Publications by authors named "Bradley Lega"

68 Publications

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

Hippocampus 2021 Feb 5. Epub 2021 Feb 5.

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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.
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http://dx.doi.org/10.1002/hipo.23309DOI Listing
February 2021

Biomarkers of memory variability in traumatic brain injury.

Brain Commun 2021 15;3(1):fcaa202. Epub 2020 Dec 15.

Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Traumatic brain injury is a leading cause of cognitive disability and is often associated with significant impairment in episodic memory. In traumatic brain injury survivors, as in healthy controls, there is marked variability between individuals in memory ability. Using recordings from indwelling electrodes, we characterized and compared the oscillatory biomarkers of mnemonic variability in two cohorts of epilepsy patients: a group with a history of moderate-to-severe traumatic brain injury ( = 37) and a group of controls without traumatic brain injury ( = 111) closely matched for demographics and electrode coverage. Analysis of these recordings demonstrated that increased high-frequency power and decreased theta power across a broad set of brain regions mark periods of successful memory formation in both groups. As features in a logistic-regression classifier, spectral power biomarkers effectively predicted recall probability, with little difference between traumatic brain injury patients and controls. The two groups also displayed similar patterns of theta-frequency connectivity during successful encoding periods. These biomarkers of successful memory, highly conserved between traumatic brain injury patients and controls, could serve as the basis for novel therapies that target disordered memory across diverse forms of neurological disease.
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http://dx.doi.org/10.1093/braincomms/fcaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850041PMC
December 2020

Factors correlated with intracranial interictal epileptiform discharges in refractory epilepsy.

Epilepsia 2021 Feb 17;62(2):481-491. Epub 2020 Dec 17.

Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

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.
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http://dx.doi.org/10.1111/epi.16792DOI Listing
February 2021

Hippocampal Theta Oscillations Support Successful Associative Memory Formation.

J Neurosci 2020 12 6;40(49):9507-9518. Epub 2020 Nov 6.

Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390

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. 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.
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http://dx.doi.org/10.1523/JNEUROSCI.0767-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724134PMC
December 2020

Time cells in the human hippocampus and entorhinal cortex support episodic memory.

Proc Natl Acad Sci U S A 2020 11 27;117(45):28463-28474. Epub 2020 Oct 27.

Department of Neurological Surgery, University of Texas Southwestern, Dallas, TX 75390;

The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of "time cells" in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of retrieved memory items. We also uncover evidence of ramping cell activity in humans, which represents a complementary type of temporal information. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.
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http://dx.doi.org/10.1073/pnas.2013250117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668099PMC
November 2020

Direct brain recordings identify hippocampal and cortical networks that distinguish successful versus failed episodic memory retrieval.

Neuropsychologia 2020 10 29;147:107595. Epub 2020 Aug 29.

Department of Neurosurgery, University of Texas Southwestern, Dallas, TX 75390, USA.

Human data collected using noninvasive imaging techniques have established the importance of parietal regions towards episodic memory retrieval, including the angular gyrus and posterior cingulate cortex. Such regions comprise part of a putative core episodic retrieval network. In free recall, comparisons between contextually appropriate and inappropriate recall events (i.e. prior list intrusions) provide the opportunity to study memory retrieval networks supporting veridical recall, and existing findings predict that differences in electrical activity in these brain regions should be identified according to the accuracy of recall. However, prior iEEG studies, utilizing principally subdural grid electrodes, have not fully characterized brain activity in parietal regions during memory retrieval and have not examined connectivity between core recollection areas and the hippocampus or prefrontal cortex. Here, we employed a data set obtained from 100 human patients implanted with stereo EEG electrodes for seizure mapping purposes as they performed a free recall task. This data set allowed us to separately analyze activity in midline versus lateral parietal brain regions, and in anterior versus posterior hippocampus, to identify areas in which retrieval-related activity predicted the recollection of a correct versus an incorrect memory. With the wide coverage afforded by the stereo EEG approach, we were also able to examine interregional connectivity. Our key findings were that differences in gamma band activity in the angular gyrus, precuneus, posterior temporal cortex, and posterior (more than anterior) hippocampus discriminated accurate versus inaccurate recall as well as active retrieval versus memory search. The left angular gyrus exhibited a significant power decrease preceding list intrusions as well as unique phase-amplitude coupling properties, whereas the prefrontal cortex was unique in exhibiting a power increase during list intrusions. Analysis of connectivity revealed significant hemispheric asymmetry, with relatively sparse left-sided functional connections compared to the right hemisphere. One exception to this finding was elevated connectivity between the prefrontal cortex and left angular gyrus. This finding is interpreted as evidence for the engagement of prefrontal cortex in memory monitoring and mnemonic decision-making.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554101PMC
October 2020

Longitudinal Differences in Human Hippocampal Connectivity During Episodic Memory Processing.

Cereb Cortex Commun 2020 14;1(1):tgaa010. Epub 2020 Apr 14.

Department of Neurosurgery, University of Texas Southwestern, Dallas, TX 75390, USA.

The question of longitudinal hippocampal functional specialization is critical to human episodic memory because an accurate understanding of this phenomenon would impact theories of mnemonic function and entail practical consequences for the clinical management of patients undergoing temporal lobe surgery. The implementation of the robotically assisted stereo electroencephalography technique for seizure mapping has provided our group with the opportunity to obtain recordings simultaneously from the anterior and posterior human hippocampus, allowing us to create an unparalleled data set of human subjects with simultaneous anterior and posterior hippocampal recordings along with several cortical regions. Using these data, we address several key questions governing functional hippocampal connectivity in human memory. First, we ask whether functional networks during episodic memory encoding and retrieval are significantly different for the anterior versus posterior hippocampus (PH). We also examine how connections differ across the 2-5 Hz versus 4-9 Hz theta frequency ranges, directly addressing the relative contribution of each of these separate bands in hippocampal-cortical interactions. While we report some overlapping connections, we observe evidence of distinct anterior versus posterior hippocampal networks during memory encoding related to frontal and parietal connectivity as well as hemispheric differences in aggregate connectivity. We frame these findings in light of the proposed AT/PM memory systems. We also observe distinct encoding versus retrieval connectivity patterns between anterior and posterior hippocampal networks, we find that overall connectivity is greater for the PH in the right hemisphere, and further that these networks significantly differ in terms of frontal and parietal connectivity. We place these findings in the context of existing theoretical treatments of human memory systems, especially the proposed AT/PM system. During memory retrieval, we observe significant differences between slow-theta (2-5 Hz) and fast-theta (4-9 Hz) connectivity between the cortex and hippocampus. Finally, we test how these distinct theta frequency oscillations propagate within the hippocampus, using phase slope index to estimate the direction slow-theta and fast-theta oscillations travel during encoding and retrieval. We uncover evidence that 2-5 Hz oscillations travel in the posterior-to-anterior direction, while 5-9 Hz oscillations travel from anterior-to-posterior. Taken together, our findings describe mnemonically relevant functional connectivity differences along the longitudinal axis of the human hippocampus that will inform interpretation of models of hippocampal function that seek to integrate rodent and human data.
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http://dx.doi.org/10.1093/texcom/tgaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446229PMC
April 2020

The effects of direct brain stimulation in humans depend on frequency, amplitude, and white-matter proximity.

Brain Stimul 2020 Sep - Oct;13(5):1183-1195. Epub 2020 May 21.

Department of Biomedical Engineering, Columbia University, New York, 10027, USA. Electronic address:

Background: Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes.

Objective: The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain.

Methods: To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations.

Results: Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity.

Conclusion: By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.
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http://dx.doi.org/10.1016/j.brs.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494653PMC
May 2020

Functionally distinct high and low theta oscillations in the human hippocampus.

Nat Commun 2020 05 18;11(1):2469. Epub 2020 May 18.

Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta's function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.
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http://dx.doi.org/10.1038/s41467-020-15670-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235253PMC
May 2020

Commentary: Awake Craniotomy and Memory Induction Through Electrical Stimulation: Why Are Penfield's Findings Not Replicated in the Modern Era?

Neurosurgery 2020 08;87(2):E138-E139

Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas.

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http://dx.doi.org/10.1093/neuros/nyaa122DOI Listing
August 2020

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

Neuroimage 2020 02 23;207:116397. Epub 2019 Nov 23.

Center for Vital Longevity, University of Texas at Dallas, 1600 Viceroy Dr. #800, Dallas, TX, 75235, USA; School of Behavioral and Brain Sciences, University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX, 75080, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, 6363 Forest Park Rd 7th Floor Suite 749, Dallas, TX, 75235, USA.

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 ​= ​16; all of whom had undergone iEEG) and age-matched healthy control (N ​= ​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.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238288PMC
February 2020

Unsupervised machine-learning classification of electrophysiologically active electrodes during human cognitive task performance.

Sci Rep 2019 11 22;9(1):17390. Epub 2019 Nov 22.

Mayo Clinic, Dept. of Neurology, Rochester, MN, USA.

Identification of active electrodes that record task-relevant neurophysiological activity is needed for clinical and industrial applications as well as for investigating brain functions. We developed an unsupervised, fully automated approach to classify active electrodes showing event-related intracranial EEG (iEEG) responses from 115 patients performing a free recall verbal memory task. Our approach employed new interpretable metrics that quantify spectral characteristics of the normalized iEEG signal based on power-in-band and synchrony measures. Unsupervised clustering of the metrics identified distinct sets of active electrodes across different subjects. In the total population of 11,869 electrodes, our method achieved 97% sensitivity and 92.9% specificity with the most efficient metric. We validated our results with anatomical localization revealing significantly greater distribution of active electrodes in brain regions that support verbal memory processing. We propose our machine-learning framework for objective and efficient classification and interpretation of electrophysiological signals of brain activities supporting memory and cognition.
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http://dx.doi.org/10.1038/s41598-019-53925-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874617PMC
November 2019

Hippocampal theta codes for distances in semantic and temporal spaces.

Proc Natl Acad Sci U S A 2019 11 13;116(48):24343-24352. Epub 2019 Nov 13.

Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104

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.
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http://dx.doi.org/10.1073/pnas.1906729116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883851PMC
November 2019

Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex.

Nat Neurosci 2019 12 11;22(12):2078-2086. Epub 2019 Nov 11.

Department of Biomedical Engineering, Columbia University, New York, NY, USA.

The medial temporal lobe is critical for both spatial navigation and memory. Although single neurons in the medial temporal lobe activate to represent locations in the environment during navigation, how this spatial tuning relates to memory for events involving those locations remains unclear. We examined memory-related changes in spatial tuning by recording single-neuron activity from neurosurgical patients performing a virtual-reality object-location memory task. We identified 'memory-trace cells' with activity that was spatially tuned to the retrieved location of the specific object that participants were cued to remember. Memory-trace cells in the entorhinal cortex, in particular, encoded discriminable representations of different memories through a memory-specific rate code. These findings indicate that single neurons in the human entorhinal cortex change their spatial tuning to target relevant memories for retrieval.
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http://dx.doi.org/10.1038/s41593-019-0523-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897360PMC
December 2019

Risk of seizures induced by intracranial research stimulation: analysis of 770 stimulation sessions.

J Neural Eng 2019 11 11;16(6):066039. Epub 2019 Nov 11.

Department of Neurological Surgery, Columbia University, New York, NY, United States of America.

Objective: Patients with medically refractory epilepsy often undergo intracranial electroencephalography (iEEG) monitoring to identify a seizure focus and determine their candidacy for surgical intervention. This clinically necessary monitoring period provides an increasingly utilized research opportunity to study human neurophysiology, however ethical concerns demand a thorough appreciation of the associated risks. We measured the incidence of research stimulation-associated seizures in a large multi-institutional dataset in order to determine whether brain stimulation was statistically associated with seizure incidence and identify potential risk factors for stimulation-associated seizures.

Approach: 188 subjects undergoing iEEG monitoring across ten institutions participated in 770 research stimulation sessions over 3.5 yr. Seizures within 30 min of a stimulation session were included in our retrospective analysis. We analyzed stimulation parameters, seizure incidence, and typical seizure patterns, to assess the likelihood that recorded seizures were stimulation-induced, rather than events that occurred by chance in epilepsy patients prone to seizing.

Main Results: In total, 14 seizures were included in our analysis. All events were single seizures, and no adverse events occurred. The mean amplitude of seizure-associated stimulation did not differ significantly from the mean amplitude delivered in sessions without seizures. In order to determine the likelihood that seizures were stimulation induced, we used three sets of analyses: visual iEEG analysis, statistical frequency, and power analyses. We determined that three of the 14 seizures were likely stimulation-induced, five were possibly stimulation-induced, and six were unlikely stimulation-induced. Overall, we estimate a rate of stimulation-induced seizures between 0.39% and 1.82% of sessions.

Significance: The rarity of stimulation-associated seizures and the fact that none added morbidity or affected the clinical course of any patient are important findings for understanding the feasibility and safety of intracranial stimulation for research purposes.
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http://dx.doi.org/10.1088/1741-2552/ab4365DOI Listing
November 2019

Connectivity of the human insula: A cortico-cortical evoked potential (CCEP) study.

Cortex 2019 11 18;120:419-442. Epub 2019 Jun 18.

Epilepsy Center, Cleveland Clinic, Neurological Institute, Cleveland, OH, USA.

Objective: The human insula is increasingly being implicated as a multimodal functional network hub involved in a large variety of complex functions. Due to its inconspicuous location and highly vascular anatomy, it has historically been difficult to study. Cortico-cortical evoked potentials (CCEPs), utilize low frequency stimulation to map cerebral networks. They were used to study connections of the human insula.

Methods: CCEP data was acquired from each sub-region of the dominant and non-dominant insula in 30 patients who underwent stereo-EEG. Connectivity strength to the various cortical regions was obtained via a measure of root mean square (RMS), calculated from each gyrus of the insula and ranked into weighted means.

Results: The results of all cumulative CCEP responses for each individual gyrus were represented by circro plots. Forty-nine individual CCEP pairs were stimulated across all the gyri from the right and left insula. In brief, the left insula contributed more greatly to language areas. Sensory function, pain, saliency processing and vestibular function were more heavily implicated from the right insula. Connections to the primary auditory cortex arose from both insula regions. Both posterior insula regions showed significant contralateral connectivity. Ipsilateral mesial temporal connections were seen from both insula regions. In visual function, we further report the novel finding of a direct connection between the right posterior insula and left visual cortex.

Significance: The insula is a major multi-modal network hub with the cerebral cortex having major roles in language, sensation, auditory, visual, limbic and vestibular functions as well as saliency processing. In temporal lobe epilepsy surgery failure, the insula may be implicated as an extra temporal cause, due to the strong mesial temporal connectivity findings.
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http://dx.doi.org/10.1016/j.cortex.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825888PMC
November 2019

Functional control of electrophysiological network architecture using direct neurostimulation in humans.

Netw Neurosci 2019 1;3(3):848-877. Epub 2019 Jul 1.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.
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http://dx.doi.org/10.1162/netn_a_00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663306PMC
July 2019

Stimulation of the Posterior Cingulate Cortex Impairs Episodic Memory Encoding.

J Neurosci 2019 09 29;39(36):7173-7182. Epub 2019 Jul 29.

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.

Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory processing, making it a potential target for responsive neuromodulation strategies outside of the hippocampal network. However, causal evidence for the role that PCC plays in memory encoding is lacking. In human female and male participants ( = 17) undergoing seizure mapping, we investigated functional properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography. We used a verbal free recall paradigm in which the PCC was stimulated during presentation of half of the study lists, whereas no stimulation was applied during presentation of the remaining lists. We investigated whether stimulation affected memory and modulated hippocampal activity. Results revealed four main findings. First, stimulation during episodic memory encoding impaired subsequent free recall, predominantly for items presented early in the study lists. Second, PCC stimulation increased hippocampal gamma-band power. Third, stimulation-induced hippocampal gamma power predicted the magnitude of memory impairment. Fourth, functional connectivity between the hippocampus and PCC predicted the strength of the stimulation effect on memory. Our findings offer causal evidence implicating the PCC in episodic memory encoding. Importantly, the results indicate that stimulation targeted outside of the temporal lobe can modulate hippocampal activity and impact behavior. Furthermore, measures of connectivity between brain regions within a functional network can be informative in predicting behavioral effects of stimulation. Our findings have significant implications for developing therapies to treat memory disorders and cognitive impairment using DBS. Cognitive impairment and memory loss are critical public health challenges. Deep brain stimulation (DBS) is a promising tool for developing strategies to ameliorate memory disorders by targeting brain regions involved in mnemonic processing. Using DBS, our study sheds light on the lesser-known role of the posterior cingulate cortex (PCC) in memory encoding. Stimulating the PCC during encoding impairs subsequent recall memory. The degree of impairment is predicted by stimulation-induced hippocampal gamma oscillations and functional connectivity between PCC and hippocampus. Our findings provide the first causal evidence implicating PCC in memory encoding and highlight the PCC as a favorable target for neuromodulation strategies using connectivity measures to predict stimulation effects. This has significant implications for developing therapies for memory diseases.
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http://dx.doi.org/10.1523/JNEUROSCI.0698-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733540PMC
September 2019

Seizures in glioma patients: An overview of incidence, etiology, and therapies.

J Neurol Sci 2019 Sep 19;404:80-85. Epub 2019 Jul 19.

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Electronic address:

Gliomas are fatal brain tumors, and even low-grade gliomas (LGGs) have an average survival of less than a decade. Seizures are a common presentation of gliomas, particularly LGGs, and substantially impact quality of life. Glioma-related seizures differ from other focal epilepsies in their pathogenesis and in the likelihood of refractory epilepsy. We review factors that predict seizure activity and response to treatment, optimal pharmacologic and surgical management of glioma-related epilepsy, and the benefit of using newer anti-seizure medications in patients with gliomas. As surgery is so often beneficial with seizure reduction, we discuss oncologic and epilepsy surgery perspectives. Treatment of gliomas has the potential to ameliorate seizures and increase rates of seizure freedom. Prospective, well-powered studies are needed to provide more definitive answers for practitioners taking care of glioma patients with seizures.
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http://dx.doi.org/10.1016/j.jns.2019.07.026DOI Listing
September 2019

Autofluorescence Technology in Glioblastoma Resection: Evolution of New Tool and Approach.

World Neurosurg 2019 06 9;126:139-141. Epub 2019 Mar 9.

Department of Neurological Surgery, The University of Texas Southwestern, Zale Lipshy Hospital, Dallas, Texas, USA.

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http://dx.doi.org/10.1016/j.wneu.2019.02.158DOI Listing
June 2019

Human Verbal Memory Encoding Is Hierarchically Distributed in a Continuous Processing Stream.

eNeuro 2019 Jan-Feb;6(1). Epub 2019 Mar 4.

Department of Neurology, Mayo Clinic, Rochester, MN 55905.

Processing of memory is supported by coordinated activity in a network of sensory, association, and motor brain regions. It remains a major challenge to determine where memory is encoded for later retrieval. Here, we used direct intracranial brain recordings from epilepsy patients performing free recall tasks to determine the temporal pattern and anatomical distribution of verbal memory encoding across the entire human cortex. High γ frequency activity (65-115 Hz) showed consistent power responses during encoding of subsequently recalled and forgotten words on a subset of electrodes localized in 16 distinct cortical areas activated in the tasks. More of the high γ power during word encoding, and less power before and after the word presentation, was characteristic of successful recall and observed across multiple brain regions. Latencies of the induced power changes and this subsequent memory effect (SME) between the recalled and forgotten words followed an anatomical sequence from visual to prefrontal cortical areas. Finally, the magnitude of the memory effect was unexpectedly found to be the largest in selected brain regions both at the top and at the bottom of the processing stream. These included the language processing areas of the prefrontal cortex and the early visual areas at the junction of the occipital and temporal lobes. Our results provide evidence for distributed encoding of verbal memory organized along a hierarchical posterior-to-anterior processing stream.
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http://dx.doi.org/10.1523/ENEURO.0214-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402539PMC
May 2019

Neural activity reveals interactions between episodic and semantic memory systems during retrieval.

J Exp Psychol Gen 2019 Jan;148(1):1-12

Department of Psychology, University of Pennsylvania.

Whereas numerous findings support a distinction between episodic and semantic memory, it is now widely acknowledged that these two forms of memory interact during both encoding and retrieval. The precise nature of this interaction, however, remains poorly understood. To examine the role of semantic organization during episodic encoding and retrieval, we recorded intracranial encephalographic signals as 69 neurosurgical patients studied and subsequently recalled categorized and unrelated word lists. Applying multivariate classifiers to neural recordings, we were able to reliably predict encoding success, retrieval success, and temporal and categorical clustering during recall. By assessing how these classifiers generalized across list types, we identified specific retrieval processes that predicted recall of categorized lists and distinguished between recall transitions within and between category clusters. These results particularly implicate retrieval (rather than encoding) processes in the categorical organization of episodic memories. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/xge0000480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419095PMC
January 2019

Gamma oscillations during episodic memory processing provide evidence for functional specialization in the longitudinal axis of the human hippocampus.

Hippocampus 2019 02 5;29(2):68-72. Epub 2018 Nov 5.

Department of Neurological Surgery, University of Texas-Southwestern Medical Center, Dallas, Texas.

The question of whether the anterior and posterior hippocampus serve different or complementary functional roles during episodic memory processing has been motivated by noteworthy findings in rodent experiments and from noninvasive studies in humans. Researchers have synthesized these data to postulate several models of functional specialization, However, the issue has not been explored in detail using direct brain recordings. We recently published evidence that theta power increases during episodic memory encoding occur in the posterior hippocampus in humans. In our current investigation we analyzed an expanded data set of 32 epilepsy patients undergoing stereo EEG seizure mapping surgery with electrodes precisely targeted to the anterior and posterior hippocampus simultaneously who performed an episodic memory task. Using a repeated measures design, we looked for an interaction between encoding versus retrieval differences in gamma oscillatory power and anterior versus posterior hippocampal location. Our findings are consistent with a recently articulated model (the HERNET model) favoring posterior hippocampal activation during retrieval related processing. We also tested for encoding versus retrieval differences in the preferred gamma frequency band (high versus low gamma oscillations) motivated by published rodent data.
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http://dx.doi.org/10.1002/hipo.23016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519081PMC
February 2019

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

Epilepsy Behav 2018 11 11;88:33-40. Epub 2018 Sep 11.

Dept. of Neurology and Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yebeh.2018.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240385PMC
November 2018

Comparison of logistic regression, support vector machines, and deep learning classifiers for predicting memory encoding success using human intracranial EEG recordings.

J Neural Eng 2018 12 13;15(6):066028. Epub 2018 Sep 13.

Department of Neurological Surgery, University of Texas-Southwestern Medical Center, Dallas, TX 75390, United States of America.

Objective: We sought to test the performance of three strategies for binary classification (logistic regression, support vector machines, and deep learning) for the problem of predicting successful episodic memory encoding using direct brain recordings obtained from human stereo EEG subjects. We also sought to test the impact of applying t-distributed stochastic neighbor embedding (tSNE) for unsupervised dimensionality reduction, as well as testing the effect of reducing input features to a core set of memory relevant brain areas. This work builds upon published efforts to develop a closed-loop stimulation device to improve memory performance.

Approach: We used a unique data set consisting of 30 stereo EEG patients with electrodes implanted into a core set of five common brain regions (along with other areas) who performed the free recall episodic memory task as brain activity was recorded. Using three different machine learning strategies, we trained classifiers to predict successful versus unsuccessful memory encoding and compared the difference in classifier performance (as measured by the AUC) at the subject level and in aggregate across modalities. We report the impact of feature reduction on the classifiers, including reducing the number of input brain regions, frequency bands, and the impact of tSNE.

Results: Deep learning classifiers outperformed both support vector machines (SVM) and logistic regression (LR). A priori selection of core brain regions also improved classifier performance for LR and SVM models, especially when combined with tSNE.

Significance: We report for the first time a direct comparison among traditional and deep learning methods of binary classification to the problem of predicting successful memory encoding using human brain electrophysiological data. Our findings will inform the design of brain machine interface devices to affect memory processing.
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http://dx.doi.org/10.1088/1741-2552/aae131DOI Listing
December 2018

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation.

Nat Commun 2018 06 21;9(1):2423. Epub 2018 Jun 21.

Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, Mail Code 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA.

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1-3-Hz "low theta" band increases when viewing subsequently remembered object-location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.
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http://dx.doi.org/10.1038/s41467-018-04847-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013427PMC
June 2018

Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration.

Nucleic Acids Res 2018 07;46(13):6576-6591

Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator in response to hypoxia and its transcriptional activity is crucial for cancer cell mobility. Here we present evidence for a novel epigenetic mechanism that regulates HIF-1 transcriptional activity and HIF-1-dependent migration of glioblastoma cells. The lysine methyltransferases G9a and GLP directly bound to the α subunit of HIF-1 (HIF-1α) and catalyzed mono- and di-methylation of HIF-1α at lysine (K) 674 in vitro and in vivo. K674 methylation suppressed HIF-1 transcriptional activity and expression of its downstream target genes PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Inhibition of HIF-1 by K674 methylation is due to reduced HIF-1α transactivation domain function but not increased HIF-1α protein degradation or impaired binding of HIF-1 to hypoxia response elements. K674 methylation significantly decreased HIF-1-dependent migration of U251MG cells under hypoxia. Importantly, we found that G9a was downregulated by hypoxia in glioblastoma, which was inversely correlated with PTGS1 expression and survival of patients with glioblastoma. Therefore, our findings uncover a hypoxia-induced negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.
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http://dx.doi.org/10.1093/nar/gky449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061882PMC
July 2018

Electrical Stimulation in Hippocampus and Entorhinal Cortex Impairs Spatial and Temporal Memory.

J Neurosci 2018 05 10;38(19):4471-4481. Epub 2018 Apr 10.

Department of Biomedical Engineering, Columbia University, New York, New York 10027,

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred. Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.
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http://dx.doi.org/10.1523/JNEUROSCI.3049-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943975PMC
May 2018

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

J Neurosci 2018 03 21;38(13):3265-3272. Epub 2018 Feb 21.

Department of Biomedical Engineering, Columbia University, New York, New York 10027,

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one's own body. Spatial computations using environmental boundaries are an integral part of the brain's spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to functional neuroimaging studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions, we identified a neural marker of boundary representation in the human subiculum.
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http://dx.doi.org/10.1523/JNEUROSCI.3216-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884460PMC
March 2018

Closed-loop stimulation of temporal cortex rescues functional networks and improves memory.

Nat Commun 2018 02 6;9(1):365. Epub 2018 Feb 6.

Department of Psychology, University of Pennsylvania, 433 South University Avenue, Philadelphia, PA, 19104, USA.

Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction.
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http://dx.doi.org/10.1038/s41467-017-02753-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802791PMC
February 2018