NONINVASIVE MODULATION OF COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
Hippocampal Neuron
Zachary Seth Goodman November, 2010
NOVEMBER 2010
ZACHARY S. GOODMAN
Introduction All aspects of emotion, sensation, perception and cognition manifest within neuronal connections of the brain. Thus, to control the behavior of these neuronal connections would allow for the modulation of all aforementioned facets of brain function. Brain stimulation, or neuromodulation, is the practice of regulating neuronal activity. Neuromodulation can produce differential outcomes obtained depending on two critical factors: (i) the brain anatomy of the region being stimulated and (ii) the timing or temporal profile of brain activity being modulated. Neuromodulation has demonstrated that the excitation of certain brain circuits can alleviate symptoms of many neurological disorders, otherwise untreatable by common medications. Brain stimulation can produce effects ranging from the enhancement of memory (Huerta & Volpe, 2009) to the quieting of Parkinson’s disease symptoms (Lozano & Snyder, 2008). Drug-resistant depression (Ressler et al., 2007) and epilepsy (Fregni et al., 2006) are other ailments that neuromodulation can effectively treat. Thus, many major medical advances have been supported by studies of brain stimulation. Because all presently employed neuromodulation approaches are limited by a poor spatial resolution or surgical invasiveness, research and development into newer generations of brain stimulation strategies and devices is in high demand. As alluded above, modern methods of neuromodulation exhibit certain drawbacks in regards to accuracy, practicality, and invasiveness despite their wide array of neurological applications. Deep-brain stimulation (DBS) modulates the firing properties of neurons through an electrode array surgically implanted into the brain. This technology, however, requires invasive surgery to implant the DBS electrodes in the brain, as well as to implant a battery and microcontroller devices (Ressler and Mayberg, 2007). Transcranial magnetic stimulation (TMS) is a noninvasive option of
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brain stimulation, but it suffers from a somewhat low spatial resolution of about 1 cm (Wagner et al., 2007), as well as the inability to reach deep-brain circuits (PascualLeone et al., 1994; Huerta & Volpe, 2009). Drugs along with other pharmacological approaches can stimulate neurons but lack targeting ability for specific parts of the brain. Therefore, chemical neuromodulation approaches often lead to undesirable sideeffects potentially disrupting mood, libido, appetite, motivation, and memory. Optogenetic approaches to neuronal excitation and inhibition offer unparalleled spatial resolution among modern neuromodulation techniques: this approach allows for selective activation or inhibition of individual neurons based on the location and density of light-controlled actuator protein expression (Szobota et al., 2007). However, this technique is also limited due to its required genetic manipulation of neurons. To selectively stimulate the genetically modified neurons with light, surgically implanted fiber optics or other photon-emitting devices are also necessary in optogenetic-based methods (Zhang et al., 2007). Ultimately, all brain stimulation approaches suffer from some critical circumscription that limits their applicability, effectiveness and mainstream adoption. Recently, transcranial pulsed ultrasound (US) has emerged as a potential neuromodulation technique that can safely stimulate the neurons of mice in vivo (Tufail et al., 2010). As early as 1929, it had been demonstrated that US could stimulate neuronal activity under certain in vitro conditions (Harvey, 1929). This initial observation from approximately eighty years ago spawned further research regarding US’s ability modulate neuronal activity. US can change the activity of different mammalian nerves (Aδ- or delta fibers and C fibers) based upon the fiber’s diameter and traits (intensity/duration) of the US being utilized (Young and Hennerman, 1961). US has also been observed to suppress neuronal activity. Inhibition of sensory-evoked potentials in a cat’s visual cortex was achieved through stimulation of the lateral geniculate nucleus NONINVASIVE MODULATION OF COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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through a cranial window using US (Fry et al., 1958). High-intensity US can modulate neuronal activity in peripheral nerves (Lele, 1963; Mihran et al., 1990; Tsui et al., 2005), cat and rabbit neuronal tissue of the cortex through a craniotomy (Velling and Shklyaruk, 1988), human peripheral somatosensory receptors (Gavrilov et al.,1976), neurons of a catâ&#x20AC;&#x2122;s spinal cord (Shealy and Henneman, 1962), and hippocampal slices from rodents (Bachtold et al., 1998; Rinaldi et al., 1991). However, thermal and mechanical damage can be induced by high-intensity US thereby circumscribing its use as a neuromodulation tool. This type of high-intensity US has, however, found therapeutic usage in ablating diseased brain circuits in humans without requiring surgery (Tyler, Tufail & Pati, 2010). While thermally-induced tissue extirpation excludes high-intensity US for brain stimulation in humans, pulsed US waves of low frequency (< 0.65 MHz) and lowintensity (< 300 mW/cm2) have been observed to excite action potentials in hippocampal slices without producing damage (Tyler et al., 2008). It is important to note that low-intensity US does not pose as many dangers to tissue as high-intensity US does and can still be focused through intact skulls in a frequency dependent manner where < 0.65 MHz US is optimal (Hynynen and Clement, 2007; Hynynen et al., 2004). A recent study capitalized on this noninvasive property by also using low-intensity US stimulus waveforms to stimulate in vivo mouse brain circuits. Tufail and colleagues (2010) recently demonstrated that low-intensity transcranial pulsed US can stimulate the intact brain circuits in mice. They further showed that US can evoke neuronal activity in vivo with a spatial resolution approximately three to five times better than that conferred by other noninvasive methods such as TMS (Tufail et al., 2010). This US brain stimulation method was also capable of selectively generating motor movement in particular limbs of the mice (e.g. tail, forepaw) and the whiskers (Tufail et al., 2010). With regards to safety, transcranial pulsed US can stimulate the brains of mice whilst NONINVASIVE MODULATION O F COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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maintaining the integrity of the blood brain barrier, without increasing cell death, and without producing ultrastructural cellular damage. Stimulation of the intact hippocampus in vivo using transcranial pulsed US was also able to produce a significant increase in the spiking frequency of neurons in the vicinity of stimulation (Tufail et al., 2010). Sharp-wave â&#x20AC;&#x153;rippleâ&#x20AC;? (SPW) oscillations in the CA1 region of the hippocampus were evoked by pulsed US stimulation of the aforementioned region of the brain. The figure at left adapted from Tufail and colleagues
(2010)
clearly
shows
transcranial US can evoke prominent SPW, which are known to be crucial to Figure 1
memory consolidation processes. Because
Endogenous neuronal activities consistent with processes of memory consolidation were generated with US (Tufail et al., 2010).
these oscillations correlate with memory storage in rodents (Girardeau et al., 2009;
Nakashiba et al., 2009), it was hypothesized by Tufail and colleagues (2010) that transcranial pulsed US may be capable of influencing the memory consolidation process, as well as other cognitive processes associated with the hippocampus, such as learning. The paper also demonstrates that US can trigger an increase in the expression of brain-derived neurotrophic factor (BDNF), a protein essential to hippocampal-dependent learning and memory consolidation (Bekinschtein et al., 2008; Tyler et al., 2002). Because noninvasively stimulating intact brain circuits with US to modulate cognitive processes such as learning and memory has profound implications for neuroscience and medicine, it is important to directly test whether transcranial pulsed US stimulation is capable affecting learning and memory, experimentally. The major goals of this project were first to test these enticing possibilities and then to
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engineer conceptual brain-machine interfaces for delivering US to intact brain circuits for modulating cognition. A specific set of rationale hypotheses that US could both enhance and disrupt learning and memory processes were developed based on our understanding of hippocampal physiology. Because electrophysiology in the hippocampus during US stimulation is consistent with similar processes observed during of learning and memory consolidation (e.g. SPW oscillations and BDNF signaling), pulsed US may affect learning and memory through mimicry, or the artificial reproduction of neuronal activity just prior to or during a learning task. Spatial learning and memory enhancement has been demonstrated in past studies that have utilized a behavioral test known as the Morris Water Maze (“MWM”) (Ruiz-Medina et al., 2008). Previous experimentation has also shown that the saturation of a specific type of plasticity known as long-term potentiation (“LTP”) before testing in the MWM can impair spatial memory and learning (Moser et al., 1998). Spatial cognitive ability relies upon place cells, which are hippocampal neurons representing relationships among cues at different points in space including an animal's geographical position in relation to environmental cues. In accordance with the mimicry hypothesis, by inducing the reactivation of these place cells, memories regarding the spatial location of an object may be generated and/or learning and memory enhanced (Morris, 2008). The present study attempted to gain preliminary behavioral evidence useful for determining whether transcranial pulsed US is capable of affecting spatial cognitive abilities in a MWM task. As indicated above, this paper also aspires to engineer basic device concepts for future brain-machine interfaces (BMI) that could utilize US to modify learning and memory consolidation, as well as other aspects of cognition. A US-based BMI would offer numerous advantages over more conventional electrical stimulation techniques. These advantages arise from the ability of US to be transmitted through the skull and NONINVASIVE MODULATION O F COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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thus not require surgery to achieve stimulation while still maintaining an accuracy that parallels currently implemented electrical stimulation methods (e.g. DBS electrodes that require neurosurgery). In this regard, its noninvasiveness is similar to TMS, but pulsed US stimulation is approximately five times more accurate with a spatial resolution of 2 mm as opposed to 1 cm. Since the brain is essentially like water with respect to the attenuation and absorption of US energy, transcranial pulsed US is also thought to be capable of stimulating deep brain circuits, unlike TMS, that can be afflicted by certain neurological disorders (Tufail et al., 2010). US-based BMIs could have multiple applications; however, this paper will delve specifically into the challenges and possibilities surrounding cognitive modulation.
Methods To assess learning and memory in mice, the MWM learning/memory paradigm was employed. In this behavioral test, mice were placed into a circular pool of water and attempted to â&#x20AC;&#x153;escapeâ&#x20AC;? by finding a hidden (submerged) platform in the pool which allowed them to stand out of the water. This methodology has been well documented and is a staple of evaluating spatial cognitive performance associated with hippocampal physiology and activity (Morris, 2008; Brandeis, Brandys & Yehuda, 1989).
The figure to the left illustrates an aerial view of a MWM as setup during training Days 1-3. Mice were initially placed in the third quadrant and attempted to find the location of an escape platform located in quadrant 1. After three days of training (four trials each day), on Day 4 the platform was removed from the maze and the time mice spent in swimming in quadrant 1 was quantified to assess memory of the escape location
Figure 2
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MORRIS WATER MAZE: A black pool (one meter in diameter) was filed to a depth of 6.5 cm. The room temperature was kept at 25.8° C and the water temperature was regulated at 22.8° C. The exterior of the pool was surrounded by four quadrants, each distinguishable by four distinct visual cues, (horizontal/vertical black stripes, black/white background) which have been previously demonstrated to assist mice in learning the location of the escape platform by providing visual spatial reference cues (Figure 2). To facilitate learning of the escape location, the 6.5 cm tall escape platform (also painted black) placed in the quadrant one (Figure 2) was marked by a small wooden “flag” protruding from the water during the first two days of training. Training on day 3 was conducted using the same escape platform location, but without the use of a "flag" signaling its location. As discussed below, the platform was removed on the test day (Day 4) to assess a mouse's memory of the escape platform location following the learning of that location during training days 1-3. Learning: To assess learning performance, escape latency, or the amount of time taken for the mice to reach the platform, was measured during each of the four trials on training days 1-3. Learning was assessed by the trend of the mice’s decreasing escape latency over time. On training days, mice were given up to three minutes to "escape" the water maze by reaching the platform and staying on it for at least ten seconds. After two minutes concluded, mice were escorted to the escape platform. Immediately following a training session, mice were dried and placed on a heating pad for twenty minutes before the next trial. Memory: To assess memory performance, the platform that was present during the first three training days was removed on the fourth day and the mice were, again, placed in the maze for four trials. The amount of time the mice spent in quadrant one (where the platform was located during initial learning/training trials) was measured. NONINVASIVE MODULATION O F COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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Mice were allowed to look for the platform for a total of three minutes before being removed. PULSED ULTRASOUND STIMULATION: Agilent arbitrary waveform generators were employed to generate US stimulus waveforms. Settings of stimulus duration frequency and the number of pulses delivered were dictated on these machines as previously described (Tufail et al, 2010). Stimulation frequency
and
acoustic
frequency
were
monitored and adjusted through an Agilent oscilloscope. An Ultran transducer delivered pulsed US to the hippocampus based on Figure 3
stereotactic coordinates. Transcranial pulsed The above illustration depicts a custom designed ultrasonic neuromodulation rig used
US was delivered to the intact hippocampus for delivering transcranial US waveforms to brain circuits of intact mice (adapted from Tufail et al.,
through an acoustic collimator, filled with US 2010). gel, at a 50째 angle from the vertical axis of the sagittal plane of the mouse. This protocol was adopted to avoid ineffective stimulation of the hippocampus due to blockage from the corpus callosum as previously described (Tufail et al., 2010). Stimulation occurred for five minutes at a 0.1 Hz stimulus frequency under the following parameters: pulse repetition frequency = 1.5-5.0 kHz; cycles per pulse = 10500; number of pulses = 100-1000; acoustic frequency = 0.25-0.60 MHz. It should be noted the exact parameters used were consistent across mice, but represent proprietary unpublished data and are therefore not disclosed here, but rather given as the ranges above, which have previously been described effective for stimulating intact hippocampal activity (Tufail et al., 2010).
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In order to restrain the mice during stimulation, the mice were placed within a custom restraining tube which exposed their head. The fur on their head was clipped with scissors and US gel was placed on their head. The treatment group of mice (n=4) was stimulated with US prior to every trial over the span of the three training days while the sham stimulation group of mice (n=4) were given sham US stimulation prior to every trial. Without US conductive gel in the acoustic collimator, US did not stimulate the hippocampus during sham trials. ANIMAL TRAITS: C57-BL6 male mice were used for this experiment. According to prior research with the MWM, only male subjects are eligible for participation over the course of a week because female mice are subject to hormonal changes during this time period which could confound results (Morris, 2008). All research was conducted in accordance with guidelines approved by the Institutional Animal Care and Use Committee at Arizona State University in the laboratory of William J. Tyler, Ph.D.
Results EFFECTS OF TRANSCRANIAL PULSED US ON LEARNING AND MEMORY The following figures illustrate the averages for the mice of both the treatment group (stimulated with pulsed US) and the sham-control group (given false US stimulation) in the MWM. Indicating normal learning, sham-treated mice increased the speed at which they reached the escape platform in the MWM across training trials and days (Figures 4 and 5). Mice in the treatment group, which were treated with transcranial pulsed US immediately prior to training, also exhibited learning, as shown by the progressively decreasing escape latency times across the training sessions and training days (Figures 4 and 5).
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Figure 4
Figure 5
The line plots above illustrate mean escape latencies obtained across trials and days. As shown, the sham/control group learned the escape platform location more rapidly and reached a plateau in escape latency more quickly than the US stimulation treatment group.
The line plots shown above illustrate mean escape latencies collapsed across trials. This plot illustrates the sham/control group had a slightly faster task acquisition (learning of the escape platform location) compared to the US stimulated treatment group.
The rate, however, at which US stimulated mice learned the MWM task was slower than sham treated control mice as shown in Figures 4 and 5. The sham-control group appears to reach a plateau in escape latency speed by the second day while the stimulated group did not achieve similar performance until the third day. Across the training sessions on Day 1 there was an overall decrease in escape latency of 69.85% for the stimulated group and 60.85% for the Sham/Control group. Specifically, on training Day 1 the average for the stimulated group was 88.31 sec. where the Sham/Control was 67.95 sec. These data indicate the sham mice learned to locate the escape platform faster than stimulated mice by the end of Day 1 training. Because US could in theory affect swimming performance to cause a similar differences between treatment groups, it is important to note that no behavioral abnormalities in swimming abilities or search strategies were observed following US stimulation of the hippocampus. Indicative of further learning and improvement in MWM escape performance across training sessions, on Day 2 the average escape latency for the Stimulated group was 38.78 sec. (a 58.1% decrease from day one) where the NONINVASIVE MODULATION OF COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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Sham/Control was 15.90 sec. (a 78.6% decrease from day one). Again these data indicate a continued increase in learning for sham mice compared to US stimulated ones. On Day 3 the average for the Stimulated group was 16.07 sec. ±4.94 (a 58.6% decrease from day two) where the Sham/Control was 13.61 sec. ±3.90 (a 14.4% decrease from day two). Collectively, these data show that stimulated mice can learn to escape the MWM as well as sham mice, but it just takes longer for them to do so. It appears that US stimulation of the hippocampus prior to MWM training had more of an effect on memory opposed to actual learning per se. Such an effect can be particularly noted upon examining the escape latency data obtained for the first two training days. The mean escape latencies for US stimulated mice were significantly worse than sham controls on Trial 1 of Day 2 although these groups of mice had learned to perform the MWM task with escape latencies similar to each other by the end of Trial 4 on Day 1 (Figure 4). In fact, at the end of Day 1 the US stimulated mice took ~14 sec less time than the sham controls whereas on Trial 1 of Day 2 it took the US stimulated mice ~70 seconds longer than sham controls. This increased escape latency time from the end of Day 1 to the beginning of Day 2 for stimulated mice compared to sham controls is indicative of forgetting or some other disrupted cognitive process affecting memory consolidation—the conversion of short-term memory into long-term memory. In order to more directly test the memory effects of stimulating the hippocampus with US prior to training, on Day 4, following the three prior training days, mice were placed in the MWM where the escape platform had been removed from the pool. It has been shown that the time spent in the quadrant where mice had learned the escape platform had previously been located can be used to assess memory. The mean time that the stimulated group spent in the correct quadrant of the MWM was noticeably lower than that of the sham control group (Figure 6, below). NONINVASIVE MODULATION O F COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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Figure 6 The above histogram shows the mean time mice spent swimming in the correct escape quadrant when the escape platform was removed on the test day.
The mean score for the Stimulated group (̅ = 20.16, SEM = 2.94, N = 16 trials total) was lower than the scores for the Sham/Control group ( ̅ = 28.40, SEM = 4.09, N = 10 trials total); T-test for equal variance, t(24) = 1.67, p = 0.0536). Although both groups showed decreasing escape latencies and roughly equal escape performance by the end of three days training, the mean time in the quadrant where the platform had previously been placed was ~29% lower in the US stimulated group compared to sham controls. These data provide evidence that US stimulation of the hippocampus may provide a mode of inhibiting learning and/or memory processes depending on the timing of stimulus delivery in relationship to cognitive demand.
DEVICES AND EMBODIMENTS OF ULTRASOUND BMI TECHNOLOGY Multiple prototype transcranial US BMIs have been engineered in the following diagrams. These BMIs reflect a modern paradigm shift in neuroscience towards modes of brain stimulation that are less invasive and more precise while maintaining an ergonomically sound design for practical implementation. Schematics for nonintrusive
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memory enhancement devices have been generated with hopes that future research may corroborate the ability of pulsed US to manipulate cognitive ability. The first BMI device, as depicted in Figure 7 was devised to free the recipient of physical constraints and encourage stimulation during natural sleeping environments since memory reconsolidation during sleep has shown to be integral to learning and memory brain processes. Thus, this BMI does not necessitate any headgear or wires that would typically interfere with normal sleep habits/comforts. A pulsed US BMI would only require the user to don a wrist strap that also acts as a feedback mechanism for brainwave states instead of the typical EEG. Utilizing a combination of actigraphy and peripheral arterial tone, this device would change the parameters (i.e. timing, frequency, intensity) of US stimulation based upon observed brain wave states such as those occurring during REM sleep which are known to underlie certain aspects of memory consolidation (Herscovici, 2007; Louie & Wilson, 2001). In this BMI prototype, an US transducer is based on the platform located behind the head of the sleeping person and a second physical feedback mechanism is required to adjust for the most efficient and precise stimulation (Figure 8). A position camera acts to monitor the headâ&#x20AC;&#x2122;s location and report these findings back to a centralized computer. The transducer is repositioned based upon these readings on a bi-dimensional set of pivoting rods that is moved and angled to stimulate the hippocampus by observing and following natural bodily movements of the head during sleep. As illustrated in Figure 7, the angle of stimulation would be further adjusted by motorized mechanism behind the transducer, itself. According to Tufail and colleagues (2010), US stimulation of the hippocampus must be angled to avoid blockage from the white matter tract of the corpus callosum. Therefore, appropriate computer programs would require development to angle US stimulation towards the hippocampus while avoiding the corpus callosum.
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Figure 7
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Figure 8
The above illustrations show a nonintrusive BMI setup for the stimulation and alteration of memory processes during sleep. Parameters of US stimulation are changed as brain wave states are detected via a wristband employing actigraphy and peripheral artery tone measurements. US is delivered to the skull via a non-contact ultrasound transducer which allows the US to travel in air without conductive substances. Illustrated above on the retractable crescent overhang, as well as by directional arrows, the platform located behind a sleeping personâ&#x20AC;&#x2122;s head will move with the person during sleep to continually stimulate the hippocampus based upon readings by the overhead position camera.
A second type of BMI has been illustrated in the Figures 9-11. Within the frames of a pair of glasses, US transducers individually aligned and directed towards the hippocampus may be manually turned on and off to assist the process of memory consolidation. This technology could be used to assist students or other professionals encode specific memories as they are experienced, with the toggle of a switch turning stimulation on. However, more experimentation is necessary to determine the appropriate parameters to facilitate more narrow memory consolidation. To generate renewable power for the transducers, piezoelectric fibers may be imbedded within clothing (Qin et al., 2010). A wireless computer chip could provide feedback for the US stimulation, as well as download different US stimulation parameters for the alleviation of different diseases and their symptoms. Similar to the BMI in Figure 7/8, the mechanism for feedback and adjustment in the simulation parameters would be achieved through a series of feedback protocol with an externally hosted computer.
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Figure 9
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Figure 10
In this BMI, US transducers placed in the frames of glasses act to stimulate the hippocampus when activated by an on/off switch. An internal computer can download programs indicative of changes in neuronal activity or software packages for the purpose of treating different diseases.
Figure 11 Above, a person is wearing a BMI device, directly powered by the movement of piezoelectric fabric embedded within clothing
Discussion and Future Directions It is apparent from this preliminary study that US stimulation of the hippocampus was able to behaviorally modify memory and learning. Treatment with US prior to each learning and memory trial at the aforementioned stimulus parameters had a negative effect upon spatial cognitive abilities. NONINVASIVE MODULATION O F COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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In the learning trials, US acted to disrupt the learning process in the treatment group, as well memory consolidation. This delay could be attributed to LTP saturation, which has previously inhibited spatial cognitive ability in the MWM (Moser et al., 1998); however, the possible effects of US on this form of plasticity are not well understood. By driving neuronal activity US could have acted to mimic and evoke memory consolidation before even being placed in the MWM task, the spatial-cognitive abilities of mice may have depreciated, in accordance to prior research. It is obvious that more research must be conducted to understand USâ&#x20AC;&#x2122;s underlying effects on neuronal activity The actual mechanisms underlying ultrasoundâ&#x20AC;&#x2122;s ability to generate neuronal action potentials are currently unknown although multiple hypotheses have been proposed and should be considered in future research. One hypothesis contends that pulsed US may force conformational changes in channel proteins embedded in the membrane of neurons, initiating local membrane depolarization and action potential. Based upon prior research with the behavior of US waveforms, it is possible that ultrasound affects the fluid environments surrounding the membrane of neurons to affect membrane conductance and thus, initiate an action potential (Tyler, 2010). While this pilot experiment has found preliminary evidence linking noninvasive US stimulation to the modification of spatial learning/memory, it is apparent that more studies with the MWM and other measures of cognitive ability should be utilized to better understand the effects that different parameters of US stimulation. As a result of this experiment, a full-fledged study employing the MWM and two or three dozen mice is currently underway. Preliminary data obtained using a different US stimulation timing regimen (mice were stimulated chronically for seven days prior to training) indicate that US can also be used to enhance cognitive processes since stimulated mice learn escape platform location faster than sham controls (personal communication, Y. Tufail and W.J. Tyler). The long-lasting consequences of US stimulation in those experiments NONINVASIVE MODULATION OF COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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are also consistent with ideas that US may be able to evoke brain plasticity mechanisms to mediate cognitive processes (Tufail et al, 2010).
Figure 12
Figure 13
Figures 12/13: Recent research based off of results garnered in this experiment’s preliminary tests is indicative of initially demonstrating effective enhancement of memory and learning processes in mice under different stimulation parameters (n=6). In the figure 12 above, the stimulation group (red trend line) has an overall enhanced escape latency performance relative to the sham/control group (black trend line), indicative of enhanced learning. In figure 13 above, the stimulation group performed ~20 % better than the sham/control group in the memory assessment trials on Day 4 in the MWM.
Data from this experiment indicates that US is capable of negatively modifying spatial memory and learning through stimulation of the hippocampus. With future research it may be inferred that US could act to enhance the memory consolidation process to better memorization as initial experimentation demonstrates (figures 12/13). Such an application would have widespread significance for most persons desiring a better cognitive ability. Alzheimer’s patients could use the technology to improve the consolidation of memories that would, otherwise, be easily forgotten, as is consistent with the disease’s obtrusive symptoms. Alzheimer’s disease is now becoming a prevalent and pervasive epidemic among the elderly. As measured in the United States census of 2000, there were 4.5 million persons living with Alzheimer’s disease. According to estimates, that number will dramatically increase by the year 2050 to 13.2 million — roughly a tripling in the number of elderly diagnosed with Alzheimer’s (Herbert et al., 2003). NONINVASIVE MODULATION O F COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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Transcranial pulsed US stimulation may help to alleviate the symptoms of memory loss associated with Alzheimerâ&#x20AC;&#x2122;s disease through US-based BMIs. Research regarding memory consolidation during sleep reports that episodic memory traces are retriggered during rapid eye movement (REM) sleep in the hippocampus. This suggests the importance of the REM sleep phase to episodic memory consolidation (Louie & Wilson, 2001). Slow-wave sleep is also revealed to be crucial to the process of creating long-term memories. A study with rats demonstrated that place cells in the CA1 region of the hippocampus that are activated during a spatial memory task are retriggered during the slow-wave sleep phase (Lee & Wilson, 2002). These observations, coupled with results from the current project, indicate that under certain parameters, transcranial pulsed US stimulation when paired with brain wave feedback mechanisms would be able to modify memory during sleep. While transcranial pulsed US stimulation has been observed as safe in mice, more studies are necessary to corroborate safety in other species (Tufail et al., 2010). That said, US stimulation lends itself well to a more accurate and less circumscribed form of noninvasive brain stimulation. Brain machine interfaces can be created to take advantage of aforementioned characteristics but more research detailing the most accurate parameters to either enhance or inhibit memory and learning must be developed. These parameters could be developed in tandem with sleep cycle consolidation periods to create a noninvasive cognition modification device during sleep (Figure 7). Parameters for portable devices of hippocampal stimulation through US also require more research to corroborate the best timing and frequency of stimulation for cognitive enhancement. Transcranial Pulsed US has demonstrated its effectiveness in in vivo stimulation of the hippocampus as well as generating movements by stimulation of the motor cortex (Tufail et al., 2010). However, this noninvasive technology could possess many other NONINVASIVE MODULATION OF COGNITIVE ABILITIES WITH TRANSCRANIAL ULTRASOUND: IMPLICATIONS FOR FUTURE BRAIN MACHINE INTERFACES
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ZACHARY S. GOODMAN outside
of
memory/learning
enhancement.
US
stimulation
could
theoretically exhibit the same neurological therapeutic potential as other brain stimulation techniques have (e.g. epilepsy, Parkinsonâ&#x20AC;&#x2122;s treatment) without any major shortcomings. Stimulation of the nucleus accumbens, or reward section of the brain, paired with an appropriate computer program, could reward a subject for performing exercise (Garner et al., 2010; Burgess et al., 2010). US stimulation fitted within the helmets of soldiers could have therapeutic value intervening against damaging chemical cascades in the brain subsequent to traumatic brain injury (Schiff et al., 2010). The aforementioned treatments are only a few of many possible applications that transcranial pulsed US is theoretically capable of adeptly performing. As both a noninvasive and relatively accurate form of neuromodulation, transcranial pulsed US offers distinct advantages over currently implemented modern brain stimulation techniques. Together with evidence presented by Tufail and colleagues (2010), this experiment has indicated that US can be employed to stimulate hippocampal neurons and modulate cognition. Development of this stimulation technique will indubitably yield medical potential in treating numerous neurological disorders, including Alzheimerâ&#x20AC;&#x2122;s. Embodiments of this novel stimulation method in the form of BMIs are capable of revolutionizing the delivery of disease-alleviating US with feedback mechanisms. Ultimately, the potential embodied in this technology makes it an extremely viable form of brain stimulation, and with further research, one with profuse applications.
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