment. Advances are also underway in the development of a technique thought to increase tDCS current focality and field intensities at desired cortical targets: high-definition tDCS (HD-tDCS). Conventional bipolar tDCS is applied with two large (35 cm2) rectangular electrodes, resulting in directional modulation of neuronal excitability. A newly designed 4 · 1 HD-tDCS protocol has been proposed for more focal stimulation according to the results of computational modeling (Datta et al., 2009). HD-tDCS utilizes small disk electrodes deployed in 4 · 1 ring configuration whereby the physiological effects of the induced electric field are thought to be grossly constrained to the cortical area circumscribed by the ring. A physiological study of motor cortex excitability demonstrated that single dose 2016 Hogrefe Publishing

J. T. Crinion: tDCS Adjunct to Aphasia Treatment

HD-tDCS resulted in larger and longer-lasting motor evoked potential changes in comparison to conventional tDCS (Kuo et al., 2013). This led Richardson, Datta, Dmochowski, Parra, and Fridriksson (2015) to ask whether multiple-session HD-tDCS would lead to larger and longerlasting changes in naming compared to conventional tDCS paired with anomia treatment (Table 1, study 9). Eight aphasic stroke patients took part in a randomized, crossover design study of tDCS versus HD-tDCS combined with 5 days of computerized anomia training. The electrode montage for each condition was visibly different (4 electrodes vs. 2), so no blind design was possible. An additional difference was that 1 mA conventional anodal tDCS was applied compared to 2 mA anodal HD-tDCS. Naming accuracy and response time improved significantly following both interventions. There were no significant differences in outcome between the two tDCS conditions. A nonsignificant trend was noted in change in accuracy of trained items. After HD-tDCS, compared to conventional tDCS, naming was numerically higher for six out of the eight patients immediately post-treatment and five patients 1 week later. Richardson et al. (2015) acknowledged that this trend may not have occurred had 2 mA been used across both conditions. Therefore, a different modulatory effect due to a higher intensity of electric current cannot be ruled out as a cause of the differences in the results. However, this does highlight that tDCS dosage, defined by electrical field at the target site, may impact on the size of behavioral effects for individual patients. Future work is needed to identify and understand dose-response relationships for tDCS and cognitive behavioral outcomes. Importantly, all these studies demonstrate that using anodal tDCS stimulation in the vicinity of peri-lesional tissue can be safe, well tolerated, and sham controlled. Encouragingly, the results suggest anodal tDCS can enhance chronic patient’s response to SALT. This confirms the importance of coupling tDCS with the behavioral training not only for immediate but also for longer-term spoken language gains.

Targeting Right Hemisphere Language Cortices An alternative possibility for aphasia recovery and treatment approaches relies on recruitment of the structurally intact right hemisphere to facilitate language improvement. Previous neuroimaging and behavioral studies found that right hemisphere homologs of ‘‘classical’’ language regions are activated by language tasks in aphasic stroke patients (Blank, Bird, Turkheimer, & Wise, 2003; Crinion & Price, 2005; Leff et al., 2002; Saur et al., 2006). What is not always clear is whether this right hemisphere activation might be the consequence of either (i) a loss of active interhemispheric inhibition from homologous regions in the lesioned left hemisphere or (ii) a compensatory neural response, contributing to functional recovery (Geranmayeh, Brownsett, & Wise, 2014; Saur & Hartwigsen, 2012). What is clear is that there is little evidence for ‘‘take-over’’ of 2016 Hogrefe Publishing

function in areas previously unrelated to language processing. A comprehensive review of both aphasic and normative fMRI language studies found that the right hemisphere regions activated in aphasic patients appear to be components of a preexisting, bilateral language network also found in healthy control subjects (Turkeltaub, Messing, Norise, & Hamilton, 2011). For aphasic patients with extensive left hemisphere lesions, upregulation of right hemispheric language homologs might be crucial, being their only option for recovery (Schlaug, Marchina, & Norton, 2009; Winhuisen et al., 2005). This is the approach used by Vines, Norton, and Schlaug (2011) (Table 1, study 4). They paired anodal tDCS delivered to right Inferior Frontal Gyrus (IFG) with melodic intonation therapy (MIT) in six severely aphasic patients with extensive left IFG lesions. Patients’ speech fluency improved when patients had tDCS paired with MIT but not when they had MIT alone (sham). Unfortunately, no supporting neuroimaging data was collected in the study. Nevertheless, the authors proposed that the observed improvement in patients’speech may be due to a positive change in functional contribution from right IFG, boosted by tDCS. However, right IFG activation is not always deemed beneficial for speech production post-stroke. For example, an open-protocol transcranial magnetic stimulation (TMS) study showed that 10 sessions of inhibitory TMS over the right pars triangularis significantly improved picture naming in four chronic aphasic patients. This effect was maintained 2 months later (Naeser et al., 2005). The inferred mechanism was that language improvement was due to suppression of maladaptive activity in the ‘‘overactive’’ right hemisphere. That is, TMS downregulated abnormally increased activity in right IFG. This in turn reduced the interhemispheric inhibition from the right, contralesional (healthy) hemisphere to the left, ipsilesional (damaged) hemisphere. This theory borrows directly from the motor recovery literature where recovery after stroke is seen as a dynamic process that involves a variety of changes in both hemispheres to achieve interhemispheric balance (Fregni & Pascual-Leone, 2006; Mansur et al., 2005; Oliveri et al., 2001; Ward & Cohen, 2004). In the case of tDCS, inhibitory cathodal tDCS applied to the primary motor cortex decreased motor cortical excitability at this site (Nitsche et al., 2003; Nitsche & Paulus, 2000; Purpura & McMurtry, 1965; Wassermann & Grafman, 2005). Furthermore, when used in chronic stroke patients, contralesional cathodal tDCS improved motor function (Boggio et al., 2007; Hummel et al., 2005). This led Kang, Kim, Sohn, Cohen, and Paik (2011) (Table 1, study 3) to investigate whether cathodal tDCS applied to the right IFG (homolog of Broca’s area) simultaneously with word-retrieval training might improve picture-naming task performance in chronic poststroke aphasics. Ten right-handed patients were enrolled in this double-blind, counterbalanced sham controlled study. Each patient received an intervention of cathodal tDCS (2 mA for 20 min) and of sham tDCS (2 mA for 1 min) delivered to right IFG daily for five consecutive days in a randomized crossover manner. There was a minimum interval of 1 week between interventions. tDCS was delivered simultaneously European Psychologist 2016; Vol. 21(1):65–77

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with daily sessions of conventional word-retrieval training. tDCS was found to have a small (4%) but significant improvement in picture naming 1 hr following the last (5th) cathodal tDCS treatment session. It was not assessed whether these effects persisted. No statistically significant changes were observed after sham tDCS (2%). It is of interest to directly contrast the size of these effects with the study by Baker et al. (2010) discussed in the previous section (Table 1, study 1). Baker and colleagues also combined tDCS with anomia treatment for 5 days but used anodal tDCS (2 mA for 20 min) delivered to left Broca’s area. They found that anodal tDCS resulted in large effects (14% improvement in naming compared to only 6% in the sham condition) that persisted for at least 1 week after intervention. This highlights an important point: tDCS does not have a simple effect on behavior. Baker et al.’s sham treatment resulted in a 6% improvement in speech recovery which was greater than Kang et al.’s (2011) 4% tDCS effect and 2% treatment effect in the sham condition. In these two studies, tDCS interacted with ongoing behavioral rehabilitation training to offer an additive effect to patients’ language recovery. This means the amount of potential tDCS ‘‘boost’’ crucially depends on the efficacy of the behavioral intervention. Choosing the ‘‘correct’’ behavioral training task is key to treatment success. This is not only for observing statistically significant treatment and adjuvant tDCS effects but also clinically meaningful language effects that enhance aphasic’s recovery immediately post-treatment and longerterm. Adopting a different approach, Floël et al. (2011) (Table 1, study 5) delivered anodal, cathodal, and sham tDCS to right temporo-parietal regions during anomia treatment. Patients all had large left hemisphere lesions. The behavioral training required them to practice a small number of items over 3 days that they consistently could not name at baseline (0%) until they reached 80% accuracy. The resulting sham effect (behavioral treatment alone) in their study was therefore very high – 83%. This meant the tDCS effect could maximally be 17%, that is, if the patients’ naming improved to a perhaps unrealistic 100%. Nevertheless, the patients’ naming did statistically improve further to 89% following anodal tDCS paired with training. This effect persisted for 2 weeks post-treatment. Cathodal tDCS had no effect in these patients. Taking this study’s behavioral result together with that reported by Kang et al.’s (2011), one could speculate that, in the context of a strong behavioral treatment effect, cathodal tDCS delivered to right hemisphere might offer little advantage but anodal tDCS may still boost language recovery. Miniussi, Harris, and Ruzzoli (2013) discuss the potential physiological mechanisms underlying why this may be the case. An alternative explanation may be that right temporal and frontal regions respond differently to anodal and cathodal tDCS when paired with anomia treatment.

Dual/Bi-Hemisphere Stimulation Dual-site stimulation using tDCS has received some attention recently in the motor recovery literature for the purpose European Psychologist 2016; Vol. 21(1):65–77

of developing more effective methods of brain stimulation. It is based on the interhemispheric rivalry theory discussed in the previous section. Theoretically, bi-hemispheric stimulation could concurrently increase the excitability of the ipsilesional cortical region and decrease the excitability of the contralesional, unaffected cortical region thereby restoring the balance between both hemispheres and promoting recovery. For example, Vines, Cerruti, and Schlaug (2008) applied simultaneous dual-hemispheric tDCS to healthy subjects, using anodal tDCS over the nondominant and cathodal tDCS over the dominant motor cortices. They found an additive effect on motor function of the nondominant hand compared with single-site stimulation. In terms of language function, the study by Lee, Cheon, Yoon, Chang, and Kim (2013) (Table 1, study 7) is the first to adopt this approach. They aimed to investigate the effect of simultaneous dual tDCS applied over the bi-hemispheric language-related regions in chronic aphasic stroke patients. Eleven patients took part in a within-subject crossover design study. Thirty minutes of tDCS was delivered concurrently with 15 min of naming practice and reading aloud on two separate occasions. One-day patients had 2 mA of anodal tDCS delivered to left IFG and on the other 4 mA of dual tDCS consisting of 2 mA anodal tDCS delivered to left IFG and 2 mA cathodal tDCS to right IFG. Both single and dual tDCS methods produced an improvement in accuracy in the picture-naming test with no adverse effect. The authors also reported a small but significant improvement in naming response time following dual tDCS but not single tDCS. These results need to be taken as preliminary due to the significant limitations of the study. In particular the authors reported, ‘‘the right tDCS electrode was only switched on for 5 s’’. So it is not at all clear what dose of dual tDCS patients actually received. In addition, lesion location was not documented or investigated in the study so we do not know how many had viable tissue in the targeted regions and how this may have impacted on the data. Nevertheless, the study does highlight an alternative and interesting approach that was tolerated in chronic aphasic stroke patients as an adjunct to aphasia intervention.

Sub-Acute Aphasia (Post-Stroke) Consistent with Volpato et al.’s (2013) study of off-line tDCS in chronic aphasics, Polanowska, Lesniak, Seniow, and Czlonkowska (2013), who studied patients in the subacute phase, found that off-line tDCS offered no benefit to their patients’ language outcomes. Therefore, in this section the focus is on three recent group studies where tDCS was delivered online with behavioral rehabilitation in subacute aphasic stroke patients (see Table 2). The hope with early intervention post-stroke is that it will significantly boost language recovery (as patients are on a steeper part of their recovery curve) and thus prevent chronic aphasia. The first two studies investigated tDCS as an adjunct to conventional SALT and its impact on standard clinical aphasia outcomes. Jung, Lim, Kang, Sohn, and Paik (2011) (Table 2, study 2) applied 1 mA cathodal tDCS to 2016 Hogrefe Publishing

2016 Hogrefe Publishing

You et al., (2011)

Jung et al. (2011)

Wu et al. (2015)

2 BG/SC (F, T, P), 5 BG/CO (F, T, P), 2 CO (F, T, P), 1 CO (T, P), 1 BG/SC (F, P), 1 BG/SC (T, P) (8 infarct/4 hemorrhage)

Anodal: 4 -L temporal 3 –L frontal Sham: 6 -L frontal 1- L parietal Range of LMCA Infarct/hemorrhage

Cathodal: 5-L frontal L temporal 1-L subcortical

Lesion location

4.5 months (3–6)

220.9 days (13 < 30; 10 > 90)

(16– 38 days)

Crossover, Sham controlled, Fixed design: S-A-S, 2 days WO

Within group all had C-tDCS

Between 3 group comparison

Design

A, S

C, A, S

tDCS type

1.2 mA for 20 min, Wernicke’s area

1 mA for 20 min, Left Brodmann area 45

2 mA for 30 min, C-RSTG-CP6, A-LSTG-CP5, S-LSTG-CP5

tDCS parameters

Picture naming (30 min)

Conventional SALT

10 (5 · 2 weeks)

Therapy task

Exposure (days)

AQ K-WAB % improved from pre- to post-therapy (14.94 ± 6.73%). Lower initial severity = better AQ% change. Naming and auditory word comprehension Improved after A

Auditory comprehension improved in all groups but C (17%) > A (10%) = S (10%)

Results

N = 18.8%, AC = 8.3%

tDCS effect

N = 1.7%, AC = 0%

10%

Bx effect

Duration of effect

PS = post-stroke; tDCS effect = this value is net of the sham or behavorial alone condition; Calculation was: tDCS + Behavioral intervention Behavioral effect alone; Bx effect = behavioral effect; L = left; R = right; A = anodal stimulation; C = cathodal stimulation; S = sham stimulation; SALT = speech and language therapy; K-WAB = Korean version of Western aphasia battery; AQ = aphasia quotient; N = naming; AC = auditory comprehension; LMCA = left middle cerebral artery; BG = basal ganglia; SC = subcortical; CO = cortical.

Authors

No.

Time PS mean (range)

Table 2. Group studies of tDCS delivered concurrently with aphasia therapy in sub-acute aphasic stroke patients (min. 6 patients) J. T. Crinion: tDCS Adjunct to Aphasia Treatment 71

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Broca’s area in all patients. The rationale behind their unexpected choice of cathodal tDCS delivered to Broca’s area as opposed to anodal tDCS, consistent with the previous literature, was not explained. There was no sham tDCS delivered nor was behavioral intervention alone delivered so it is not possible to judge the effects of tDCS on behavioral outcomes. Patients with both infarction and hemorrhagic stroke, where the risk of epileptic fits in the first-year post-stroke is higher, were included. Lesion distribution was not controlled and it is not clear how many patients had structurally intact tissue in the vicinity of the stimulating electrode. Nonetheless, 10 days SALT paired with tDCS was well tolerated by all, and no adverse events were reported. Behaviorally, the least aphasic patients made the best language improvements, that is, recovered quickly, while more severely aphasic patients changed little. You, Kim, Chun, Jung, and Park (2011) (Table 2, study 1) conducted a between-group study in 21 aphasics. Patients were divided into three groups depending on whether they received SALT paired with 2 mA tDCS delivered as (1) cathodal tDCS to right Superior Temporal Gyrus (STG); (2) anodal tDCS to left STG; or (3) sham tDCS. The cathodal tDCS group recovered significantly more auditory comprehension (17%) than the sham group (10%) and the anodal tDCS group (10%). The authors interpret this result as evidence that suppression of activity in the ‘‘overactive’’ right hemisphere after left-hemisphere stroke may promote recovery. However, on closer examination, patients assigned to the cathodal group were behaviorally the least impaired on auditory comprehension testing at baseline. This suggests that their tDCS effect may be confounded by aphasia severity. In addition, when baseline performance is not stable or equivalent between groups, failing to detect a difference between groups is more likely, especially if the effects of the treatment are small or variable (such as here, sham = anodal). Contributing to this variability, lesion distribution was not equivalent in all three groups. Of particular note is that four of the seven patients in the anodal tDCS group had lesions involving the left temporal lobe. The authors do not state whether the patients had structurally intact cortex underneath the left STG stimulating electrode. Nevertheless, their result is consistent with Jung et al.’s (2011) study, showing that aphasia severity may be a reliable predictor of aphasia treatment outcome in the sub-acute stage post-stroke. The third study and final study in this section was performed by Wu, Wang, and Yuan (2015) (Table 2, study 3). In this study, they targeted Wernicke’s area in a group of 12 aphasic stroke patients. Each tDCS block (sham, anodal, and then sham again) was paired with picture-naming treatment for five consecutive days. Following the anodal tDCS block, patients were found to have improved not only naming abilities but also auditory word comprehension significantly more than following the two other blocks of treatment with sham tDCS. This is the only study that has reported an improvement in speech comprehension. It is also the only study that reported an improvement in both language comprehension and production. This suggests that, early post-stroke, there may be potential for generalization of tDCS and language treatment effects across both European Psychologist 2016; Vol. 21(1):65–77

comprehension and production abilities. This has not been reported in the chronic aphasic stroke patient treatment studies to date. The four studies of chronic aphasic patients that targeted Wernicke’s area all reported changes only in naming and speech production coherence (see Table 1, studies 2, 6, 8, 9). There are a number of reasons as to why this may be the case. Chronic speech comprehension impairments, especially at the single word level, are rare post aphasic stroke. Anomia is the most common symptom post aphasic stroke irrespective of the lesion location. It is the symptom that frustrates patients and their families the most. Most interventions in chronic aphasic patients therefore reflect this need and focus on improving speech production abilities. Nevertheless, it is of interest that Fridriksson and colleagues in their two studies (Table 1, studies 2 and 9) chose to use an auditory comprehension task: single word-to-picture matching, as the behavioral adjunct to tDCS to improve naming abilities in their patients. A comprehension difficulty was not reported in their patients and no change in speech comprehension abilities was documented. None of the chronic studies from Table 1 reported if there had been any change in their patients’ auditory sentence comprehension abilities that can be commonly affected long-term post-stroke. In light of Wu et al.’s study (2015), this would be of interest. In conclusion, it is impossible to judge at this stage whether tDCS offers any significant benefit to aphasia treatment in the sub-acute stage post-stroke. Not one of the studies followed up their patients to see the longer-term impact on language recovery. Importantly however, these three studies have shown in a relatively large number of patients (n = 70) that 2 mA, 1 mA, and 1.2 mA cathodal and anodal tDCS can be well tolerated and safe when delivered for 10–15 days in combination with SALT. This is encouraging and suggests that tDCS and aphasia treatment studies in this early stage post-stroke are feasible.

Primary Progressive Aphasia An important avenue more recently being pursued is the application of tDCS as an adjunct to SALT in patients with primary progressive aphasia (PPA). PPA is a neurodegenerative condition that involves a progressive loss of language function. In general, it begins very gradually and initially is experienced as difficulty in thinking of common everyday words while speaking or writing. It then progressively worsens to the point where verbal communication (including language comprehension) by any means is very difficult. In the early stages, memory, reasoning, and visual perception are not affected by the disease. This means that individuals with early stage PPA can function normally in many routine daily living activities despite the aphasia, and they also retain the cognitive capacity to learn. However, as the illness progresses, other cognitive abilities also decline. Therefore, early behavioral intervention is key to facilitate language function. 2016 Hogrefe Publishing

Spelling therapy 15 (5 · 3 weeks) 1–2 mA for 20 min, LIFG A, S Within-subject crossover 2 months WO 5.5 years (3–10) 4 logopenic, 2 nonfluent, agrammatic Tsapkini et al. (2014) 2

Cotelli et al. (2014) 1

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Behavioral effect alone; PO = post onset of symptoms; DLPFC = dorsolateral prefrontal cortex; FT = fronto-temporal lobe; IFG = inferior frontal gyrus; tDCS effect was calculated by: tDCS + Behavioral intervention WO = washout time between interventions; Bx effect = behavioral effect; L = left; R = right; A = anodal stimulation; S = sham stimulation.

2 months 16% 19%

3 months 34.3% 11.5%

Naming improved overall: A group learnt significantly more treated items: A (45.8%) > S (34.3%); untreated ns: A (21.3%) = S (20.75%) Spelling improved overall, Trained items A (35%) > S (16%); Computerized picture naming 25 min bd 10 (5 · 2 weeks) 2 mA for 25 min, L DLPFC A, S Between-group comparison Approx. 2.2 years Agrammatic – L DLPFC atrophy and L FT asymmetric atrophy

Design PPA variant n Authors No.

Therapy task Exposure (days) tDCS parameters tDCS type Time PO mean (range)

Table 3. Group studies of tDCS delivered concurrently with aphasia therapy in primary progressive aphasic patients (PPA)

Results

tDCS effect

Bx effect

Duration of effect

J. T. Crinion: tDCS Adjunct to Aphasia Treatment

PPA is caused by Alzheimer’s disease (AD) in approximately 30–40% of cases and by fronto-temporal lobar degeneration (FTLD) in approximately 60–70% of cases (Cairns et al., 2007; Rogalski & Mesulam, 2009). Because of the 30–40% probability of Alzheimer’s disease (AD), AD drugs such as Exelon (rivastigmine), Razadyne (galantamine), Aricept (donepezil), or Namenda (memantine) have been tried. None have been shown to improve PPA. SALT can improve the patient’s quality of life. The primary goal of treatment is to improve the ability to communicate. However, the emphasis in PPA, as opposed to aphasia post-stroke, is to enable individuals to maintain their language abilities for as long as possible, that is, long-term to slow down the rate of language decline rather than recovery of function. Researchers investigating PPA currently recognize three behavioral (language) subtypes: agrammatic, logopenic, and semantic. Cotelli et al. (2014) (Table 3, study 1) targeted 16 patients with FTLD and a 2-year symptomatic history of agrammatic PPA. Patients with this subtype have nonfluent, effortful speech, reduced in quantity: pronouns, conjunctions, and articles are often lost first. Sentences become gradually shorter and word-finding difficulties become more frequent, occasionally giving the impression of stammering or stuttering. tDCS was delivered to left dorsolateral prefrontal cortices concurrently with SALT focused on picture naming for 10 days. Half of the patients had sham while the others had 25 min of 2 mA anodal tDCS. The patients who received anodal tDCS learnt significantly more treated items than those who had SALT and sham. The effects were maintained for 3 months. Just like in the studies of aphasic stroke patients, there was no generalization of improvements to untreated items. However, unlike all the previous tDCS studies in aphasic stroke patients, the size of the tDCS effect in these patients was much smaller than the behavioral effect: 12% versus 34%. Possible causes for this include: differences in the underlying nature of their brain disease (degeneration vs. stroke); the brain region targeted with tDCS – which in this study was the left DLPFC which, located dorsal to Broca’s area in the middle frontal gyrus, is not a classical language area and is rarely activated in fMRI studies using picturenaming tasks. Thus, tDCS may not have been optimally targeting the brain regions engaged by the behavioral training (using picture-naming tasks). Had the authors targeted Broca’s area (left IFG), they might have seen a larger tDCS effect when paired with the anomia therapy. The second study (Table 3, study 2), reported by Tsapkini, Frangakis, Gomez, Davis, and Hillis (2014), targeted a mixed group of agrammatic (n = 2) and logopenic (n = 4) PPA patients. Logopenic PPA has a particularly high probability of being caused by AD and often is associated with atrophy in temporo-parietal regions. Speech is fluent during informal conversations but is marked with mispronunciations and word-finding difficulties on confrontation naming tasks. Spelling errors are common in both PPA subtypes especially early on. Tsapkini and colleagues delivered spelling behavioral therapy in conjunction with tDCS delivered to left IFG. Left IFG is an area commonly associated with spelling function. The 1–2 mA European Psychologist 2016; Vol. 21(1):65–77

J. T. Crinion: tDCS Adjunct to Aphasia Treatment

anodal/sham tDCS was delivered to six patients in a 2month within-subject crossover design study. The spelling training worked, as it led to a 16% improvement. Following 3 weeks of anodal tDCS, delivered in conjunction with the behavioral training, there was an additional 19% improvement in spelling. Importantly, the effects were maintained 2 months later. The sample size tested in this study is small but it does suggest two things. Firstly, large tDCS effect sizes in PPA patients are possible, that is, of comparable size (at least) to the behavioral intervention. Secondly, delivering SALT concurrently with tDCS delivered to a brain area known to be actively involved in the behavioral intervention can boost the efficacy of therapy.

Summary By linking data and approaches from these complementary studies, I hoped to deliver an integrated picture of current aphasia rehabilitation research using tDCS. The field is still new and clearly many more studies with larger samples of patients are needed but a number of themes have emerged. I highlight a few of these below: • The majority of studies to date have focused on tDCS as an adjunct to treatment of speech production difficulties. The most compelling evidence to date comes from studies of chronic aphasics post-stroke. Here, anodal tDCS has been most effective when delivered to the patient’s residual spoken language network (left hemisphere if preserved or when extensively damaged right hemisphere homolog). • It looks promising that tDCS delivered over multiple sessions may boost consolidation of aphasia rehabilitation rather than a simple (or temporary, immediate) effect on language performance. Too few multiplesession studies exist for a valid meta-analysis. A challenge for future tDCS research with this population will be optimizing techniques, such as the dose. • In the majority of studies, irrespective of the patient population, the reported effects of anodal tDCS were greater than or at least equivalent to the size of the behavioral treatment effects alone (see Tables 1–3). Studies that found large tDCS effect sizes tended to also have large SALT effect sizes. tDCS therefore appears to offer little advantage if the behavioral treatment effects are small. It is a true interaction between the two interventions. Stimulation/activation of a brain region by a therapy task in conjunction with tDCS targeting the same brain region appears to be a valid technique for optimizing the efficacy of SALT. • Where tDCS had a positive effect on patients’ language function, there was no reported cognitive cost. However, it is not clear from the reported studies how many formally evaluated this. • Paired with SALT, tDCS is feasible in sub-acute stroke and PPA patients. But too few studies have been done to assess its efficacy. European Psychologist 2016; Vol. 21(1):65–77

• We are far from tailoring treatment to individual patients. As illustrated in this review, huge variability exists in the reported effects of SALT, with great variability in the tDCS effect sizes and even contradictory results reported. There are many interindividual factors that may contribute to this variability including baseline behavior, anatomy, age, and the inherent variability in the injured brain (see Li, Uehara, & Hanakawa, 2015). Future studies in larger groups of patients that control for lesion distribution and aphasia severity may provide us with a means of identifying those who are likely to respond to specific tDCS and behavioral therapies. This would provide an empirical basis from which to investigate specific aphasia interventions in future multicenter clinical trials and could greatly improve the quality of aphasia treatment for stroke patients.

Future Directions tDCS Brain Current Flow and Anatomy (Structural and Functional) Models How current flow is affected by variation in normal anatomy (sulci and gyri) of the targeted cortices and different lesions in the vicinity of the stimulating electrodes is an important emerging theme in tDCS research. In chronic stroke patients, even when electrodes are placed on an area of the scalp away from the lesion, cerebrospinal fluid-filled lesions may alter current flow and serve as an attractor for current. A single case study by Datta, Baker, Bikson, and Fridriksson (2011) demonstrated how different electrode configurations influenced the flow of electrical current through brain tissue in a chronic stroke patient with a large lesion who responded positively to tDCS paired with anomia treatment. Individualized tDCS modeling and targeting procedures have been developed to take into account the patients’ lesions (Dmochowski et al., 2013) with the aim of achieving maximum stimulation intensity at the target cortical regions. Richardson et al. (2015) implemented these techniques in their study of chronic aphasic patients demonstrating they are feasible in a clinical population. However, the data is insufficient to judge whether they had an impact on tDCS efficacy. Hence, the complexity of tDCS current flow modulation by detailed normal and pathologic brain anatomy needs further understanding. Galletta and colleagues (2015) have started developing computational models to understand the impact of the lesion on resting state tDCS current flow. The next step will be to understand the impact of the lesion on interactions between tDCS current flow and ongoing task-driven functional brain activation during SALT.

tDCS as a Novel Therapeutic Intervention? Presently, there is insufficient data to establish if tDCS may be useful in clinical treatment of aphasia populations. tDCS 2016 Hogrefe Publishing

J. T. Crinion: tDCS Adjunct to Aphasia Treatment

use in aphasia is currently largely restricted as small-scale lab-based experiments limiting its translational impact. The aim for future studies is to combine the benefits of tDCS, namely low-intensity, safe, neuromodulation with detailed behavioral interventions (SALT) to assess its effectiveness in boosting language recovery outcomes. This approach could provide clinical researchers with a compelling platform and much promise as an adjunct to neurorehabilitation. If successful, tDCS could increase the amount of aphasia recovery individual patients make, as well as free up more SALT time. Further tDCS studies in larger samples of aphasic patients are necessary to identify which patients (lesion location · language impairment · time post-stroke) and which tDCS protocol (electrode montage · stimulation type (anodal vs. cathodal)) may be the best candidates for this approach. Development of current models to account for these multiple factors would ensure translation and successful implementation of treatment research findings into novel and timely clinical practice.

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Received March 29, 2015 Accepted October 14, 2015 Published online March 23, 2016

About the author Jenny Crinion is a Welcome Trust Senior Research Fellow in Clinical Science and joint leader of the Neurotherapeutics Group at the Institute of Cognitive Neuroscience, University College London, UK. Her research focuses on understanding the neural mechanisms underpinning language recovery. The group’s mission is to develop novel, evidenced-based therapies for patients with aphasia and related disorders and to investigate how, at a neural network level, these therapies work.

Jennifer Crinion Institute of Cognitive Neuroscience University College London 17 Queen Square London WC1N 3AZ UK Tel. +44 (0)207 679 1129 Fax +44 (0)207 813 2835 E-mail j.crinion@ucl.ac.uk

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Special Issue: Noninvasive Brain Stimulation Original Articles and Reviews

Transcranial Electrical Stimulation (tES) for the Treatment of Neuropsychiatric Disorders Across Lifespan Carolina Pérez,1 Jorge Leite,1,2 Sandra Carvalho,1,2 and Felipe Fregni1 1

Spaulding Neuromodulation Center, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2Neuropsychophysiology Laboratory, CIPsi, School of Psychology (EPsi), University of Minho, Braga, Portugal Abstract. Transcranial electrical stimulation (tES) is a safe, painless, and inexpensive noninvasive brain stimulation (NIBS) technique. tES has been shown to reduce symptoms in a variety of neuropsychiatric conditions such as depression, schizophrenia, anxiety, autism, and craving. There are many factors that can influence the effects of tES, such as current intensity, duration, baseline level of activity, gender, and age. Age is a critical variable, since the human brain undergoes several anatomical and functional changes across the lifespan. Therefore, tES-induced effects may not be the same across the lifespan. In this review we summarize the effects of tES, including tDCS, tACS, and tRNS, on clinical outcomes in several neuropsychiatric conditions, using a framework in which studies are organized according to the age of subjects. The use of tES in neuropsychiatric disorders has yielded promising results with mild, if any, adverse effects. Most of the published studies with tES have been conducted with tDCS in adult population. Future studies should focus on interventions guided by surrogate outcomes of neuroplasticity. A better understanding of neuroplasticity across the lifespan will help optimize current tES stimulation parameters, especially for use with children and elderly populations. Keywords: Transcranial electrical stimulation, neuropsychiatric disorders, lifespan

Transcranial electrical stimulation (tES) techniques have been widely used for treating a variety of neuropsychiatric conditions. tES has shown promising results in ameliorating symptomatology in subjects that failed to respond to conventional treatments. Studies have shown that the clinical beneficial effects of these techniques are followed by changes at neuronal level, as measured by neuropsychological tools (Fidalgo et al., 2014). Moreover, these changes outlast the period of stimulation for most clinical conditions, showing sustained effects of tES interventions (Goldsworthy, Pitcher, & Ridding, 2014). However, most of the studies were performed in adults, making it difficult to understand the effects of tES across the lifespan. Across the lifespan, the human brain undergoes several neuroplastic changes at both the neuroanatomical and European Psychologist 2016; Vol. 21(1):78–95 DOI: 10.1027/1016-9040/a000252

neurofunctional level. For instance, during healthy aging there are several cognitive changes that occur (Salthouse, 2009), which have been associated with changes at the macrostructural level of the brain, mainly to an increased ventricular volume and brain shrinkage (see Fjell & Walhovd, 2010 for review). The annual reduction in cortical thickness can be up to 1% (Raz et al., 2005). Similarly, while there is a trend for global increase in white matter during childhood and adolescence, the total volume seems to peak around the age of 50, starting then to gradually decrease (Westlye et al., 2009). In the developing brain, on the other hand, there are several mechanisms such as apoptosis, where a programmed neural death is undertaken, limiting the neural overgrowth (Kuan, Roth, Flavell, & Rakic, 2000), ensuring the correct morphology and function Ó 2016 Hogrefe Publishing

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development (e.g., Fuchs & Steller, 2011). These changes support the notion that plasticity mechanisms are different across the lifespan. For instance, the decrease of white and gray matter in the elderly has an effect of how neural networks respond to electrical stimulation. However, although evidence seems to suggest that plasticity is indeed different across lifespan, it is not clear how different is the response to brain stimulation when comparing the neural response in a younger versus older subject. tES is a safe, painless, and inexpensive noninvasive brain stimulation (NIBS) technique . It uses a battery-driven current stimulator to apply weak electrical currents directly to the head (Priori, 2003). Depending on the number of sessions and the tES modality, the generated electrical fields are able to neuromodulate ongoing neuronal activity and induce neuroplasticity. There are various systems of classifying tES techniques. We used the one that was recently published (Guleyupoglu, Schestatsky, Edwards, Fregni, & Bikson, 2013). Therefore, we revise studies using direct current stimulation (tDCS), transcranial alternating current stimulation (tACS); transcranial pulsed current stimulation (tPCS), or transcranial random noise stimulation (tRNS). Short-term effects of tDCS are associated with induced changes in membrane polarization depolarization under anodal tDCS and hyperpolarization under cathodal tDCS – without inducing action potentials in the cortical neurons (Fregni et al., 2014; Nitsche et al., 2008; Tehovnik, 1996; Wagner et al., 2007). Long-term effects of tDCS are likely to be explained by neuroplastic processes of long-term potentiation (LTP) and long-term depression (LTD) (Nitsche, Muller-Dahlhaus, Paulus, & Ziemann, 2012; Nitsche et al., 2008). Less is known about the mechanisms of action of tACS, tRNS, and tPCS. tACS consists of delivering an oscillatory electrical current to the head in a frequency-specific fashion, causing an interference with ongoing oscillatory brain activity and inducing changes in cortical excitability as measured by electroencephalography (Antal & Paulus, 2013). tRNS is a new technique that consists of applying alternating current at random frequencies to the head, ranging from 0.1 Hz to 640 Hz. Some studies have found that high-frequency tRNS (hf-tRNS; 101–640 Hz) is able to increase motor cortical excitability (by inducing depolarization), as measured by MEP (Motor Evoked Potential) amplitude increase; these changes outlast the duration of the stimulation (Chaieb, Antal, & Paulus, 2011; Terney, Chaieb, Moliadze, Antal, & Paulus, 2008). hf-tRNS is also able to improve performance in perceptual learning task when compared to low-frequency tRNS (lf-tRNS; 0.1– 100 Hz), placebo stimulation, and active tDCS (anodal and cathodal) (Pirulli, Fertonani, & Miniussi, 2013). tPCS consists of delivering pulsed current at different frequency ranges through surface electrodes placed on the ears. Modeling studies show that tPCS-induced effects can reach cortical and subcortical areas (Datta, Dmochowski, Guleyupoglu, Bikson, & Fregni, 2013). It can interact with endogenous oscillatory activity inducing significant changes in cortical excitability measured by quantitative electroencephalography (Castillo Saavedra et al., 2014; Morales-Quezada et al., 2014). Ó 2016 Hogrefe Publishing

There are many factors that can influence the effects of tES, such as intensity, duration, baseline level of activity, gender, and age (Krause & Cohen Kadosh, 2014). Age is a critical variable, since the human brain undergoes several anatomic and functional changes across the lifespan. For instance, research has shown that between childhood and adolescence there is a phenomenon called synaptic pruning (Chechik, Meilijson, & Ruppin, 1999), where some synapses are eliminated. Research shows also that the maturation of the frontal lobe is not completed until adulthood (Johnson, Blum, & Giedd, 2009). The adult brain, on the other hand, is quite anatomically stable, with most neuroplasticity processes resulting mainly from new learning experiences, damage, or other types of neuromodulation. Therefore, the objective of this review is to summarize the available literature about the effects of tES in treating neuropsychiatric conditions using a framework in which studies are classified according to the age of participants. The neuropsychiatric conditions discussed are mood disorders (Major Depression and Bipolar disorder), schizophrenia, anxiety (Anxiety, OCD spectrum, and stress-related disorders), autism spectrum disorders (ADS), and craving disorders (alcohol, smoking, drugs, and food).

Methodology For this literature review, we performed an electronic search in PubMed database for articles published from January 2000 through January 2015, combining tES (and its variants) with different neuropsychiatric disorders as keywords. Only articles with the keywords of the neuropsychiatric disorder in the title were retrieved and inspected. The references of the retrieved papers were manually inspected. Studies retrieved were summarized according to the neuropsychiatric condition and age category. For the purpose of this review, children and adolescents were defined as being younger than 18 years old, adults as between 18 and 65 years old, and the elderly as over 65 years old. A total of 61 studies were analyzed, including case reports, openlabel studies, and Randomized Clinical Trials (RCTs).

Transcranial Electrical Stimulation in Neuropsychiatric Disorders Mood Disorders Major Depression Disorder (MDD) MDD is characterized by persistent low mood, low selfesteem, and loss of interest or pleasure in most daily activities. Functionally, depression is associated with increased right hemisphere activation and decreased left hemispheric activation (Nitsche, Boggio, Fregni, & Pascual-Leone, 2009). In addition, depression has been associated with European Psychologist 2016; Vol. 21(1):78–95

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dysfunctional plasticity (Normann, Schmitz, Furmaier, Doing, & Bach, 2007; Spedding, Neau, & Harsing, 2003). Therefore, tES interventions aim to increase LTPlike plasticity, increase left hemisphere activity, and/or decrease right hemisphere activity (Schonfeldt-Lecuona et al., 2010). There are 13 studies using tDCS and one case report using tRNS in adults with MDD. We also retrieved one case report using tDCS in elderly adults with MDD. Effects in Adults Anodal tDCS protocols, which aim to increase activity over the left hemisphere, have successfully shown symptom amelioration in major depression (see Table 1). Anodal tDCS over the left DLPFC for five consecutive days is able to induce significant clinical improvements in newly diagnosed patients (Fregni et al., 2006). Increasing the current intensity (up to 2 mA) and the number of sessions (15) sustains the clinical improvement up to 1 month (Boggio, Rigonatti, et al., 2008; Knotkova et al., 2012; Loo et al., 2012); this effect is comparable to the one found with 20 mg of fluoxetine (Rigonatti et al., 2008). Bi-frontal tDCS protocols (i.e., anode over the left DLPFC and cathode over the right DLPFC) have also been showing promising results (Brunoni, Ferrucci, et al., 2013; Brunoni et al., 2011; Dell’Osso et al., 2012). A study assessing the effects of bi-frontal tDCS, sertraline, or the combination of both found that tDCS alone improved depression ratings significantly and similarly extension to that of sertraline. Remarkably enough, the combination of tDCS and sertraline was more effective than each intervention alone (Brunoni, Valiengo, et al., 2013). Nonetheless, there are some trials where anodal tDCS in the left hemisphere (Palm et al., 2012) and bi-frontal tDCS (Blumberger, Tran, Fitzgerald, Hoy, & Daskalakis, 2012) were not effective in reducing depressive symptomatology. Another trial (Loo et al., 2012) showed that anodal tDCS over the left DLPFC was able to significantly improve mood, but with a similar remission rate (i.e., 13%) when compared to sham. The use of weaker currents, reduced number of sessions, or greater depression severity contribute to explain the negative results. Interestingly enough, moving the return electrode to an extra-cephalic position increased the initial treatment response in patients that were resistant to bi-frontal tDCS (Martin et al., 2011). If ‘‘continuation tDCS’’, given weekly during 3 months and then once per fortnight for another 3 months, is performed after the acute daily tDCS, the remission rate seems to be kept at about 80% after 3, and 50% after 6 months (Martin et al., 2013). So far, there is one case report where transcranial random noise stimulation (tRNS) was able to decrease the depression clinical ratings in a female patient. After 15 sessions of 1 mA tRNS with electrodes positioned at F3 and F8, the patient improved 63% in the Montgomery-Asberg Depression Rating Scale (MADRS), compared with 31% and 25% improvement in the two previous treatments of 15 daily sessions of tDCS using the same electrode montage (Chan et al., 2012). European Psychologist 2016; Vol. 21(1):78–95

Effects in Elderly Adults There is one case report with tDCS in the elderly adult population as a potential treatment for major depression (Shiozawa, da Silva, et al., 2014). A 92-year-old patient was subjected to 10 daily sessions of tDCS (2 mA for 30 min) with the anode electrode placed over the left DLPFC and the cathode electrode over the contralateral deltoid. This resulted in a 17-point decrease in the Hamilton Depression Rating Scale (HAM-D) when comparing to the baseline. This effect was sustained for 3 weeks. Bipolar Disorder Manic symptoms in bipolar disorder may be associated with the opposite pattern of prefrontal activation found in MDD – right hypoactivity and left prefrontal hyperactivity; this makes tES an attractive intervention to be tested in clinical trials. So far, there is only one study published on tES for adults with Bipolar disorder (see Table 1). This study was a case report, showing that five consecutive days of 2 mA/20 min anodal tDCS over the right DLPFC was able to induce fast alleviation of acute symptoms (Schestatsky, Janovik, et al., 2013).

Schizophrenia Schizophrenia is a severe and disabling chronic disorder characterized by hallucinations, delusions, and disorganized speech, behavior, and thinking. The pathophysiology involved in schizophrenia is still largely unknown, however several functional and anatomical brain changes have been reported in the literature (Meyer-Lindenberg & Tost, 2014). Neuroimaging studies have shown that schizophrenia patients with hallucinations exhibit hyperactivity on the left temporo-parietal area (McGuire, Shah, & Murray, 1993), Broca’s area (Jardri, Pouchet, Pins, & Thomas, 2011; McGuire et al., 1993), its right homolog (Dierks et al., 1999; Silbersweig et al., 1995), Heschl’s gyrus (Dierks et al., 1999), and the superior temporal gyrus (Jardri et al., 2011; Shergill, Brammer, Williams, Murray, & McGuire, 2000). In addition, hypoactivity over the prefrontal cortex has been described and associated with the development of positive symptoms and cognitive function impairments (Lawrie, McIntosh, & Nadeem, 2002; Takeshi, Nemoto, Fumoto, Arita, & Mizuno, 2010). Young adulthood seems to be the critical stage for the development of schizophrenia. Nonetheless, the childhood-onset is a rare and severe form of schizophrenia (Nicolson & Rapoport, 1999) that seems to be continuous with the adult-onset (David et al., 2011). Neuroimaging studies show it is similar to the neurophysiology seen in adults (Heimer, Harlan, Alheid, Garcia, & de Olmos, 1997; Shergill, Bullmore, Simmons, Murray, & McGuire, 2000; Silbersweig et al., 1995). So far, there are eight case studies, two open-label studies, and six RCTs assessing the effects of tES in adult patients with schizophrenia (see Table 2). Only one study has been conducted in children with childhood-onset Ó 2016 Hogrefe Publishing

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10 (5)

64 (28)

11 (8)

MDD

Martin MDD et al. (2011) Martin MDD et al. (2013)

Anodal over F3

tDCS Sham controlled, double-blind RCT/open label fluoxetine Case report tDCS

Elderly (92) Case report

1 (M)

tDCS

Anodal over F3

2 mA

35 cm2

25 cm2

35 cm2

36 cm2

35 cm2

32 cm2

N/A

2 mA

35 cm2

Cathodal over the right deltoid

Cathodal over the left SO

Cathodal over the right SO

N/A

35 cm2

20 min/twice a day for five consecutive days. 20 min/twice a day for five consecutive days.

20 min/day for 15 consecutive days excluding weekends.

Treatment protocol

2 mA

30 min/day for 10 consecutive days excluding weekends.

tDCS – 30 min/day for 10 consecutive days excluding weekends followed by two sessions every other week. Sertraline – 50 mg/day. 2 mA range – 20 min/day for 4 weeks 1 mA offset excluding weekends. 2 mA 20 min/twice a day for five consecutive days. 1 mA 20 min/day for five alternating days. 2 mA 20 min/day for 10 consecutive days excluding weekends. 2 mA 20 min/day for 15 consecutive days excluding weekends. 2 mA 20 min/day for 20 consecutive days excluding weekends. 2 mA Continuation treatment for 20 min/session weekly for the first 3 months and one per fortnight for the final 3 months. 1 mA (10 subjects) 20 sessions (10 active/10 2 mA (12 subjects) sham) for 20 min/day within 4 weeks. No washout period. 2 mA 20 min/day for 10 consecutive days excluding weekends. 2 mA 20 min/day for five consecutive days.

2 mA

Intensity/ frequency

35 cm2

Active electrode size

Cathodal over the 35 cm2 right upper arm 35 cm2 Study 1 – Cathodal over F8. Study 2 – Cathodal over the right upper arm Cathodal over 35 cm2 the right SO

Cathodal over the right SO Cathodal over the right SO Cathodal over F8

Cathodal over F4

Cathodal over F8

Cathodal over F4

Reference electrode

Results

Positive

Negative (no significant difference) Positive

Positive

HAM-D, BAI, MOCA

Positive

YMRA, NOISE

BDI, HDRS

Surviving without Positive relapse, time to relapse, MADRS HDRS, BDI, CGI, Negative PANAS (no significant difference)

MADRS

MADRS, IDS, CGI-S

HDRS, MADRS

HDRS, BDI

MADRS, HDRS

MADRS, QIDS

MADRS, HDRS

HDRS, BDI

MADRS, HRSD-17, BPRS, BDI HDRS, BDI

Main outcomes

MDD = Major Depressive Disorder; F3 = left dorsolateral prefrontal cortex; F4 = right dorsolateral prefrontal cortex; F8 = right fronto-temporal region; SO = Supraorbital region; MADRS = Montgomery-Asberg Depression Rating Scale; HRSD = Hamilton Depression Rating Scale; BPRS = Brief Psychiatric Rating Scale; BDI = Beck Depression Inventory; QIDS = Quick Inventory of Depressive Symptoms; IDS = Inventory of Depressive Symptomatology; CGI-S = Clinical Global Impression – Severity of Illness; CGI = Clinical Global Impression; PANAS = Positive and Negative Affect Scale; BAI = Beck Anxiety Inventory; MOCA = Montreal Cognitive Assessment Scale; YMRA = Young mania rating scale (YMRS); NOSIE = Nurses’ Observation Scale for Inpatient Evaluation.

Adults (41)

1 (M)

Anodal over F4

Anodal over F3

tDCS

Sham controlled, double-blind crossover study

Open label prospective

Schestatsky, Bipolar Disorder Janovik, et al. (2013) MDD Shiozawa, da Silva, et al. (2014)

Adults (42–56)

Adults (36–79)

Anodal over F3 Anodal over F3 Anodal over F3 Anodal over F3 Anodal over F3

Anodal over F3

Anodal over F3 Anodal over F3

Anodal over F3

Anodal over F3 Anodal over F3

tDCS

tRNS

tDCS

Active Technique electrode

tDCS

Open label

Sham controlled, double-blind RCT

Sham controlled, double-blind RCT Open label

Open label

Case report

42 (28)

22 (14)

Adults (33–59) Adults (33-70)

Adults (35) Adults (18–80) Adults (32–52) Adults (38–59) Adults (35–61)

Placebo controlled, double-blind, factorial RCT

Open label

Sham controlled, double-blind RCT

Study design

Rigonatti MDD et al. (2008)

Palm MDD et al. (2012)

23 (15)

MDD

26 (18)

1 (F)

MDD

Chan et al. (2012) Dell’Osso et al. (2012) Fregni et al. (2006) Knotkova et al. (2012) Loo et al. (2012)

Adults (18–65)

120

82 (54)

Adults (30–70) Adults (43–65)

31 (23)

Brunoni MDD et al. (2011) MDD Brunoni, Ferrucci et al. (2013) Brunoni, MDD Valiengo, et al. (2013)

Adults (18–65)

24 (20)

Age group (years old)

Blumberger MDD et al. (2012)

Author

No. of subjects Condition (females)

Table 1. Studies on major depression disorder and bipolar disorder

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Sham controlled, tDCS double-blind RCT

Adults (27–51)

Adults (25–41)

Göder et al., 2013

Adults (31) Adults (29)

Adults (24) Adults (31)

Nawani Schizophrenia 1(M) et al. (2014) Palm Schizophrenia 1 (M) et al. (2013)

Rakesh Schizophrenia 1 (M) et al. (2013) Shiozawa Schizophrenia 1 (M) et al. (2013)

tDCS

Case – control, cross over study

tDCS

Case report

tDCS

tRNS

Case report

tDCS

Case report

Sham controlled, tDCS double-blind RCT

Case report

Sham controlled, so-tDCS double-blind, pseudorandomized trial Case report tRNS

Cathodal over the left temporo-parietal cortex

Cathodal over the midway between T3 and P3 (TPJ) Cathodal over the left temporo-parietal cortex

Reference electrode

Anodal over F3

Study 1 – Bilateral anodal over Fp1 and Fp2. Study 2 – Bilateral cathodal over T3 and T4 Anodal over F3

Cathodal over the left temporo-parietal junction (Wernicke’s area)

Anodal over F3

2 mA

35 cm2

Cathode over the right SO

Treatment protocol

20 min/day for 15 consecutive days excluding weekends.

20 min/twice a day for five consecutive days.

20 min/session twice a day for five consecutive days.

2 mA

35 cm2 35 cm

35 cm2

2 mA

2 mA range – 1 mA offset Frequency: 100–640 Hz 2 mA

2 mA

35 cm2

2 mA

25 cm2

Main outcomes

Positive

PANSS, AHRS

Negative (a subset did improve with tDCS, especially those with greater scores at baseline)

Positive

PANSS, AVH Positive frequency, source monitoring performances PoMS, Attention Positive testing (computerized) PANSS, SANS, Positive Calgary Depression Scale

Arterial spin labeling, Positive Hallucination Change Scale, PANSS, Psychotic Symptom Rating Scale Vital sign monitoring, Positive MMSE, EEG, EKG, MRI

Positive

AHRS, Insight Rating Scale PANSS, Launay-Slade Hallucination Scale and the AHRS

Results

Negative (no significant difference)

Positive

Rey Auditory-Verbal Learning Test

PANSS, SANS, Calgary Depression Scale

PANSS, AHRS

AHRS, PANSS

PSYRATS, SAI, AHS

Intermittent boosters of two AHS of the PSYRATS sessions per day of 20 min for a single day as maintenance treatment of hallucinations. 20 min/session. One active and WAIS-III, one sham session on a randomized WTAR, PANSS order and a washout period of 8 day in average.

20 min/session twice a day for five consecutive days. 20 min/day for 20 consecutive days.

20 min/session twice daily for five consecutive days. 20 min/session twice a day for 10 consecutive days.

20 min/session twice a day for five consecutive days.

20 min/day for 10 consecutive days excluding weekends.

8 mm Frequency: 0.75 Hz Sleep phase 2–5 blocks diameter Intensity: as tolerated of five min sessions of between 0 and 300 lA stimulation/1 min interval free of stimulation. 2 2 mA range – 1 mA 20 min/session twice a 35 cm offset Frequency: day for five consecutive days. 100–640 Hz 2 35 cm 1 mA 15 min/daily for 10 consecutive days.

2 mA

N/A

2 mA

35 cm2

Intensity/frequency 2 mA

35 cm2

Active electrode size

Cathodal over the left 35 cm2 temporo-parietal junction. First 10 sessions – Cathodal 35 cm2 on the occipital area. Last 10 sessions – Cathodal on the left temporo-parietal area Cathodal over the left 35 cm2 temporo-parietal junction

Cathodal over the left temporo-parietal area Cathodal over the right orbitofrontal region

Cathode over the left temporo-parietal junction

Reference electrode on the nondominant forearm

Anodal over the right SO

Cathodal over the left temporo-parietal junction

1. Unilateral tDCS Cathodal over the – Anodal over F4 right temporo-parietal area 2. Bilateral tDCS – Anodal over the F3 and F4 Electrodes were located on F3 and F4 and at the mastoids.

Anodal over F3

Active electrode

PSYRATS = The Psychotic Symptom Rating Scales; SAI = Schedule for Assessment of Insight; AHS = Auditory hallucinations Score; AHRS = Auditory Hallucination Rating Scale; PANSS = Positive and Negative Syndrome Scale; MMSE = Mini-Mental State Examination; EEG = Electroencephalogram; EKG = Electrocardiogram; MRI = Magnetic Resonance Imaging; AVH = Auditory Verbal Hallucination; PoMS = Profile of Mood State; WAIS-III = Wechsler Adult Intelligence Scale III; WTAR = Wechsler test of Adult Reading; F3 = Left dorsolateral prefrontal cortex; F4 = Right dorsolateral prefrontal cortex, Fp1 = Left fronto-parietal cortex; Fp2 = Right fronto-parietal cortex; T3 = Left temporal cortex; T4 = Right temporal cortex; SO = Supraorbital region; M = Male; F = Female.

Adults (19–42)

Adults (26–58)

Mondino Schizophrenia 28 (16) et al. (2015)

Vercammen Schizophrenia 20 (10) et al. (2011)

Children (10–17)

Mattai Schizophrenia 12 (7) et al. (2011)

Adults (42)

Adults (44)

Homan Schizophrenia 1 (M) et al. (2011)

Shivakumar Schizophrenia 1 (F) et al. (2014)

Adults (26)

Haesebaert Schizophrenia 1 (F) et al. (2014)

Schizophrenia 14

Case series

Adults (46, 29)

tDCS

Sham controlled, tDCS double-blind RCT

Adults (30–50)

Technique tDCS

Brunelin, Schizophrenia 30 (8) Mondino, Gassab, et al. (2012) Brunelin, Schizophrenia 2 Mondino, Haesebaert, et al. (2012) Fitzgerald Schizophrenia 24 (9) et al. (2014)

Study design

Open label

Adults (20–45)

Condition

Bose Schizophrenia 21 (12) et al. (2014)

Author

No. of Age subjects group (females) (years old)

Table 2. Studies on schizophrenia

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schizophrenia. Most of them used tDCS, while only two of them investigated tRNS effects in schizophrenia. Effects in Children/Adolescents Only one study in this category was published so far, which aimed to investigate the tolerability of tDCS in childhoodonset schizophrenia (Mattai et al., 2011). In this study, 13 children were assigned randomly to receive either bilateral anodal DLPFC tDCS (n = 8) or bilateral cathodal superior temporal gyrus (STG) tDCS (n = 5). Although no significant clinical improvements were reported, tDCS within the applied parameters seemed to be well tolerated in children. Effects in Adults tES has been tested using two main approaches. One is increasing cortical excitability in the abnormally depressed frontal areas in order to improve the cognitive function and negative symptoms. The other is inhibiting the hyperactivity on the temporo-parietal areas, which is thought to be related with positive symptoms such as hallucinations. Most of the studies using both strategies have shown promising results. Several case reports, open-label studies, and RCTs investigating tDCS effects in order to decrease negative symptoms in schizophrenia have mainly used anodal stimulation over the DLPFC. This intervention with sessions ranging from 1 to 10 was able to improve cognitive functioning, namely working memory, verbal fluency, learning, and insight facilitation (Bose et al., 2014; Vercammen et al., 2011). With the aim of improving positive symptoms, several cathodal tDCS protocols over the fronto-temporal area have been conducted and shown both monotherapy and add-on therapy of tDCS significantly decreased auditory and verbal hallucinations (Brunelin, Mondino, Gassab, et al., 2012; Brunelin, Mondino, Haesebaert, et al., 2012; Homan et al., 2011; Mondino, Haesebaert, Poulet, Suaud-Chagny, & Brunelin, 2015; Nawani et al., 2014; Rakesh et al., 2013; Shiozawa, da Silva, Cordeiro, Fregni, & Brunoni, 2013; Shivakumar et al., 2014). Despite the promising results of tDCS in Schizophrenia, there are also negative findings. In two small RCTs testing the effects of anodal tDCS over DLPFC and cathodal stimulation over the temporo-parietal junction, both unilaterally and bilaterally, no effects were found in either hallucinations or negative symptoms (Fitzgerald, McQueen, Daskalakis, & Hoy, 2014). One possible explanation for these negative results is that tDCS was administered once daily, in contrast to other studies where tDCS was administered twice daily. Also, in this negative study, the population was noticeably heterogeneous, which could have also contributed to the failure of the therapy (Fitzgerald et al., 2014). One study used intermittent tDCS (as current intensity varies over time) in schizophrenic patients (Göder et al., 2013). Sinusoidal currents at the same frequency of slow sleep oscillations, when delivered during non-rapid eye Ó 2016 Hogrefe Publishing

movement sleep, were able to improve mood and the retention of verbal materials in 14 patients. tRNS has also been recently studied for the management of schizophrenia. So far, two case reports were published. In one anodal tRNS over the DLPFC, it was shown to substantially improve positive symptoms and paranoia (Haesebaert, Mondino, Saoud, Poulet, & Brunelin, 2014); while on the other, anodal tRNS over DLPFC significantly decreased the negative symptoms (Palm, Hasan, Keeser, Falkai, & Padberg, 2013).

Anxiety: Generalized Anxiety Disorder (GAD) Cathodal tDCS protocols, which aim to decrease activity over the right DLPFC, have successfully shown symptom amelioration in GAD. There are only four studies using tES in adults with GAD: one using tDCS and three other with tPCS (see Table 3).

Effects in the Adults A case report showed that cathodal tDCS over the right DLPFC, applied during 15 sessions, substantially improved anxiety symptoms in a female subject with severe refractory GAD. Interestingly, 1 month after the tDCS intervention the subject was reported to be asymptomatic with several significant clinical improvements (Shiozawa, Leiva, et al., 2014) tPCS has also shown significant effects in adults with GAD. Three studies using daily tPCS reduced both anxiety and comorbid, depressive symptoms in adults with GAD. Daily tPCS at a frequency of 0.5 Hz 60 min for 6 weeks had significant clinical effects in patients with anxiety and concomitant depression (Bystritsky, Kerwin, & Feusner, 2008). In the same line, daily 60 min of tPCS delivered at a frequency of 0.5 Hz, during 5 weeks, in 115 subjects, was able to reduce both anxiety and comorbid, depressive symptoms in adults with GAD (Barclay & Barclay, 2014). tPCS was also able to reduce anxiety levels and withdrawal responses in undergoing thyroidectomy as compared to placebo stimulation (Lee et al., 2013).

Obsessive-Compulsive (OCD) Spectrum Disorders Obsessive-Compulsive Disorder (OCD) OCD is a neuropsychiatric disorder, characterized by the presence of repetitive, upsetting, and unwanted thoughts and/or images and behavior and/or mental rituals. Cortico-striato-thalamo-cortical (CSTC) loops are implicated in the pathophysiology of OCD (Goncalves et al., 2011). Effects in Adults There are two case studies published using tDCS in adults with OCD. Anodal tDCS applied twice a day, European Psychologist 2016; Vol. 21(1):78–95

Tourette Syndrome

Preoperative 50 (50) anxiety

OCD

Carvalho et al. (2014)

Lee et al. (2013)

Narayanaswamy et al. (2014)

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4 (0)

PTSD

GAD

OCD

Saunders et al. (2014)

Shiozawa et al. (2014)

Volpato et al. (2013)

Adults (35)

Adults (58)

Adults (55–65)

Children (10–14)

Adults (39, 24)

Adults (35–60)

Technique

Open label

tDCS

Case report

Pilot study

tDCS

Sham controlled, so-tDCS double-blind, case control crossover study

Case series

Sham controlled, tPCS double-blind RCT

tDCS

tPCS

Sham controlled, tPCS double-blind RCT

Adolescent Case report (16)

Adults (29–58)

Adults (28–56)

Study design

Anodal extra-cephalic on the right deltoid muscle

Reference electrode

25 cm2

N/A

Active electrode size Frequency: 0.5 Hz Intensity: minimum of 100 lA Frequency: 0.5 Hz Intensity: as tolerated between 10 and 500 lA 1.425 mA

Intensity/frequency

30 min/daily for 1-consecutive day excluding weekends.

60 min/day for 6 weeks.

1 hr/day for 5 weeks.

Treatment protocol

YGTSS, fMRI signals

HAM-A, CGI-S, CGI-I, HAM-D

HAM-A, HAM-D

Main outcomes

Clipped electrodes on both earlobes

N/A

Frequency: 0.5 Hz Intensity: 100 lA

20 min/session. One session on the night before surgery and another one on the morning of surgery.

Anxiety Scores, Pain Scores, ACTH and Cortisol levels, withdrawal response to Rocuronium Anodal over the left Cathodal over 35 cm2 2 mA 20 min/twice daily for YBOCS, HAM-A, pre-SMA/SMA the right SO 10 consecutive days. HAM-D, fMRI BOLT signal ‘‘Concentration or 8 mm Sleep phase 2–5 Electrodes were Frequency: 0.75 Hz Memory’’ Task, located on F4 and diameter Intensity: as tolerated blocks of 5 min Wechsler sessions of F3 and at the mastoids. between 0 and Intelligence Scale for stimulation/1 min 250 lA Children, interval free of Polysomnography stimulation. EEG Anodal over F3 Cathodal over 35 cm2 Cognitive and 1 mA 20 min/session once the right SO emotional a week for five assessments; P3 ERP consecutive weeks. Cathodal over F4 Anodal extra-cephalic 25 cm2 GAD 7 item scale, 2 mA 30 min/day for 15 over the contralateral Beck Anxiety consecutive days deltoid Inventory, excluding weekends. HAM-A, HAM-D Cathodal over F3 Anodal over the 35 cm2 2 mA 20 min/day for 10 fMRI, YBOCS, posterior neck base consecutive days HAM-A, HAM-D excluding weekends.

Cathodal over the left pre-SMA

Clipped electrodes on both earlobes

Active electrode

Results

Negative (no effect on OC symptoms, only in depression and anxiety)

Positive

GAD = Generalized Anxiety Disorder; OCD = Obsessive-Compulsive Disorder; ADHD = Attention Deficit and Hyperactivity Disorder; PTSD = Post-traumatic Stress Disorder; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; CGI-I = The Clinical Global Impressions Scale (Improvement Index); CGI-S = The Clinical Global Impressions Scale (Severity Index); YGTSS = Yale Global Tic Severity Scale; fMRI = Functional Magnetic Resonance Imaging; ACTH = Adrenocorticotropic Hormone; EEG = Electroencephalogram; YBOCS = Yale-Brown Obsessive Compulsive Scale; SAM = Supplementary Motor Area; F3 = Left Dorsolateral Prefrontal Cortex; F4 = Right Dorsolateral Prefrontal Cortex; SO = Supraorbital region; OC = Obsessive-Compulsive; M = Male; F = Female; P3 ERP = P300 Event Related Potential.

1 (M)

1 (F)

ADHD: 12 (0)

Prehn-Kristensen ADHD et al. (2014)

2 (1)

1 (M)

12 (9)

GAD

Bystritsky et al. (2008)

115 (78)

GAD

Condition

Barclay and Barclay (2014)

Author

Age No. of group subjects (females) (years old)

Table 3. Studies in anxiety disorders

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during 10 days, over the pre- and supplementary motor area (pre-SMA/SMA) leads to significant clinical improvements in obsessions, compulsions, depressive and anxiety symptoms in two selective serotonin reuptake inhibitor-resistant (SSRI) OCD patients (Narayanaswamy et al., 2014). In another case study, tDCS had no effects on obsessivecompulsive symptoms, however it reduced anxiety and depression levels (Volpato et al., 2013).

by difficulties in sustained focus, attention, inhibition control, and/or hyperactivity. Neuroimaging data shows that these symptoms are related to abnormal cortical activity in frontal, parietal, and cingulate regions (Bush, 2011). Given the chronic nature of this disorder and limited effects of pharmacological agents, tES is an attractive option to be tested. In fact, only one study was published so far using tES in children with ADHD.

Tourette Syndrome

Effects in Children/Adolescents

TS is characterized by the presence of rapid, stereotyped movements and vocalizations (i.e., tics) (Vicario et al., 2010). Neuroimaging data shows that tics severity is associated with increased activation over motor pathways and reduced activation over the control areas of the corticostriato-thalamo-cortical circuits (Wang et al., 2011). The temporal pattern of tic generation suggests that cortical precedes subcortical activation, with the SMA playing a key role in tics generation (Neuner et al., 2014).

So far, only one study has been published using tES in children with ADHD (see Table 3). Transcranial oscillating direct current stimulation applied bilaterally to the DLPFC at 0.75 Hz during slow wave sleep was able to increase slow wave power and boost memory performance in 12 children with ADHD to a level similar to that of healthy controls (Prehn-Kristensen et al., 2014). It is worthy to note that the patients were regularly taking methylphenidate but were asked to discontinue their treatment for the study sessions.

Effects in Adolescents There is only one case report testing the feasibility of this approach in an adolescent with TS. This study shows that delivering 10 daily sessions of cathodal tDCS over the pre-SMA is able to decrease tic severity, which can be sustained up to 6 months (Carvalho et al., 2014). No studies have been published so far in adults or elderly adults.

Post-Traumatic Stress Disorder (PTSD) PTSD is a neuropsychiatric disorder that is developed after exposure to life-threatening situations. A recent metaanalysis showed that when exposed to negative stimulus, PTSD patients exhibit an amygdala and mid-ACC hyperactivation, accompanied by decreased activation over the lateral and medial prefrontal cortex (Hayes, Hayes, & Mikedis, 2012). For PTSD, there is only one pilot study. Effects in Adults In a pilot study involving four subjects, anodal tDCS over the left DLPFC in combination with working memory (WM) training induced significant clinical improvements in patients with PTSD and poor WM (Saunders et al., 2014).

Attention-Deficit and Hyperactivity Disorder (ADHD) ADHD is a disabling brain condition, highly prevalent in childhood and continuing throughout adolescence into adulthood (Sharma & Couture, 2014). It is characterized Ó 2016 Hogrefe Publishing

Autism Spectrum Disorders (ASD) ASD are characterized by severe social communication deficits with repetitive behaviors or restrictive interests (Anagnostou & Taylor, 2011). Neuroimaging data suggests changes in connectivity. Cortical-cortical connectivity is decreased, while subcortical-cortical connectivity is increased, thus suggesting an ineffective system with abnormal signal-to-noise ratio (Minshew & Keller, 2010). There are also evidences of abnormal cortical excitability and plasticity. More specifically, an altered synapse development in regions related to language and social skills in the frontal and prefrontal cortices has been thought to create an imbalance of excitation and inhibition, leading to an inappropriate hyperactivity of the brain (Rubenstein & Merzenich, 2003). Furthermore, several studies have identified a reduction in the GABAergic activity in these regions in patients with autism (Oberman, Pascual-Leone, & Rotenberg, 2014). There is limited data on the therapeutic effects of tES on autism. There are three published studies: one open label in children, one RCT in children, and one case study in adults (see Table 4). Effects in Children/Adolescents In an open-label study, anodal tDCS over the Broca’s area was able to improve language acquisition in 10 autistic children with minimal verbal language (Schneider & Hopp, 2011). A recent study, conducted in 2014 with 20 autistic children, showed that five consecutive daily sessions of anodal tDCS applied over the DLPFC were able to significantly decrease symptomatology on several standardized scales (Amatachaya & Auvichayapat, 2014). These effects outlasted tDCS for 7 days. European Psychologist 2016; Vol. 21(1):78–95

1.5 mA

2 mA

25 cm2

25 cm2 Open label ASD Schneider and Hopp (2011)

10 (2)

Children/adolescents (6–14)

tDCS

Anodal over F3

Anodal extracephalic over the right deltoid Cathodal over the right SO Cathodal over F3 tDCS Adults (26) ASD D’Urso et al. (2014)

1 (M)

ASD Amatachaya and Auvichayapat (2014)

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ASD = Autism Spectrum Disorders; CARS = Childhood Autism Rating Scale; ATEC = Autism Treatment Evaluation Checklist; CGAS = Children’s Global Assessment Scale; M = Male; ABC Score = Aberrant Behavior Checklist; F3 = Left Dorsolateral Prefrontal Cortex; SO = Supraorbital Region.

Positive Syntax testing

Positive

Results

1 mA Cathodal over the right shoulder tDCS

Sham controlled, double-blind crossover study Case report Children (5–8)

Condition Author

20 (0)

Technique

Anodal over F3

35 cm2

20 min/day for 10 consecutive days excluding weekends. 30 min of stimulation.

CARS, ATEC, CGAS ABC score

Main outcomes Treatment protocol Intensity Active electrode size Reference electrode Active electrode Study design Age group (years old) No. of subjects (females)

Table 4. Studies in autism spectrum disorders

Positive

C. Pérez et al.: tES for the Treatment of Neuropsychiatric Disorders

20 min/day for five consecutive days.

Effects in Adults Only one case study to date has been published reporting the use of electrical stimulation in the adult population. A refractory adult with autistic disorder received 10 sessions of cathodal tDCS over the DLPFC. The patient manifested an overall clinical improvement in his behavior that was still present 3 months after the stimulation had ended (D’Urso et al., 2014).

Craving Disorders Addictive disorders are characterized by abuse or dependence of a behavior or substance (e.g., tobacco). These disorders are thought to involve the brain reward network, where prefrontal regions play an important role in inhibitory control mechanisms (Bechara, 2005). Bi-frontal tDCS has been commonly used in addictive disorders because it is thought to modulate general decision-making process (Fecteau et al., 2007; Leite, Carvalho, Fregni, Boggio, & Goncalves, 2013). In fact, using tES for craving modulation has been one of the first applications tested in psychiatry. There have been five studies testing tES for food craving and 13 studies in drug craving (see Table 5). All of these studies were conducted in adults. Alcohol Craving/Addiction Five studies were conducted assessing the effects of tDCS on alcohol craving. Positive acute effects following right anodal/left cathodal and left cathodal/right anodal tDCS have been reported in alcohol craving (Boggio, Sultani, et al., 2008), as well as relapse reduction following consecutive sessions of tDCS (Klauss et al., 2014). This relapse prevention was also found when only the left DLFPC was stimulated (da Silva et al., 2013; Nakamura-Palacios et al., 2012). However, a recent study with heavy drinkers found no effects of stimulating the inferior frontal gyrus (den Uyl, Gladwin, & Wiers, 2014). Smoking Craving Six studies have been published assessing the effects of tDCS on tobacco craving. Bi-frontal tDCS is also effective in reducing the number of smoked cigarettes (Fregni, Liguori, et al., 2008), and when five consecutive sessions of bi-frontal tDCS (anodal left/cathodal right or cathodal left/anodal right) are applied, craving reductions were also observed (Boggio et al., 2009; Fecteau et al., 2014). Interestingly enough, it seems that if the anode is placed over the left DLPFC and the cathode over the contralateral supraorbital area, only mood (but no craving) is improved in overnight abstinent tobacco-dependent smokers (Xu, Fregni, Brody, & Rahman, 2013). Another study, using cathodal tDCS bilaterally over the frontal-parietal-temporal association area (FPT), was also able to significantly reduce daily cigarette consumption (Meng, Liu, Yu, & Ma, 2014). Ó 2016 Hogrefe Publishing

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Smoking craving

Alcohol craving

Smoking craving

Alcohol craving

Fregni, Liguori et al. (2008)

Klauss et al. (2014)

Meng et al. (2014)

Nakamura-Palacios et al. (2012)

24 (3)

30 (0)

49 (4)

30 (0)

33 (1)

24 (11)

12 (7)

41 (26)

13 (0)

25 (10)

27 (15)

13 (2)

Adults (28–59)

Adults (20–45)

Adults (39–58)

Adults (16–30)

Adults (36–55)

Adults (17–32)

Adults (21–64)

Adults (19–24)

Adults (20–26) Adults (29–59)

Adults (18–34)

Adults (35–47)

Age group (Years Old)

Sham controlled, double-blind, randomized, crossover study

Sham controlled, double-blind, randomized crossover study

Sham controlled, double-blind crossover study

Sham controlled, double-blind RCT

Sham controlled, double-blind, randomized crossover study Sham controlled, double-blind, randomized crossover study Sham controlled, double-blind RCT

Sham controlled, double-blind RCT

Sham controlled, double-blind, randomized crossover study Sham controlled, double-blind RCT Sham controlled, double-blind RTC

Sham controlled, double-blind crossover study

Study design Technique

tDCS

Anodal over F3

Anodal over F4

Anodal over F3

1. Cathodal over the right FPT 2. two cathodes over each FPT

Cathodal over F3

1. Anodal over F3 2. Anodal over F4

1. Anodal over F3 2. Anodal over the right inferior gyrus 1. Anodal F3 2. Anodal F4

1. Anodal F3 2. Anodal F3 Anodal over F3

Anodal over F3

1. Anodal over F3 2. Anodal over F4

Active electrode

Cathodal over the right SO

Cathodal over the left SO

1. Anodal over the left FPT 2. two anodes over the occipital lobes bilaterally Cathodal over the right supra-deltoid area.

Anodal over F4

1. Cathodal over F4 2. Cathodal over F3

Cathodal over the contralateral SO

1. Cathodal over F4 2. Cathodal over F3 Cathodal over the right supra-deltoid area.

Cathodal over F4

1. Cathodal over F4 2. Cathodal over F3

Reference electrode

2 mA

35 cm2

2 mA

35 cm2

1 mA

2 mA

35 cm2

2 mA

Anode: 35 cm2 Cathode: 100 cm2

1 mA

2 mA

35 cm2

6.5 cm diameter

1 mA

35 cm2

35 cm 2 mA

2 mA

Anode: 35 cm2 Cathode: 100 cm2

2 mA

Intensity/frequency

35 cm2

Active electrode size Treatment protocol

20 min/daily for a single session of each type in a randomized order, washout period of 48 hr

10 min/session for 2 sessions, one of each condition in a randomized order – 7 day washout period 20 min/session for a single session of each type in a randomized order. Washout period of 72 hr.

30 min/ daily for a single session of each type in a randomized order, washout period of 3 months. 20 min/session for a single session of each condition in a randomized order – 48 hr washout period. 13 min/twice daily with an interval of 20 min for five consecutive days. 20 min/session for one session only.

20 min/session for three sessions, one of each condition in a randomized order – 48 hr washout period. 20 min/daily for five consecutive days for each condition in a randomized order. 15 min/session for one session only. 20 min/weekly stimulation sessions for five consecutive weeks. 10 min/session, for a single session.

Main outcomes

PANAS, VAS for craving, Computerized cue-induced craving assessment task POMS, UTS, Attention testing (computerized)

FAB, OCDS, MMSE, ERPs

Alcohol use relapse, FAB, MMSE, OCDS, HAM-D Eye tracking, cigarette consumption, questionnaires about smoking sensations

Cigarette diary, time between awakening and first cigarette, FTND, BIS, BDI VAS for mood and smoking craving, FTND

SOCRATES Scale, SADD questionnaire, AUQ, VAS for mood VAS for mood and smoking craving, FTND, cigarette smoking diary VAS for craving, Risk task FAB, MMSE, OCDS, HAM-D, HAM-A, EEG, ERPs AIT, AAAQ, AUDIT

Results

Positive

SADD = Alcohol Dependence Data Questionnaire; AUQ = Alcohol Urge Questionnaire; VAS = Visual Analog Scale; FAB = Frontal Assessment Battery; MMSE = Mini-Mental State Examination; OCDS = Obsessive-Compulsive Drinking Scale; HAM-D = Hamilton Depression Rating Scale; HAM-A = Hamilton Anxiety Rating Scale; EEG = Electroencephalogram; ERPs = Event Related Potentials; AIT = Alcohol Implicit Association Test; AAAQ = The Approach and Avoidance of Alcohol Questionnaire; AUDIT = Alcohol Use Disorders Identification Test; FTND = Fagerstrom Test for Nicotine Dependence; PoMS = Profile of Mood State; BIS = Barratt Impulsiveness Scale; BDI = Beck Depression Inventory; PANAS = Positive and Negative Affect Schedule; F3 = Left Dorsolateral Prefrontal Cortex; F4 = Right Dorsolateral Prefrontal Cortex; FPT = Fronto-Parietal-Temporal; SO = Supraorbital region.

Smoking craving

Fecteau et al. (2014)

Xu et al. (2013)

Alcohol craving

den Uyl et al. (2014)

Methamphetamine craving

Marijuana craving Alcohol craving

Boggio et al. (2010) da Silva et al. (2013)

Shahbabaie et al. (2014)

Smoking craving

Boggio et al. (2009)

Condition

Alcohol craving

Author

Boggio, Sultani, et al. (2008)

No. of subjects (Females)

Table 5. Studies in drug craving disorders

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Marijuana and Methamphetamine Craving

Effects in Adults

Right anodal/left cathodal bi-frontal tDCS is also associated with diminished craving in chronic marijuana users (Boggio et al., 2010); and when the anode is placed over the right DLPFC and the cathode over the contralateral supraorbital region, craving is also reduced in the rest condition for methamphetamine users (Shahbabaie et al., 2014). But if a craving inducing task was performed, anodal tDCS actually increases craving revealing the state dependency effects (Shahbabaie et al., 2014).

Different NIBS techniques have been proposed as possible adjuvant therapies for eating disorders, however only one study has been performed using tES so far. Khedr, Elfetoh, Ali, and Noamany (2014) performed an open-label study in seven adults suffering from AN. These patients received a daily session of anodal tDCS over the left DLPFC for 10 consecutive days. Three subjects showed significant improvements after the intervention sessions and 1 month later, as assessed by three scales – The Eating Attitude Test (EAT), The Eating Disorder Inventory (EDI), and the Beck Depression Inventory (BDI). Two patients showed improvements only right after the intervention and only one showed improvements in mood as assessed by the BDI.

Food Craving Binge eating and food craving are important eating disorders with rapidly growing incidence. Food craving has been defined as the ‘‘irresistible urge to eat’’ and is directly related with overweight and obesity, turning it into a big public health concern. The pathophysiology behind this problem has been widely studied and has been found to be similar to that of addiction and drug craving, suggesting a shared nature and a similar possible treatment approach (Pelchat, 2009). Similar to other craving behaviors, food-craving behavior has been attributed to specific changes in inhibitory circuits in lateral prefrontal areas. Some abnormalities in dopaminergic pathways are also thought to lead to a deficient cortical inhibitory control (Goldstein & Volkow, 2011). Effects in Adults Five studies have been conducted assessing the effects of tDCS on food craving and overeating (see Table 6). Bi-frontal tDCS was able to reduce food-craving behavior and the consumption of food (Fregni, Orsati, et al., 2008). Several groups have replicated these results, more specifically when the anode is located over the right DLPFC and the cathode over the left DLPFC (Goldman et al., 2011; Kekic et al., 2014; Lapenta, Sierve, de Macedo, Fregni, & Boggio, 2014). Interestingly, the reduction of craving has been more prominent for sweet food and carbohydrates (Goldman et al., 2011). In an interesting study, the combination of anodal tDCS over the left DLPFC with aerobic exercises was able to decrease the urge to eat and increased satiety more than tDCS and exercise alone (Montenegro et al., 2012). Eating Disorders In addition to food-craving modulation in a healthy subject, studies have also been conducted in Anorexia and Bulimia Nervosa. These conditions are severe psychiatric conditions that represent a life-threating problem to patients. Neuroimaging data using taste/reward conditioning task suggest that brain-related dopaminergic activity is physiologically hypersensitive in Anorexia Nervosa (AN) and hyporesponsive in Bulimia Nervosa (BN) (Frank, 2015). European Psychologist 2016; Vol. 21(1):78–95

Discussion Transcranial electrical stimulation (tES), similar to other noninvasive brain stimulation techniques (NIBS), has been showing promising results as potential therapeutic interventions for mood disorders, schizophrenia, and craving in adults. Most of the studies so far have focused on adults. There are promising results for Depression, schizophrenia, Generalized Anxiety Disorder, Obsessive-compulsive disorder Post-traumatic Stress disorder, Autism, and craving disorders. But most of the studies reviewed seem to be lacking long-term assessments of tES efficacy. Studies on depression are an exception, where we have several studies with larger number of sessions, and extended follow-ups (Boggio, Rigonatti, et al., 2008; Brunoni, Ferrucci, et al., 2013; Brunoni, Valiengo, et al., 2013; Brunoni et al., 2011). There is still limited data about the effects of tDCS on children, which hinders the assessment of tES efficacy for this specific population. Potentially, one of the major concerns for using tES in children is safety. Krishnan, Santos, Peterson, and Ehinger (2015) reviewed safety concerns in 48 studies using NIBS in pediatric population with different neuropsychological conditions (with a total of 513 children/ adolescents). Most of the side effects reported in the literature are mild and transient. Therefore, if the standard parameters of stimulation are correctly followed, these techniques are quite safe for use in children. There is very limited data available on the effects of tES on the elderly for the treatment of neuropsychiatric conditions. There was one case report of tDCS in a 92-year-old patient with major depression. Due to the complex nature of depression and age, future systematic studies are needed in order to truly assess the results found in that study. Also it is important to note that tDCS on the aging brain could have a different impact than the one found in children and adults (Shiozawa, da Silva, et al., 2014). For instance, Fertonani, Brambilla, Cotelli, and Miniussi (2014) showed that anodal tDCS over the left DLPFC only improved naming task performance if it were applied during the actual task performance. While in younger adults the tDCS-dependent effects were identical regardless of the timing of tDCS Ó 2016 Hogrefe Publishing

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19 (13)

Food craving and overeating

Anorexia nervosa 7 (6)

Food craving and overeating

Goldman et al. (2011)

Kekic et al. (2014)

Khedr et al. (2014) Lapenta et al. (2014)

Montenegro et al. (2012)

Adults (20–32)

Adults (13–30) Adults (20–27)

Adults (19–34)

Adults (21–45)

Adults (18–30)

Technique

tDCS

Sham-controlled, tDCS double-blind, randomized crossover study Sham-controlled, tDCS double-blind, randomized crossover study

Open label

Sham controlled, tDCS double-blind, randomized crossover study Sham controlled, tDCS double-blind, randomized crossover study Sham-controlled, tDCS double-blind, randomized crossover study

Study design

Cathodal over F3

Anodal over F4

Anodal over F3

2 mA

35 cm2

Cathodal over 35 cm2 right SO

2 mA

25 cm2

2 mA

35 cm2

35 cm

Active electrode size Intensity/frequency

24 cm

Anodal Cathodal over the F3 over the SO Anodal Cathodal over F4 over F3

1. Cathodal over F4 2. Cathodal over F3 Cathodal over F3

Reference electrode

1. Anodal over F3 2.Anodal over F4 Anodal over F4

Active electrode

Main outcomes

20 min/session for a single session FCI, CESD-10, of each type in a randomized order. CVAS for craving after exposure to food photos with the IAPS 20 min/session for a single session Food craving of each type in a randomized order. Questionnaire – Trait, VAS for hunger, food challenge task, FCQ-State, saliva sample, TD Task 25 min/day for 10 consecutive days EAT, EDI, BDI excluding weekends. 20 min/session for a single session ERPs Go/Noof each type in a randomized order. Go task, eye tracking, Washout period for 1 week. VAS for food craving 20 min/session for a single session VAS for hunger and of each type in a randomized order. craving, maximal cardiorespiratory Washout period of 48–120 hr. exercise test,

20 min/session for a single session VAS for mood and of each type in a randomized order. food craving, Washout period of 48 hr. eye tracking

Treatment protocol

Positive

Results

VAS = Visual Analog Scale; FCI = Food Craving Inventory; CESD-10 = Center for Epidemiological Studies Depression Scale; CVAS = Craving Visual Analog Scale; IAPS = International Affective Picture System; FCQ = Food Craving Questionnaire; TD = Temporal Discounting; ERPs = Event Related Potentials; EAT = Eating Attitude Test; EDI = Eating Disorder Inventory; BDI = Beck Depression Inventory; F3 = Left Dorsolateral Prefrontal Cortex; F4 = Right Dorsolateral Prefrontal Cortex; SO = Supraorbital region.

9 (4)

9 (9)

17 (17)

23 (21)

Condition

Fregni, Orsati, Food craving et al. (2008) and overeating

Author

Age No. of group subjects (females) (years old)

Table 6. Studies in food craving and overeating C. Pérez et al.: tES for the Treatment of Neuropsychiatric Disorders 89

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administration (i.e., prior or during task performance). Additionally, Fujiyama et al. (2014) showed that although anodal tDCS was able to increase cortical excitability in younger and older adults, older adults exhibited a delayed plastic response. These are clear evidences that more studies are still needed to help us understand the true impact of tES in the aging brain. The available data so far does not allow drawing definite conclusions about the effects of tES across lifespan. Namely, on how the neurophysiological changes across lifespan are effect modifiers to tES. Especially, during ‘‘critical periods’’ which are thought to be more sensitive to environmental influences and stimulation than other periods (Takesian & Hensch, 2013). Although, there is available evidence to support that the mechanisms of plasticity in cortical areas decrease progressively with aging (Freitas et al., 2011), there is also data to support that brain’s plasticity is not immutable after a consolidation process in early life. On the contrary, across development, brain plasticity seems to be diminished by brake-like factors which can be overturned (Takesian & Hensch, 2013). Therefore, the optimization of tES interventions must rely on a better integration between neuroplasticity changes due to normal and abnormal development and stimulation parameters. These interventions should be guided by surrogate outcomes of neuroplasticity. For instance, by coupling tES interventions with TMS measurements, such as the paired-associative stimulation (PAS), it is possible to mimic the long-term depression and potentiation protocols used in animal models (Chen & Udupa, 2009) and therefore assess neuroplasticity effects. Also tES may be coupled with EEG so as to assess in real time neuroplasticity changes and therefore guide the intervention. Recent have proposed the use of closed-loop system as a method to optimize tES parameters (Schestatsky, Morales-Quezada, & Fregni, 2013). Finally, recent research with near-infrared spectroscopy (NIRS) may also be useful for monitoring and adjustment of tES parameters (Dutta, Jacob, Chowdhury, Das, & Nitsche, 2015). It is possible that these efforts could be hindered by safety concerns, especially in children and elderly. However, most of the studies across lifespan conducted so far report no or mild adverse effects, thus demonstrating that tES has a satisfactory safety profile, even when applied during several consecutive days. Although the ease-of-use, portability, and safety profile make tES (and especially tDCS) ideal to combine with other therapies, most of the studies so far have been using tES alone. The combination of tES with other therapies is highly recommended, as synergistic effects could arise from them (Brunoni, Valiengo, et al., 2013). The use of tES in neuropsychiatric disorders has yielded promising results. It is usually well tolerated and produces significant clinical outcomes where conventional approaches fail to do so. Future studies should focus on interventions guided by surrogate outcomes of neuroplasticity. Better understanding of plasticity across the lifespan will help in the optimization of the current tES stimulation parameters, especially for use with children and elderly populations. European Psychologist 2016; Vol. 21(1):78–95

Acknowledgments Carolina Pérez, Jorge Leite, and Sandra Carvalho share first coauthorship. Jorge Leite (SFRH/BPD/86027/2012) and Sandra Carvalho (SFRH/BPD/86041/2012) are supported by grants from the Portuguese Foundation for Science and Technology (FCT) and European Union (FSE-POPH). The authors wish to thank Melanie French for the editing and proofreading.

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Rakesh, G., Shivakumar, V., Subramaniam, A., Nawani, H., Amaresha, A. C., Narayanaswamy, J. C., & Venkatasubramanian, G. (2013). Monotherapy with tDCS for Schizophrenia: A case report. Brain Stimulation, 6, 708–709. doi:10.1016/ j.brs.2013.01.007 Raz, N., Lindenberger, U., Rodrigue, K. M., Kennedy, K. M., Head, D., Williamson, A., . . . Acker, J. D. (2005). Regional brain changes in aging healthy adults: General trends, individual differences and modifiers. Cerebral Cortex, 15, 1676–1689. Rigonatti, S. P., Boggio, P. S., Myczkowski, M. L., Otta, E., Fiquer, J. T., Ribeiro, R. B., . . . Fregni, F. (2008). Transcranial direct stimulation and fluoxetine for the treatment of depression. European psychiatry: The Journal of the Association of European Psychiatrists, 23, 74–76. doi: 10.1016/ j.eurpsy.2007.09.006 Rubenstein, J. L., & Merzenich, M. M. (2003). Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes, Brain, and Behavior, 2, 255–267. Salthouse, T. A. (2009). When does age-related cognitive decline begin? Neurobiology of Aging, 30, 507–514. Saunders, N., Downham, R., Turman, B., Kropotov, J., Clark, R., Yumash, R., & Szatmary, A. (2014). Working memory training with tDCS improves behavioral and neurophysiological symptoms in pilot group with post-traumatic stress disorder (PTSD) and with poor working memory. Neurocase, 21, 271–278. doi: 10.1080/13554794.2014.890727 Schestatsky, P., Janovik, N., Lobato, M. I., Belmonte-de-Abreu, P., Schestatsky, S., Shiozawa, P., & Fregni, F. (2013). Rapid therapeutic response to anodal tDCS of right dorsolateral prefrontal cortex in acute mania. Brain Stimulation, 6, 701–703. doi: 10.1016/j.brs.2012.10.008 Schestatsky, P., Morales-Quezada, L., & Fregni, F. (2013). Simultaneous EEG monitoring during transcranial direct current stimulation. Journal of Visualized Experiments: JoVE, 76, e50426. doi: 10.3791/50426 Schneider, H. D., & Hopp, J. P. (2011). The use of the Bilingual Aphasia test for assessment and transcranial direct current stimulation to modulate language acquisition in minimally verbal children with autism. Clinical Linguistics & Phonetics, 25, 640–654. doi: 10.3109/02699206.2011.570852 Schonfeldt-Lecuona, C., Lefaucheur, J. P., Cardenas-Morales, L., Wolf, R. C., Kammer, T., & Herwig, U. (2010). The value of neuronavigated rTMS for the treatment of depression. Neurophysiologie Clinique = Clinical Neurophysiology, 40, 37–43. doi: 10.1016/j.neucli.2009.06.004 Shahbabaie, A., Golesorkhi, M., Zamanian, B., Ebrahimpoor, M., Keshvari, F., Nejati, V., . . . Ekhtiari, H. (2014). State dependent effect of transcranial direct current stimulation (tDCS) on methamphetamine craving. The International Journal of Neuropsychopharmacology/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 17, 1591–1598. doi: 10.1017/ s1461145714000686 Sharma, A., & Couture, J. (2014). A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). The Annals of Pharmacotherapy, 48, 209–225. doi: 10.1177/1060028013510699 Shergill, S. S., Brammer, M. J., Williams, S. C., Murray, R. M., & McGuire, P. K. (2000). Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Archives of General Psychiatry, 57, 1033–1038. Shergill, S. S., Bullmore, E., Simmons, A., Murray, R., & McGuire, P. (2000). Functional anatomy of auditory verbal imagery in schizophrenic patients with auditory hallucinations. The American Journal of Psychiatry, 157, 1691–1693. Shiozawa, P., da Silva, M. E., Cordeiro, Q., Fregni, F., & Brunoni, A. R. (2013). Transcranial direct current stimulation (tDCS) for the treatment of persistent visual and European Psychologist 2016; Vol. 21(1):78–95

auditory hallucinations in schizophrenia: A case study. Brain Stimulation, 6, 831–833. doi: 10.1016/j.brs.2013.03.003 Shiozawa, P., da Silva, M. E., Dias, D. R., Chaves, A. C., de Oliveira Diniz, B. S., & Cordeiro, Q. (2014). Transcranial direct current stimulation for depression in a 92-year-old patient: A case study. Psychogeriatrics: The Official Journal of the Japanese Psychogeriatric Society, 14, 269–270. doi: 10.1111/psyg.12100 Shiozawa, P., Leiva, A. P., Castro, C. D., da Silva, M. E., Cordeiro, Q., Fregni, F., & Brunoni, A. R. (2014). Transcranial direct current stimulation for generalized anxiety disorder: A case study. Biological Psychiatry, 75, e17–e18. doi: 10.1016/j.biopsych.2013.07.014 Shivakumar, V., Narayanaswamy, J. C., Agarwal, S. M., Bose, A., Subramaniam, A., & Venkatasubramanian, G. (2014). Targeted, intermittent booster tDCS: A novel add-on application for maintenance treatment in a schizophrenia patient with refractory auditory verbal hallucinations. Asian Journal of Psychiatry, 11, 79–80. doi: 10.1016/j.ajp.2014.05.012 Silbersweig, D. A., Stern, E., Frith, C., Cahill, C., Holmes, A., Grootoonk, S., . . . Frackowiak, J. (1995). A functional neuroanatomy of hallucinations in schizophrenia. Nature, 378, 176–179. doi: 10.1038/378176a0 Spedding, M., Neau, I., & Harsing, L. (2003). Brain plasticity and pathology in psychiatric disease: Sites of action for potential therapy. Current Opinion in Pharmacology, 3, 33–40. Takeshi, K., Nemoto, T., Fumoto, M., Arita, H., & Mizuno, M. (2010). Reduced prefrontal cortex activation during divergent thinking in schizophrenia: A multi-channel NIRS study. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34, 1327–1332. doi: 10.1016/j.pnpbp.2010.07.021 Takesian, A. E., & Hensch, T. K. (2013). Balancing plasticity/ stability across brain development. Progress in Brain Research, 207, 3–34. Tehovnik, E. J. (1996). Electrical stimulation of neural tissue to evoke behavioral responses. Journal of Neuroscience Methods, 65, 1–17. Terney, D., Chaieb, L., Moliadze, V., Antal, A., & Paulus, W. (2008). Increasing human brain excitability by transcranial high-frequency random noise stimulation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28, 14147–14155. doi: 10.1523/jneurosci.4248-08.2008 Vercammen, A., Rushby, J. A., Loo, C., Short, B., Weickert, C. S., & Weickert, T. W. (2011). Transcranial direct current stimulation influences probabilistic association learning in schizophrenia. Schizophrenia Research, 131, 198–205. doi: 10.1016/j.schres.2011.06.021 Vicario, C. M., Martino, D., Spata, F., Defazio, G., Giacche, R., Martino, V., . . . Cardona, F. (2010). Time processing in children with Tourette’s syndrome. Brain and Cognition, 73, 28–34. doi: 10.1016/j.bandc.2010.01.008 Volpato, C., Piccione, F., Cavinato, M., Duzzi, D., Schiff, S., Foscolo, L., & Venneri, A. (2013). Modulation of affective symptoms and resting state activity by brain stimulation in a treatment-resistant case of obsessive-compulsive disorder. Neurocase, 19, 360–370. doi: 10.1080/13554794.2012. 667131 Wagner, T., Fregni, F., Fecteau, S., Grodzinsky, A., Zahn, M., & Pascual-Leone, A. (2007). Transcranial direct current stimulation: A computer-based human model study. NeuroImage, 35, 1113–1124. doi: 10.1016/j.neuroimage.2007.01.027 Wang, Z., Maia, T. V., Marsh, R., Colibazzi, T., Gerber, A., & Peterson, B. S. (2011). The neural circuits that generate tics in Tourette’s syndrome. The American Journal of Psychiatry, 168, 1326–1337. doi: 10.1176/appi.ajp.2011.09111692 Westlye, L. T., Walhovd, K. B., Dale, A. M., Bjørnerud, A., Due-Tønnessen, P., Engvig, A., . . . Fjell, A. M. (2009). Ó 2016 Hogrefe Publishing

C. Pérez et al.: tES for the Treatment of Neuropsychiatric Disorders

Jorge Leite, MSc, PhD, is a Research Scientist at the Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital and the Neuropsychophysiology Lab, CIPsi, School of Psychology, University of Minho. His current research interests include how the effectiveness of neuromodulation techniques can be improved, and how plasticity mechanisms can be used to modulate themselves.

Life-span changes of the human brain white matter: Diffusion tensor imaging (DTI) and volumetry. Cerebral Cortex, 20, 2055–2068. Xu, J., Fregni, F., Brody, A. L., & Rahman, A. S. (2013). Transcranial direct current stimulation reduces negative affect but not cigarette craving in overnight abstinent smokers. Frontiers in Psychiatry, 4, 112. doi: 10.3389/ fpsyt.2013.00112

Received February 6, 2015 Accepted September 22, 2015 Published online March 23, 2016

Sandra Carvalho, MSc, PhD, is a Research Scientist at the Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital and the Neuropsychophysiology Lab, CIPsi, School of Psychology, University of Minho. Her current research interests include how neuromodulation techniques can augment the effects of neurocognitive rehabilitation, and how brain plasticity can be assessed and modulated.

About the authors Felipe Fregni, MD, PhD, MPH, Med, is an Associate Professor of Physical Medicine & Rehabilitation and Associate Professor of Neurology at Harvard Medical School. He is the Director of the Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital and the Director of the Collaborative Learning in Clinical Research Program – Principles and Practice of Clinical Research offered by the Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School. His current research is focused on understanding neuroplastic changes after neural lesion; and how neuromodulation techniques can be used to study the mechanisms underlying such neuroplastic changes, as well as to develop new rehabilitation interventions. Carolina Perez, MD, is a Research Fellow at the Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital. Her current research interests include how neuromodulation techniques can improve motor functioning after stroke.

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Felipe Fregni Spaulding Rehabilitation Center 96 13th Street Charlestown, MA 02129 USA Tel. +1 617-952-6156 Fax +1 617-952-6060 E-mail felipe.fregni@ppcr.hms.harvard.edu

European Psychologist 2016; Vol. 21(1):78–95

news and views News and Announcements From the EFPA Network of National News Correspondents Collated by Eleni Karayianni In this issue, the news section contains contributions from Germany, Slovenia, and Denmark. The Federation of German Psychologists Associations reports on a parliamentary evening aimed at improving the quality of psychological expert opinion. The Slovenian Psychologists’ Association organized activities and monthly meetings covering diverse topics. The Danish Psychological Association informs about their new maganzine called ‘‘P,’’ first launched in August 2015.

Germany (NNC: Christoph Steinbach) On Wednesday, December 2, 2015, the Federation of German Psychologists Associations (DGPs and the forensic psychology section of the BDP) invited to a parliamentary evening on ‘‘Quality standards of expert opinion in family matters.’’ Numerous members of the German parliament as well as representatives of the ministries, science, and practice followed the invitation to discuss the now available minimum standards as well as further legislative activities. In recent years, many controversial verdicts and studies brought discussions about the quality of expert opinion into the focus of both the media and the political public. With their coalition contract, the ruling parties in Germany agreed upon ‘‘improving the quality of expert opinion, especially in the sector of family law, in collaboration with professional institutions.’’ The invited keynote speakers, Prof. Gabriele Britz, judge at the German Federal Constitutional Court, Prof. Max Steller, retired professor of forensic psychology, and Dr. Axel Bötticher, retired judge at the German Federal Court of Justice, commented on the topic from different angles. In their introductory addresses, Dr. Sabine SütterlinWaack, correspondent for family law of the Christian democrat CDU/CSU parliamentary group, Dr. Johannes Fechner, spokesman on law and politics of the social democrat SPD fraction, and Dr. Stefanie Hubig, undersecretary of state in the Federal Ministry, welcomed the new minimum requirements for expert opinion in family law. On September 16, 2015, the Federal Ministry of Justice and Consumer Protection presented a ministerial draft bill European Psychologist 2016; Vol. 21(1):96–97 DOI: 10.1027/1016-9040/a000258

for the alteration of the law concerning experts at court as well as further alterations of the law on causes of the family court (FamFG). The draft law is now in the parliamentary process. Dr. Anja Kannegießer, leading organizer of the consensus finding process, came to a positive conclusion on the parliamentary evening: ‘‘Tonight has shown once again the importance of interdisciplinary exchange. As psychological experts for courts, we work at the junction with law and need knowledge about requirements and contents of other areas of expertise. We are especially happy that the positive meaning and impact of expert opinion in the judiciary has also been emphasized. After all, this will contribute to finding good solutions for families and especially for children.’’ ‘‘The evening was a complete success,’’ sums up Prof. Andrea Abele-Brehm, President of the Federation of German Psychologists Associations and the DGPs. ‘‘We were able to unite the different perspectives on the debate about quality standards. We are especially glad about the consensus of all speakers that different sides have to be taken into account to assure quality: Experts need sufficient qualification and their neutrality has to be proven. At the same time, judges must be qualified to choose suitable experts, assess expert opinion, and integrate the expert opinion in the judicial decision-making process.’’

Slovenia (NNC: Vesna Mlinaricˇ Lešnik) In recent months, the Slovenian Psychologists’ Association (SPA) has organized monthly professional meetings on the topics ‘‘Insights from the European Congress of Psychology,’’ ‘‘Coaching,’’ and ‘‘Psychological aspects of pain.’’ SPA has also been active in coordinating and educating psychologists concerning psychosocial help for refugees. The conference of the project SUPER PSIHOLOG (Supervised practice of psychologists: Development of a training program for mentors and a model of supervised practice) was also held successfully. Ó 2016 Hogrefe Publishing

EFPA News and Views

Denmark (NNC: Ulrikke Moustgaard) Mental health and well-being are topics gaining increasing attention in the public and political arenas in Denmark. For this reason, the Danish Psychological Association (Dansk Psykolog Forening) has launched a new monthly magazine called ‘‘P’’ as a part of the Association’s strategic aim to raise public awareness about psychology, human well-being, mental health, and the crucial role of psychologists in this field. The magazine replaces the former publication of the Danish Psychological Association, which has served members since 1956 with profession- and organization-related news, as well as content primarily based on member’s contributions. The new magazine covers a diverse range of topics from the areas of politics, society, science, research, culture, ethics, professionalism, and more from the perspective of psychology, and is based on the principles of professional journalism, news values, and investigative reporting. The

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aim is to address a wider audience: not only Danish psychologists, but also decision-makers, politicians, and the public. The first edition came out in August, 2015, and the strategy has been successful so far. Several stories from the magazine have hit the mainstream media and gained public attention, and the new approach has been largely embraced by members of the Danish Psychological Association. In 2016 and onwards, the magazine wants to establish an editorial cooperation between EFPA member states magazines, if possible. Interested editors are encouraged to contact the Danish editor, Ulrikke Moustgaard, at: ulm@dp.dk

For regular news updates, please visit the journal’s website and the EFPA facebook page! Eleni Karayianni EFPA Executive Council member (CY) E-mail eleni.karayianni@efpa.eu

European Psychologist 2016; Vol. 21(1):96–97

news and views Meeting Calendar March 31–April 4, 2016 Second World Conference on Personality, Buzios, Brazil Contact: www.perpsy2016.com April 11–13, 2016 12th Conference of the European Academy of Occupational Health Psychology, Athens, Greece Contact: www.eaohp.org/conference. html April 28–May 1, 2016 VII Dubrovnik Conference on Cognitive Science, Dubrovnik, Croatia Contact: http://www.cecog.eu/ducog/ page_invitation.php May 1–8, 2016 30th European Federation of Psychology Student Associations Congress (EFPSA), Vimeiro, Portugal Contact: http://more.efpsa.org/ congress2016/ May 29–June 2, 2016 15th WAIMH Conference (World Association for Infant Mental Health), Prague, Czech Republic Contact: http://www.waimh.org/i4a/ pages/index.cfm?pageid=1 June 22–25, 2016 8th World Congress of Behavioural and Cognitive Therapies 2016 (WCBCT), Brisbane, Australia Contact: http://www.wcbct2016. com.au/invitation/ June 27–July 1, 2016 International Association for People-Environment Studies, Lund, Sweden Contact: http://www.iaps24.se/ June 28 – July 1, 2016 8th European Conference of Positive Psychology (ECPP8), Angers, France Contact: http://www.enpp.eu/ European Psychologist 2016; Vol. 21(1):98 DOI: 10.1027/1016-9040/a000260

July 1–4, 2016 10th Conference of the International Test Commission (ITC2016): Assessment and Testing for Improving Policy and Practice: Opportunities and Challenges in an International Setting, Vancouer, Canada Contact: http://conferences.educ.ubc. ca/index.php/itc2016/itc2016 July 5–8, 2016 European Association for Psychology and Law (EAPL) 2016 Conference, Toulouse, France Contact: http://eapl2016.sciencesconf.org/?lang=en July 10–14, 2016 24th Biennial Meeting of the International Society for the Study of Behavioural Development (ISSBD), Vilnius, Lithuania Contact: http://www.issbd2016.com/en/ July 14–17, 2016 Annual Meeting of the International Society of Political Psychology, Warsaw, Poland Contact: http://www.ispp.org/meetings July 20–23, 2016 38th International School Psychology Conference, Amsterdam, the Netherlands Contact: http://ispa2016.org/ July 20–24, 2016 2016 Biennial Conference of the International Association for Relationship Research, Toronto, ON, Canada Contact: http://www.iarr.org/ announcements/2014/4/25/announcements-about-future-conferences.html July 24–29, 2016 31st International Congress of Psychology (ICP2016): Diversity in Harmony – Insights from Psychology, Yokohama, Japan Contact: http://www.icp2016.jp

July 30–August 3, 2016 International Congress of the International Association for CrossCultural Psychology, Nagoya, Japan Contact: http://www.iaccp2016.com/ August 2–5, 2016 International Conference on Traffic and Transport Psychology, Brisbane, Australia Contact: http://icttp2016.com/ August 4–7, 2016 124th Annual Convention of the American Psychological Association, Denver, CO, USA Contact: http://www.apa.org/ convention/ August 23–27, 2016 European Health Psychology Society Conference, Aberdeen, UK Contact: http://www.ehps.net/node/ 202 August 28–September 2, 2016 XXth International Congress for Analytical Psychology, Kyoto, Japan Contact: http://www.iaap.org/ congresses-and-conferences-events/ congresses/2016-kyoto.html September 18–22, 2016 22nd World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions: Fighting stigma, promoting resiliency and positive mental health, Calgary, AB, Canada Contact: http://www.iacapap2016.org/ November 10, 2016 32nd Annual Meeting, International Society for Traumatic Stress Studies, Dallas, TX, USA Contact: http://www.istss.org/ meetings-events/events-calendar/istss32nd-annual-meeting.aspx Ó 2016 Hogrefe Publishing

Instructions to Authors - European Psychologist European Psychologist is a multidisciplinary journal that serves as the voice of psychology in Europe, seeking to integrate across all specializations in psychology and to provide a general platform for communication and cooperation among psychologists throughout Europe and worldwide. European Psychologist publishes the following types of articles: Original Articles and Reviews and EFPA News and Views. Manuscript Submission: Original Articles and Reviews manuscripts should be submitted online via the journal’s website at http://www.hogrefe.com/journals/ep/. Items for inclusion in the EFPA New and Views section should be submitted by email to the EFPA News and Views editor Eleni Karayianni (eleni.karayianni@ efpa.eu). Detailed instructions to authors are provided at http://www. hogrefe.com/periodicals/european-psychologist/advice-for-authors/ Copyright Agreement: By submitting an article, the author confirms and guarantees on behalf of him-/herself and any coauthors that he or she holds all copyright in and titles to the submitted contribution, including any figures, photographs, line drawings, plans, maps, sketches and tables, and that the article and its contents do not infringe in any way on the rights of third parties. The author indemnifies and holds harmless the publisher from any third-party claims. The author agrees, upon acceptance of the article for publication, to transfer to the publisher on behalf of him-/herself and any coauthors the exclusive right to reproduce and distribute the article and its contents, both physically and in nonphysical, electronic, and other form, in the journal to which it has been submitted and in other independent publications, with no limits on the number of copies or on the form or the extent of the distribution. These rights are transferred for the duration of copyright as defined by international law. Furthermore, the author transfers to the publisher the following exclusive rights to the article and its contents:

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European Psychologist 2016; Vol. 21(1)

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O¨sterreichische Gesellschaft fu¨r Psychologie Pan-Albanian Association of Psychologists Polskie Towarzystwo Psychologiczne Psychological Society of Ireland Russian Psychological Society Sindicato Nacional dos Psicologos Slovenian Psychological Association Slovenska Komora Psychologov Sociedade Portuguesa de Psicologia Socie´te´ Francaise de Psychologie Socie´te´ Luxembourgeoise de Psychologie Socie´te´ Suisse de Psychologie Suomen Psykologiliitto Swedish Psychological Association The European Health Psychology Society Turkish Psychological Association Unie Psychologickych Asociaci CR Union of Estonian Psychologists

Assessment methods in health psychology “This book is an excellent overview of measurement issues that are central to health psychology.” David French, PhD, Professor of Health Psychology, University of Manchester, UK

Yael Benyamini / Marie Johnston / Evangelos C. Karademas (Editors)

Assessment in Health Psychology (Series: Psychological Assessment – Science and Practice – Vol. 2) 2016, vi + 346 pp. US $69.00 / € 49.95 ISBN 978-0-88937-452-2 Also available as eBook

Assessment in Health Psychology presents and discusses the best and most appropriate assessment methods and instruments for all specific areas that are central for health psychologists. It also describes the conceptual and methodological bases for assessment in health psychology, as well as the most important current issues and recent progress in methods. A unique feature of this book, which brings together leading authorities on health psychology assessment, is its emphasis on the bidirectional link between theory and practice. Assessment in Health Psychology is addressed to masters and doctoral students in health psychology, to all

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those who teach health psychology, to researchers from other disciplines, including clinical psychology, health promotion, and public health, as well as to health policy makers and other healthcare practitioners. This latest volume in the series Psychological Assessment – Science and Practice provides a thorough and authoritative record of the best available assessment tools and methods in health psychology, making it an invaluable resource both for students and academics as well as for practitioners in their daily work.

Using movies to help learn about mental illness

“I have been a fan of Movies and Mental Illness from the first edition.” Steven Pritzker, PhD, psychology professor (Saybrook University) and former Hollywood script writer

Danny Wedding / Ryan M. Niemiec

Movies and Mental Illness

Using Films to Understand Psychopathology 4th edition 2014, xviii + 456 pp. US $59.00 / € 42.95 ISBN 978-0-88937-461-4 Also available as eBook Films can be a powerful aid to learning about mental illness and psychopathology – for students of psychology, psychiatry, social work, medicine, nursing, counselling, literature or media studies, and for anyone interested in mental health. Movies and Mental Illness, written by experienced clinicians and teachers who are themselves movie aficionados, has established a great reputation as a uniquely enjoyable and highly memorable text for learning about psychopathology. The new edition has been fully updated to include DSM-5 and ICD-10 diagnoses.

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The core clinical chapters each use a fabricated case history and MiniMental State Examination along with synopses and discussions about specific movies to explain, teach, and encourage discussion about all the most important mental health disorders. Each chapter also includes: Critical Thinking Questions; “Authors’ Picks” (Top 10 Films); What To Read if You Only Have Time to Read One Book or Article; and Topics for Group Discussions.