WORKING MEMORY IMPAIRMENTS IN SCHIZOPHRENIA

SOURCES OF WORKING MEMORY IMPAIRMENTS IN SCHIZOPHRENIA

AN OVERVIEW FOCUSING ON THE IDENTIFICATION OF WORKING MEMORY IMPAIREMENTS AND THEIR CELLULAR BASIS

By Deniz Eracar Shayna Cohen

history of schizophreniA

Schizophrenia is a neuropsychological disorder which is associated with dramatic impairments in neurocognitive functions such as selective attention and memory. The first accounts that indicate an association between schizophrenia and memory dysfunction date back to Kraepelin’s clinical observations in 1919, which state that patients with schizophrenia “[..](could) not keep a thought in mind” (Kraeoplin, 1919). This observation has paved the way for publications of numerous research studies involving schizophrenic patients and memory tasks. Over time, multiple research groups have realized that the cognitive symptoms, or their lack thereof, of schizophrenic patients were compatible with the presence of an underlying deficit in working memory processes.

worKing memory processes

By Baddeley and Hitch’s definition (1974), working memory processes describe a limited-capacity “working space” for information processing. The cognitive deficits in working memory in schizophrenia patients appear to reflect a disturbance in executive control and the processes that facilitate complex information processing and behavior, which are, as the research of numerous research groups have indicated, functions that the dorsolateral prefrontal cortex (DLPFC) is responsible for (Carter et al.,1999). Comparably, similarities between schizophrenic symptoms and the symptoms observed in patients with frontal lobe dysfunctions were pointed out almost two decades ago (Park et al., 1992) and made evident through the usage of electrophysiology and delayed response tasks. In these tasks, non primate subjects were momentarily shown the location of a food item that was then quickly placed behind an opaque screen and tested to see whether they remember the correct location of the food item after a delay period of a few seconds. The studies with delayed-response tasks lead to two significant conclusions: Firstly, It was observed that primates with dorsolateral prefrontal cortex, just like schizophrenics, performed poorly on these tasks (Kojima et al., 1982) and secondly, the tasks demonstrated that the neurons in and around the principal sulcus of the prefrontal cortex became activated during the delay period, hypothetically to keep the presented information in the mind when the visual stimuli leading to that information was kept out of view.

worKing memory tAsKs And pArAdigms

However, the idea that neuronal activity during the delayed periods was reflective of a working memory process was resisted until Goldman-Rakic (1994) used a oculomotor-response paradigm to study delayed-response performance, which showed that the prefrontal neuronal activity sharply increased at the end of the presentation of a visual stimulus, remained active during the delay period in the absence of the stimulus but prior to a response, and then decreased abruptly at the end of the delay. All of these observations pointed towards a working memory process. By combining this observation with anatomical studies, GoldmanRakic was able to conclude, without pinpointing the location of the lesion, that the deficits seen in working memory in schizophrenic patients were either directly or indirectly caused by injury to the cortico cortical and cortico subcortical pathways that establish inner models of reality and adjust them to contemporary demands. This preliminary statement relating working memory deficits to prefrontal dysfunction was followed by later studies that utilized brain scanning techniques, which provided direct evidence that the working memory impairments were caused by DLPFC impairments. When schizophrenic patients and control groups were engaged in the Wisconsin Card Sort Task, it was observed that the regional cerebral blood flow in the DLPFC of the control group participants was increased whereas the blood flow to the same region in schizophrenics was not (Weinberger et al., 1986), once again highlighting the role for the DLPFC in the psychopathologic character of schizophrenia. To specify further the dorsolateral prefrontal contribution to schizophrenia symptoms, Park and Holzman (1992) devised a research study that not only tested schizophrenic patients on the oculomotor delayed-response (ODR) task, but also included a haptic version of the same task and two additional control tasks of which one did not require working memory and the other was a digit-span task. The performance of schizophrenic patients was compared to the performance of normal controls and bipolar patients, and it was concluded that the schizophrenics performed poorer than the two other groups being tested in memory-guided delayed responses, regardless of the modality of the task.

cellulAr bAsis of worKing memory impAirments

Park et al.’s findings were in accordance with the previous findings that local blockage of dopamine D1 receptors in the DLPFC impaired performance on ODR tasks (Kojima et al., 1990), which definitively identified DLPFC as the cardinal source of working memory deficits in patients with schizophrenia. Rao et al., by utilizing the past observation that schizophrenic patients showed alterations in the markers of GABA neurotransmission, were able to observe that injecting GABA antagonists to primate research subjects disrupted their working memory performance. Additionally, it was shown that when bicuculline methiodide (BMI), a GABAA receptor antagonist, was delivered to rhesus monkey subjects performing spatial ODR tasks, an increase in the overall activities of both

interneurons (FS) and putative pyramidal cells (RS) was observed. The major implication of this increased activity was decreases in both the iso-directional and the cross-directional inhibition of both cell types, which further caused both RS and FS neurons to lose their spatial tuning, consequently resulting in GABAA mediated inhibition in the spatial working memory process (Rao et al., 2000; Arnsten et al., 2012). The scientific community’s current understanding of the neurophysiological mechanisms underlying working memory deficits in schizophrenia is built on the recent research observations that nearby neurons with spatial tuning rely on connections on spines to maintain firing without the need for bottom-up sensory stimulation (Goldman-Rakic, 1995; Gonzalez-Burgos et al., 2000; Arnsten et al., 2012) . Wang et al.’s recent iontophoretic studies as well as their predictive computational models have suggested the dependence of the persistent firing of nearby neurons on NMDA receptors (Wang et al., 2011) , and specifically the NR2B subunits found in the synapse, as persistent neuronal firing is only made possible with the slower kinetics of the NR2B receptor (Wang, 1999). As working memory arises from excitation within layer III prefrontal cortex pyramidal cell NMDA circuits, the deep layer III microcircuits are thought to be afflicted in schizophrenia, which is a significant contributing factor to DLPFC dysfunction (Glantz and Lewis, 2000).

relevAnce to our society

Although the specifics of the neurophysiological mechanism underlying the working memory deficits observed in schizophrenia patients require further investigation, dorsolateral prefrontal cortex dysfunction has been repeatedly identified as the main source of the working memory impairments observed in schizophrenics. As schizophrenia is one of the prominent diseases whose treatment with neuroleptic drugs is still the focus of the neuropharmacology sector, an overview of the neurocognitive processes that it is known to affect along with the neurophysiological processes that result in these impairments is necessary for an understanding of the efficiency of these drugs.

Kraepelin, E., Robertson, G. M., & Barclay, R. M. (1919). Dementia praecox and paraphrenia.

Chicago: Chicago Medical Book Co. Baddeley, A. D., & Hitch, G. (1974). Working memory. In Psychology of learning and motivation (Vol. 8, pp. 47-89). Academic press. Carter, C. S., Botvinick, M. M., & Cohen, J. D. (1999). The contribution of the anterior cingulate cortex to executive processes in cognition. Reviews in the Neurosciences, 10(1), 49-58. Kojima, S., Kojima, M., & Goldman-Rakic, P. S. (1982). Operant behavioral analysis of memory loss in monkeys with prefrontal lesions. Brain research, 248(1), 51-59. Goldman-Rakic, P. S. (1994). Working memory dysfunction in schizophrenia. The Frontal

Lobes and Neuropsychiatric Illness. Washington,

DC, 71-82. Rao, S. G., Williams, G. V., & Goldman-Rakic, P.

S. (2000). Destruction and creation of spatial tuning by disinhibition: GABAA blockade of prefrontal cortical neurons engaged by working memory. Journal of Neuroscience, 20(1), 485-494. Arnsten, A. F., Wang, M. J., & Paspalas, C.

D. (2012). Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron, 76(1), 223-239. Goldman-Rakic, P. S. (1995). Cellular basis of working memory. Neuron, 14(3), 477-485. González-Burgos, G., Barrionuevo, G., & Lewis,

D. A. (2000). Horizontal synaptic connections in monkey prefrontal cortex: an in vitro electrophysiological study. Cerebral Cortex, 10(1), 82-92. Wang, M., Gamo, N. J., Yang, Y., Jin, L. E., Wang,

X. J., Laubach, M., ... & Arnsten, A. F. (2011).

Neuronal basis of age-related working memory decline. nature, 476(7359), 210-213. Wang, X. J. (1999). Synaptic basis of cortical persistent activity: the importance of NMDA receptors to working memory. Journal of

Neuroscience, 19(21), 9587-9603. Glantz, L. A., & Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of general psychiatry, 57(1), 65-73.