Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Machine learning classifiers for electrode selection in the design of closed-loop neuromodulation devices for episodic memory improvement.

Successful neuromodulation approaches to alter episodic memory require closed-loop stimulation predicated on the effective classification of brain states. The practical implementation of such strategies requires prior decisions regarding electrode implantation locations. Using a data-driven approach, we employ support vector machine (SVM) classifiers to identify high-yield brain targets on a large data set of 75 human intracranial electroencephalogram subjects performing the free recall (FR) task. Further, we address whether the conserved brain regions provide effective classification in an alternate (associative) memory paradigm along with FR, as well as testing unsupervised classification methods that may be a useful adjunct to clinical device implementation. Finally, we use random forest models to classify functional brain states, differentiating encoding versus retrieval versus non-memory behavior such as rest and mathematical processing. We then test how regions that exhibit good classification for the likelihood of recall success in the SVM models overlap with regions that differentiate functional brain states in the random forest models. Finally, we lay out how these data may be used in the design of neuromodulation devices.

Distinct neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex.

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood-oxygen-level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modelling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70-150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30-70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex.Significance Statement:The blood-oxygen-level-dependent (BOLD) signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in frontal and parietal cortex. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.

Hippocampal theta codes for distances in semantic and temporal spaces.

The medial temporal lobe (MTL) is known to support episodic memory and spatial navigation, raising the possibility that its true function is to form "cognitive maps" of any kind of information. Studies in humans and animals support the idea that the hippocampal theta rhythm (4 to 8 Hz) is key to this mapping function, as it has been repeatedly observed during spatial navigation tasks. If episodic memory and spatial navigation are 2 sides of the same coin, we hypothesized that theta oscillations might reflect relations between explicitly nonspatial items, such as words. We asked 189 neurosurgical patients to perform a verbal free-recall task, of which 96 had indwelling electrodes placed in the MTL. Subjects were instructed to remember short lists of sequentially presented nouns. We found that hippocampal theta power and connectivity during item retrieval coded for semantic distances between words, as measured using word2vec-derived subspaces. Additionally, hippocampal theta indexed temporal distances between words after filtering lists on recall performance, to ensure adequate dynamic range in time. Theta effects were noted only for semantic subspaces of 1 dimension, indicating a substantial compression of the possible semantic feature space. These results lend further support to our growing confidence that the MTL forms cognitive maps of arbitrary representational spaces, helping to reconcile longstanding differences between the spatial and episodic memory literatures.

Hippocampal Theta Oscillations Support Successful Associative Memory Formation.

Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we used an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2-5 Hz and 5-9 Hz theta oscillations, by which power increases in 2-5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding and distinguished recollected from nonrecollected items at retrieval, as well as contributing to relatively greater reinstatement of encoding-related patterns for recollected versus nonrecollected items. Our results provide direct electrophysiological evidence that 2-5 Hz hippocampal theta oscillations preferentially support the formation of associative memories, although we also observed memory-related effects in the 5-9 Hz frequency range using measures such as phase reset and reinstatement of oscillatory activity.SIGNIFICANCE STATEMENT Models of episodic memory encoding predict that theta oscillations support the formation of interitem associations. We used an associative recognition task designed to elicit strong hippocampal activation to test this prediction in human neurosurgical patients implanted with intracranial electrodes. The findings suggest that 2-5 Hz theta oscillatory power and phase reset in the hippocampus are selectively associated with associative memory judgments. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection. Collectively, the findings support a role for hippocampal theta oscillations in human associative memory.

Cross-regional phase amplitude coupling supports the encoding of episodic memories.

Phase amplitude coupling (PAC) between theta and gamma oscillations represents a key neurophysiological mechanism that promotes the temporal organization of oscillatory activity. For this reason, PAC has been implicated in item/context integration for episodic processes, including coordinating activity across multiple cortical regions. While data in humans has focused principally on PAC within a single brain region, data in rodents has revealed evidence that the phase of the hippocampal theta oscillation modulates gamma oscillations in the cortex (and vice versa). This pattern, termed cross-regional PAC (xPAC), has not previously been observed in human subjects engaged in mnemonic processing. We use a unique dataset with intracranial electrodes inserted simultaneously into the hippocampus and seven cortical regions across 40 human subjects to (1) test for the presence of significant cross-regional PAC (xPAC), (2) to establish that the magnitude of xPAC predicts memory encoding success, (3) to describe specific frequencies within the broad 2-9 Hz theta range that govern hippocampal-cortical interactions in xPAC, and (4) compare anterior versus posterior hippocampal xPAC patterns. We find that strong functional xPAC occurs principally between the hippocampus and other mesial temporal structures, namely entorhinal and parahippocampal cortices, and that xPAC is overall stronger for posterior hippocampal connections. We also show that our results are not confounded by alternative factors such as inter-regional phase synchrony, local PAC occurring within cortical regions, or artifactual theta oscillatory waveforms.

Factors correlated with intracranial interictal epileptiform discharges in refractory epilepsy.

OBJECTIVE: This study was undertaken to evaluate the influence that subject-specific factors have on intracranial interictal epileptiform discharge (IED) rates in persons with refractory epilepsy. METHODS: One hundred fifty subjects with intracranial electrodes performed multiple sessions of a free recall memory task; this standardized task controlled for subject attention levels. We utilized a dominance analysis to rank the importance of subject-specific factors based on their relative influence on IED rates. Linear mixed-effects models were employed to comprehensively examine factors with highly ranked importance. RESULTS: Antiseizure medication (ASM) status, time of testing, and seizure onset zone (SOZ) location were the highest-ranking factors in terms of their impact on IED rates. The average IED rate of electrodes in SOZs was 34% higher than the average IED rate of electrodes outside of SOZs (non-SOZ; p < .001). However, non-SOZ electrodes had similar IED rates regardless of the subject's SOZ location (p = .99). Subjects on older generation (p < .001) and combined generation (p < .001) ASM regimens had significantly lower IED rates relative to the group taking no ASMs; newer generation ASM regimens demonstrated a nonsignificant association with IED rates (p = .13). Of the ASMs included in this study, the following ASMs were associated with significant reductions in IED rates: levetiracetam (p < .001), carbamazepine (p < .001), lacosamide (p = .03), zonisamide (p = .01), lamotrigine (p = .03), phenytoin (p = .03), and topiramate (p = .01). We observed a nonsignificant association between time of testing and IED rates (morning-afternoon p = .15, morning-evening p = .85, afternoon-evening p = .26). SIGNIFICANCE: The current study ranks the relative influence that subject-specific factors have on IED rates and highlights the importance of considering certain factors, such as SOZ location and ASM status, when analyzing IEDs for clinical or research purposes.

Features of intracranial interictal epileptiform discharges associated with memory encoding.

OBJECTIVE: Interictal epileptiform discharges (IEDs) were shown to be associated with cognitive impairment in persons with epilepsy. Previous studies indicated that IED rate, location, timing, and spatial relation to the seizure onset zone could predict an IED's impact on memory encoding and retrieval if they occurred in lateral temporal, mesial temporal, or parietal regions. In this study, we explore the influence that other IED properties (e.g., amplitude, duration, white matter classification) have on memory performance. We were specifically interested in investigating the influence that lateral temporal IEDs have on memory encoding. METHODS: Two hundred sixty-one subjects with medication-refractory epilepsy undergoing intracranial electroencephalographic monitoring performed multiple sessions of a delayed free-recall task (n = 671). Generalized linear mixed models were utilized to examine the relationship between IED properties and memory performance. RESULTS: We found that increased IED rate, IEDs propagating in white matter, and IEDs localized to the left middle temporal region were associated with poorer memory performance. For lateral temporal IEDs, we observed a significant interaction between IED white matter categorization and amplitude, where IEDs with an increased amplitude and white matter propagation were associated with reduced memory performance. Additionally, changes in alpha power after an IED showed a significant positive correlation with memory performance. SIGNIFICANCE: Our results suggest that IED properties may be useful for predicting the impact an IED has on memory encoding. We provide an essential step toward understanding pathological versus potentially beneficial interictal epileptiform activity.

Comparison of fMRI correlates of successful episodic memory encoding in temporal lobe epilepsy patients and healthy controls.

Intra-cranial electroencephalographic brain recordings (iEEG) provide a powerful tool for investigating the neural processes supporting episodic memory encoding and form the basis of experimental therapies aimed at improving memory dysfunction. However, given the invasiveness of iEEG, investigations are constrained to patients with drug-resistant epilepsy for whom such recordings are clinically indicated. Particularly in the case of temporal lobe epilepsy (TLE), neuropathology and the possibility of functional reorganization are potential constraints on the generalizability of intra-cerebral findings and pose challenges to the development of therapies for memory disorders stemming from other etiologies. Here, samples of TLE (N â€‹= â€‹16; all of whom had undergone iEEG) and age-matched healthy control (N â€‹= â€‹19) participants underwent fMRI as they studied lists of concrete nouns. fMRI BOLD responses elicited by the study words were segregated according to subsequent performance on tests of delayed free recall and recognition memory. Subsequent memory effects predictive of both successful recall and recognition memory were evident in several neural regions, most prominently in the left inferior frontal gyrus, and did not demonstrate any group differences. Behaviorally, the groups did not differ in overall recall performance or in the strength of temporal contiguity effects. However, group differences in serial position effects and false alarm rates were evident during the free recall and recognition memory tasks, respectively. Despite these behavioral differences, neuropathology associated with temporal lobe epilepsy was apparently insufficient to give rise to detectable differences in the functional neuroanatomy of episodic memory encoding relative to neurologically healthy controls. The findings provide reassurance that iEEG findings derived from experimental paradigms similar to those employed here generalize to the neurotypical population.

Human Genomic Signatures of Brain Oscillations During Memory Encoding.

Memory encoding is an essential step for all learning. However, the genetic and molecular mechanisms underlying human memory encoding remain poorly understood, and how this molecular framework permits the emergence of specific patterns of brain oscillations observed during mnemonic processing is unknown. Here, we directly compare intracranial electroencephalography recordings from the neocortex in individuals performing an episodic memory task with human gene expression from the same areas. We identify genes correlated with oscillatory memory effects across 6 frequency bands. These genes are enriched for autism-related genes and have preferential expression in neurons, in particular genes encoding synaptic proteins and ion channels, supporting the idea that the genes regulating voltage gradients are involved in the modulation of oscillatory patterns during successful memory encoding across brain areas. Memory-related genes are distinct from those correlated with other forms of cognitive processing and resting state fMRI. These data are the first to identify correlations between gene expression and active human brain states as well as provide a molecular window into memory encoding oscillations in the human brain.

Ripple oscillations in the left temporal neocortex are associated with impaired verbal episodic memory encoding.

BACKGROUND: We sought to determine if ripple oscillations (80-120 Hz), detected in intracranial electroencephalogram (iEEG) recordings of patients with epilepsy, correlate with an enhancement or disruption of verbal episodic memory encoding. METHODS: We defined ripple and spike events in depth iEEG recordings during list learning in 107 patients with focal epilepsy. We used logistic regression models (LRMs) to investigate the relationship between the occurrence of ripple and spike events during word presentation and the odds of successful word recall following a distractor epoch and included the seizure onset zone (SOZ) as a covariate in the LRMs. RESULTS: We detected events during 58,312 word presentation trials from 7630 unique electrode sites. The probability of ripple on spike (RonS) events was increased in the SOZ (p < 0.04). In the left temporal neocortex, RonS events during word presentation corresponded with a decrease in the odds ratio (OR) of successful recall, however, this effect only met significance in the SOZ (OR of word recall: 0.71, 95% confidence interval (CI): 0.59-0.85, n = 158 events, adaptive Hochberg, p < 0.01). Ripple on oscillation (RonO) events that occurred in the left temporal neocortex non-SOZ also correlated with decreased odds of successful recall (OR: 0.52, 95% CI: 0.34-0.80, n = 140, adaptive Hochberg, p < 0.01). Spikes and RonS that occurred during word presentation in the left middle temporal gyrus (MTG) correlated with the most significant decrease in the odds of successful recall, irrespective of the location of the SOZ (adaptive Hochberg, p < 0.01). CONCLUSION: Ripples and spikes generated in the left temporal neocortex are associated with impaired verbal episodic memory encoding. Although physiological and pathological ripple oscillations were not distinguished during cognitive tasks, our results show an association of undifferentiated ripples with impaired encoding. The effect was sometimes specific to regions outside the SOZ, suggesting that widespread effects of epilepsy outside the SOZ may contribute to cognitive impairment.

Theta band power increases in the posterior hippocampus predict successful episodic memory encoding in humans.

Functional differences in the anterior and posterior hippocampus during episodic memory processing have not been examined in human electrophysiological data. This is in spite of strong evidence for such differences in rodent data, including greater place cell specificity in the dorsal hippocampus, greater sensitivity to the aversive or motivational content of memories in ventral regions, connectivity analyses identifying preferential ventral hippocampal connections with the amygdala, and gene expression analyses identifying a dorsal-ventral gradient. We asked if memory-related oscillatory patterns observed in human hippocampal recordings, including the gamma band and slow-theta (2.5-5 Hz) subsequent memory effects, would exhibit differences along the longitudinal axis and between hemispheres. We took advantage of a new dataset of stereo electroencephalography patients with simultaneous, robotically targeted anterior, and posterior hippocampal electrodes to directly compare oscillatory subsequent memory effects during item encoding. This same data set allowed us to examine left-right connectivity and hemispheric differences in hippocampal oscillatory patterns. Our data suggest that a power increase during successful item encoding in the 2.5-5 Hz slow-theta frequency range preferentially occurs in the posterior hippocampus during the first 1,000 ms after item presentation, while a gamma band power increase is stronger in the dominant hemisphere. This dominant-nondominant pattern in the gamma range appears to reverse during item retrieval, however. Intrahippocampal phase coherence was found to be stronger during successful item encoding. Our phase coherence data are also consistent with existing reports of a traveling wave for theta oscillations propagating along the septotemporal (longitudinal) axis of the human hippocampus. We examine how our findings fit with theories of functional specialization along the hippocampal axis.

Episodic boundaries affect neural features of representational drift in humans.

A core feature of episodic memory is representational drift, the gradual change in aggregate oscillatory features that supports temporal association of memory items. However, models of drift overlook the role of episodic boundaries, which indicate a shift from prior to current context states. Our study focuses on the impact of task boundaries on representational drift in the parietal and temporal lobes in 99 subjects during a free recall task. Using intracranial EEG recordings, we show boundary representations reset gamma band drift in the medial parietal lobe, selectively enhancing the recall of early list (primacy) items. Conversely, the lateral temporal cortex shows increased drift for recalled items but lacked sensitivity to task boundaries. Our results suggest regional sensitivity to varied contextual features: the lateral temporal cortex uses drift to differentiate items, while the medial parietal lobe uses drift-resets to associate items with the current context. We propose drift represents relational information tailored to a region's sensitivity to unique contextual elements. Our findings offer a mechanism to integrate models of temporal association by drift with event segmentation by episodic boundaries.

Bibliometric Analysis and Applications of a Modified H-Index Examining the Research Productivity of Neurosurgery Faculty at High-Ranking Academic Institutions.

OBJECTIVE: A major critique of the h-index is that it may be inflated by noncritical authorship. We propose a modified h-index (hm), incorporating critical authorship, complementary to the h-index. We analyze its relationship to the traditional h-index, and how each varies across professional categories relevant to academic neurosurgery. This analysis is not meant to critique authorship decisions, affect career development, alter academic legacy, or imply that the concepts of team science or midlevel authorship contributions are not valuable. METHODS: H-indices and hms were gathered and computed for clinical neurosurgical faculty at the top 32 ranked academic neurosurgical programs based on the current literature. Hm was computed for faculty at each program, using articles in which the individual was first, second, last, or co-corresponding author. Individuals were further identified based on chair status, leadership status, neurosurgical subspecialty, and National Institutes of Health funding status. Further analysis was performed to determine factors influencing h-index and hm. RESULTS: The median h-index for the 225 physicians included in the final dataset is 48 (interquartile range [IQR], 39-61), whereas the median hm was 32 (IQR, 24-43). The median difference between h-index and hm is 15 (IQR, 10-23). The median hm/h was 64% (IQR, 57-74). National Institutes of Health funding and subspecialty (neurosurgical oncology, neurocritical care, and cerebrovascular) were associated with significant change from h to hm. CONCLUSIONS: The h-index can be influenced by noncritical authorship, and hm, using critical contributions, can be used as a complement reflecting critical academic output in neurosurgery. Leaders deciding on hiring or promotion should consider disparities in productivity predicated on noncritical authorship contributions.

Neuronal activity in the human subthalamic nucleus encodes decision conflict during action selection.

The subthalamic nucleus (STN), which receives excitatory inputs from the cortex and has direct connections with the inhibitory pathways of the basal ganglia, is well positioned to efficiently mediate action selection. Here, we use microelectrode recordings captured during deep brain stimulation surgery as participants engage in a decision task to examine the role of the human STN in action selection. We demonstrate that spiking activity in the STN increases when participants engage in a decision and that the level of spiking activity increases with the degree of decision conflict. These data implicate the STN as an important mediator of action selection during decision processes.

Biomarker-guided neuromodulation aids memory in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset of patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Human hippocampal theta oscillations and the formation of episodic memories.

The importance of the hippocampal theta oscillation (4-8 Hz) to memory formation has been well-established through studies in animals, prompting researchers to propose comprehensive theories of memory and learning that rely on theta oscillations for integrating information in the hippocampus and neocortex. Yet, empirical evidence for the importance of 4-8 Hz hippocampal theta oscillations to memory formation in humans is equivocal at best. To clarify this apparent interspecies discrepancy, we recorded intracranial EEG (iEEG) data from 237 hippocampal electrodes in 33 neurosurgical patients as they performed an episodic memory task. We identified two distinct patterns of hippocampal oscillations, at ∼3 and ∼8 Hz, which are at the edges of the traditional 4-8 Hz human theta band. The 3 Hz "slow-theta" oscillation exhibited higher power during successful memory encoding and was functionally linked to gamma oscillations, but similar patterns were not present for the 8 Hz "fast-theta" oscillation. For episodic memory, slow-theta oscillations in the human hippocampus appear to be analogous to the memory-related theta oscillations observed in animals. Both fast-theta and slow-theta oscillations exhibit evidence of phase synchrony with oscillations in the temporal cortex. We discuss our findings in the context of recent research on the electrophysiology of human memory and spatial navigation, and explore the implications of this result for theories of cortico-hippocampal communication.

Riding brain "waves" to identify human memory genes.

While there is extensive research on memory-related oscillations and brain gene expression, the relationship between oscillations and gene expression has rarely been studied. Recently, progress has been made to identify specific genes associated with oscillations that are correlated with episodic memory. Neocortical regions, in particular the temporal pole, have been examined in this line of research due to their accessibility during neurosurgical procedures. By harnessing this accessibility, a unique and powerful study design has allowed gene expression and intracranial oscillatory data to be sourced from the same human patients. These studies have identified a plethora of understudied gene targets that should be further characterized with respect to human brain function. Future work should extend to other brain regions to increase our understanding of the genetic signatures of oscillations and, ultimately, human cognition.

A Control-Theoretical System for Modulating Hippocampal Gamma Oscillations Using Stimulation of the Posterior Cingulate Cortex.

Closed-loop stimulation for targeted modulation of brain signals has emerged as a promising strategy for episodic memory restoration. In parallel, closed-loop neuromodulation strategies have been applied to treat brain conditions including drug-resistant depression, Parkinson's Disease, and epilepsy. In this study, we seek to apply control theoretical principles to achieve closed loop modulation of hippocampal oscillatory activity. We focus on hippocampal gamma power, a signal with an established association for episodic memory processing, which may be a promising 'biomarker' for the modulation of memory performance. To develop a closed-loop stimulation paradigm that effectively modulates hippocampal gamma power, we use a novel data-set in which open-loop stimulation was applied to the posterior cingulate cortex and hippocampal gamma power was recorded during the encoding of episodic memories. The dataset was used to design and evaluate a linear quadratic integral (LQI) servo-controller in order to determine its viability for in-vivo use. In our simulation framework, we demonstrate that applying an LQI servo controller based on an autoregressive with exogenous input (ARX) plant model achieves effective control of hippocampal gamma power in 15 out of 17 experimental subjects. We demonstrate that we are able to modulate gamma power using stimulation thresholds that are physiologically safe and on time scales that are reasonable for application in a clinical system. We outline further experimentation to test our proposed system and compare our findings to emerging closed-loop neuromodulation strategies.