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Attention aids in prioritizing information relevant to our present goals. For example, attention may augment sensory processing by modulating neural activity for low-level features of the attended items. Attention can also prioritize the contents of memory, facilitating our ability to remember some pieces of information while ignoring others. Here, we examine how using attention to modulate the contents of memory affects temporally organized sequences of neuronal spiking in the human anterior temporal lobe. These spike sequences represent higher-level semantic information and occur repeatedly and consistently as participants process and encode words into memory. Our results demonstrate that attention deployed to prioritize words for memory increases the consistency of these spike sequences. Further, retroactively cueing words elicits the replay of these sequences. Our data, therefore, suggest that paying attention to prioritizing semantic content for memory may improve the temporal organization of neural spiking representations of semantic information in the anterior temporal lobe., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Objective: Whereas a scalp electroencephalogram (EEG) is important for diagnosing epilepsy, a single routine EEG is limited in its diagnostic value. Only a small percentage of routine EEGs show interictal epileptiform discharges (IEDs) and overall misdiagnosis rates of epilepsy are 20% to 30%. We aim to demonstrate how network properties in EEG recordings can be used to improve the speed and accuracy differentiating epilepsy from mimics, such as functional seizures - even in the absence of IEDs., Methods: In this multicenter study, we analyzed routine scalp EEGs from 218 patients with suspected epilepsy and normal initial EEGs. The patients' diagnoses were later confirmed based on an epilepsy monitoring unit (EMU) admission. About 46% ultimately being diagnosed with epilepsy and 54% with non-epileptic conditions. A logistic regression model was trained using spectral and network-derived EEG features to differentiate between epilepsy and non-epilepsy. Of the 218 patients, 90% were used for training and 10% were held out for testing. Within the training set, 10-fold cross validation was performed. The resulting tool was named "EpiScalp.", Results: EpiScalp achieved an area under the curve (AUC) of 0.940, an accuracy of 0.904, a sensitivity of 0.835, and a specificity of 0.963 in classifying patients as having epilepsy or not., Interpretation: EpiScalp provides an accurate diagnostic aid from a single initial EEG recording, even in more challenging epilepsy cases with normal initial EEGs. This may represent a paradigm shift in epilepsy diagnosis by deriving an objective measure of epilepsy likelihood from previously uninformative EEGs. ANN NEUROL 2025., (© 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Neural coding has traditionally been examined through changes in firing rates and latencies in response to different stimuli 1-5 . However, populations of neurons can also exhibit transient bursts of spiking activity, wherein neurons fire in a specific temporal order or sequence 6-8 . The human brain may utilize these neuronal sequences within population bursts to efficiently represent information 9-12 , thereby complementing the well-known neural code based on spike rate or latency. Here we examined this possibility by recording the spiking activity of populations of single units in the human anterior temporal lobe as eight participants performed a visual categorization task. We find that population spiking activity organizes into bursts during the task. The temporal order of spiking across the activated units within each burst varies across stimulus categories, creating unique stereotypical sequences for individual categories as well as for individual exemplars within a category. The information conveyed by the temporal order of spiking activity is separable from and complements the information conveyed by the units' spike rates or latencies following stimulus onset. Collectively, our data provide evidence that the human brain contains a complementary code based on the neuronal sequence within bursts of population spiking to represent information., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Remembering our everyday experiences involves dynamically coordinating information distributed across different brain regions. Investigating how momentary fluctuations in connectivity in the brain are relevant for episodic memory formation, however, has been challenging. Here we leverage the high temporal precision of intracranial EEG to examine sub-second changes in functional connectivity in the human brain as 20 participants perform a paired associates verbal memory task. We first identify potential functional connections by selecting electrode pairs across the neocortex that exhibit strong correlations with a consistent time delay across random recording segments. We then find that successful memory formation during the task involves dynamic sub-second changes in functional connectivity that are specific to each word pair. These patterns of dynamic changes are reinstated when participants successfully retrieve the word pairs from memory. Therefore, our data provide direct evidence that specific patterns of dynamic changes in human brain connectivity are associated with successful memory formation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Epileptic seizures are debilitating because of the clinical symptoms they produce. These symptoms, in turn, may stem directly from disruptions in neural coding. Recent evidence has suggested that the specific temporal order, or sequence, of spiking across a population of cortical neurons may encode information. Here, we investigate how seizures disrupt neuronal spiking sequences in the human brain by recording multi-unit activity from the cerebral cortex in five male participants undergoing monitoring for seizures. We find that pathological discharges during seizures are associated with bursts of spiking activity across a population of cortical neurons. These bursts are organized into highly consistent and stereotyped temporal sequences. As the seizure evolves, spiking sequences diverge from the sequences observed at baseline and become more spatially organized. The direction of this spatial organization matches the direction of the ictal discharges, which spread over the cortex as traveling waves. Our data therefore suggest that seizures can entrain cortical spiking sequences by changing the spatial organization of neuronal firing, providing a possible mechanism by which seizures create symptoms., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: A well-established bidirectional relationship exists between sleep and epilepsy. Patients with epilepsy tend to have less efficient sleep and shorter rapid eye movement (REM) sleep. Seizures are far more likely to arise from sleep transitions and non-REM sleep compared to REM sleep. Delay in REM onset or reduction in REM duration may have reciprocal interactions with seizure occurrence. Greater insight into the relationship between REM sleep and seizure occurrence is essential to our understanding of circadian patterns and predictability of seizure activity. We assessed a cohort of adults undergoing evaluation of drug-resistant epilepsy to examine whether REM sleep prior to or following seizures is delayed in latency or reduced in quantity., Methods: We used a spectrogram-guided approach to review the video-electroencephalograms of patients' epilepsy monitoring unit admissions for sleep scoring to determine sleep variables., Results: In our cohort of patients, we found group- and individual-level delay of REM latency and reduced REM duration when patients experienced a seizure before the primary sleep period (PSP) of interest or during the PSP of interest. A significant increase in REM latency and decrease in REM quantity were observed on nights where a seizure occurred within 4 h of sleep onset. No change in REM variables was found when investigating seizures that occurred the day after the PSP of interest. Our study is the first to provide insight about a perisleep period, which we defined as 4-h periods before and after the PSP., Significance: Our results demonstrate a significant relationship between seizures occurring prior to the PSP, during the PSP, and in the 4-h perisleep period and a delay in REM latency. These findings have implications for developing a biomarker of seizure detection as well as longer term seizure risk monitoring., (© 2024 International League Against Epilepsy.)

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD. Eighteen study participants (SP) underwent video-EEG, and seven had follow-up EEG recordings. Seizures typically occurred by age of 2 years. Thirteen (65%) had non-febrile seizures, requiring anti-seizure medications in nine. Four had febrile seizures. Seizures were bilateral tonic-clonic in 7 SP and focal impaired awareness in 5 SP; often responding to 1 to 2 antiseizure medications. EEG showed slowing in 5 SP, beta activity in 6 SP, and focal/multifocal, and/or generalized epileptiform activity in 9 SP. Follow-up EEGs in 7 SP showed emergence of epileptiform activity in 1 SP, and increased activity in 2 SP. In conclusion, seizures were frequent in our cohort but tended to respond to antiseizure medications. Longitudinal follow up provided further insight into emergence of seizures and EEG abnormalities soliciting future studies with long term follow up. Biomarkers of epileptogenicity in CTD are needed to predict seizures in this population., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

N -methyl-D-aspartate receptors (NMDARs) are crucial for neuronal development and synaptic plasticity. Dysfunction of NMDARs is associated with multiple neurodevelopmental disorders, including epilepsy, autism spectrum disorder, and intellectual disability. Understanding the impact of genetic variants of NMDAR subunits can shed light on the mechanisms of disease. Here, we characterized the functional implications of a de novo mutation of the GluN2A subunit (P1199Rfs*32) resulting in the truncation of the C-terminal domain. The variant was identified in a male patient with epileptic encephalopathy, multiple seizure types, severe aphasia, and neurobehavioral changes. Given the known role of the CTD in NMDAR trafficking, we examined changes in receptor localization and abundance at the postsynaptic membrane using a combination of molecular assays in heterologous cells and rat primary neuronal cultures. We observed that the GluN2A P1199Rfs*32-containing receptors traffic efficiently to the postsynaptic membrane but have increased extra-synaptic expression relative to WT GluN2A-containing NMDARs. Using in silico predictions, we hypothesized that the mutant would lose all PDZ interactions, except for the recycling protein Scribble1. Indeed, we observed impaired binding to the scaffolding protein postsynaptic protein-95 (PSD-95); however, we found the mutant interacts with Scribble1, which facilitates the recycling of both the mutant and the WT GluN2A. Finally, we found that neurons expressing GluN2A P1199Rfs*32 have fewer synapses and decreased spine density, indicating compromised synaptic transmission in these neurons. Overall, our data show that GluN2A P1199Rfs*32 is a loss-of-function variant with altered membrane localization in neurons and provide mechanistic insight into disease etiology., (Copyright © 2024 the authors.)

Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Interictal epileptiform discharges have been shown to propagate from focal epileptogenic sources as travelling waves or through more rapid white matter conduction. We hypothesize that both modes of propagation are necessary to explain interictal discharge timing delays. We propose a method that, for the first time, incorporates both propagation modes to identify unique potential sources of interictal activity. We retrospectively analysed 38 focal epilepsy patients who underwent intracranial EEG recordings and diffusion-weighted imaging for epilepsy surgery evaluation. Interictal discharges were detected and localized to the most likely source based on relative delays in time of arrival across electrodes, incorporating travelling waves and white matter propagation. We assessed the influence of white matter propagation on distance of spread, timing and clinical interpretation of interictal activity. To evaluate accuracy, we compared our source localization results to earliest spiking regions to predict seizure outcomes. White matter propagation helps to explain the timing delays observed in interictal discharge sequences, underlying rapid and distant propagation. Sources identified based on differences in time of receipt of interictal discharges are often distinct from the leading electrode location. Receipt of activity propagating rapidly via white matter can occur earlier than more local activity propagating via slower cortical travelling waves. In our cohort, our source localization approach was more accurate in predicting seizure outcomes than the leading electrode location. Inclusion of white matter in addition to travelling wave propagation in our model of discharge spread did not improve overall accuracy but allowed for identification of unique and at times distant potential sources of activity, particularly in patients with persistent postoperative seizures. Since distant white matter propagation can occur more rapidly than local travelling wave propagation, combined modes of propagation within an interictal discharge sequence can decouple the commonly assumed relationship between spike timing and distance from the source. Our findings thus highlight the clinical importance of recognizing the presence of dual modes of propagation during interictal discharges, as this may be a cause of clinical mislocalization., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

Sequences of spiking activity have been heavily implicated as potential substrates of memory formation and retrieval across many species. A parallel line of recent evidence also asserts that sequential activity may arise from and be constrained by pre-existing network structure. Here we reconcile these two lines of research in the human brain by measuring single unit spiking sequences in the temporal lobe cortex as participants perform an episodic memory task. We find the presence of an average backbone spiking sequence identified during pre-task rest that is stable over time and different cognitive states. We further demonstrate that these backbone sequences are composed of both rigid and flexible sequence elements, and that flexible elements within these sequences serve to promote memory specificity when forming and retrieving new memories. These results support the hypothesis that pre-existing network dynamics serve as a scaffold for ongoing neural activity in the human cortex., (© 2023. Springer Nature Limited.)

Purpose: Non-invasive imaging studies play a critical role in the presurgical evaluation of patients with drug-resistant temporal lobe epilepsy (TLE), particularly in helping to lateralize the seizure focus. Arterial Spin Labeling (ASL) MRI has been widely used to non-invasively study cerebral blood flow (CBF), with somewhat variable interictal alterations reported in TLE. Here, we compare temporal lobe subregional interictal perfusion and symmetry in lesional (MRI+) and non-lesional (MRI-) TLE compared to healthy volunteers (HVs)., Methods: Twenty TLE patients (9 MRI+, 11 MRI-) and 14 HVs under went 3 T Pseudo-Continuous ASL MRI through an epilepsy imaging research protocol at the NIH Clinical Center. We compared normalized CBF and absolute asymmetry indices in multiple temporal lobe subregions., Results: Compared to HVs, both MRI+ and MRI- TLE groups demonstrated significant ipsilateral mesial and lateral temporal hypoperfusion, specifically in the hippocampal and anterior temporal neocortical subregions, with additional hypoperfusion in the ipsilateral parahippocampal gyrus in the MRI+ and contralateral hippocampus in the MRI- TLE groups. Contralateral to the seizure focus, there was significant relative hypoperfusion in multiple subregions in the MRI- compared to the MRI+ TLE groups. The MRI+ group therefore had significantly greater asymmetry across multiple temporal subregions compared to the MRI- TLE and HV groups. No significant differences in asymmetry were found between the MRI- TLE and HV groups., Conclusion: We found a similar extent of interictal ipsilateral temporal hypoperfusion in MRI+ and MRI- TLE. However, significantly increased asymmetries were found only in the MRI+ group due to differences in perfusion contralateral to the seizure focus between the patient groups. The lack of asymmetry in the MRI- group may negatively impact the utility of interictal ASL for seizure focus lateralization in this patient population., Competing Interests: Declarations of Competing Interest Dr. Abdennadher receives research support from the Simon Grinspoon Award and the Integrated Pilot Grant Award at Boston University for research not related to this study. The remaining authors have no conflicts of interest., (Published by Elsevier B.V.)

Microstimulation can modulate the activity of individual neurons to affect behavior, but the effects of stimulation on neuronal spiking are complex and remain poorly understood. This is especially challenging in the human brain where the response properties of individual neurons are sparse and heterogeneous. Here we use microelectrode arrays in the human anterior temporal lobe in 6 participants (3 female) to examine the spiking responses of individual neurons to microstimulation delivered through multiple distinct stimulation sites. We demonstrate that individual neurons can be driven with excitation or inhibition using different stimulation sites, which suggests an approach for providing direct control of spiking activity at the single-neuron level. Spiking responses are inhibitory in neurons that are close to the site of stimulation, while excitatory responses are more spatially distributed. Together, our data demonstrate that spiking responses of individual neurons can be reliably identified and manipulated in the human cortex. SIGNIFICANCE STATEMENT One of the major limitations in our ability to interface directly with the human brain is that the effects of stimulation on the activity of individual neurons remain poorly understood. This study examines the spiking responses of neurons in the human temporal cortex in response to pulses of microstimulation. This study finds that individual neurons can either be excited or inhibited depending on the site of stimulation. These data suggest an approach for modulating the spiking activity of individual neurons in the human brain., (Copyright © 2023 the authors.)

While seizure activity may be electrographically widespread, increasing evidence has suggested that ictal discharges may in fact represent travelling waves propagated from a focal seizure source. Interictal epileptiform discharges (IEDs) are an electrographic manifestation of excessive hypersynchronization of cortical activity that occur between seizures and are considered a marker of potentially epileptogenic tissue. The precise relationship between brain regions demonstrating IEDs and those involved in seizure onset, however, remains poorly understood. Here, we hypothesize that IEDs likewise reflect the receipt of travelling waves propagated from the same regions which give rise to seizures. Forty patients from our institution who underwent invasive monitoring for epilepsy, proceeded to surgery and had at least one year of follow-up were included in our study. Interictal epileptiform discharges were detected using custom software, validated by a clinical epileptologist. We show that IEDs reach electrodes in sequences with a consistent temporal ordering, and this ordering matches the timing of receipt of ictal discharges, suggesting that both types of discharges spread as travelling waves. We use a novel approach for localization of ictal discharges, in which time differences of discharge receipt at nearby electrodes are used to compute source location; similar algorithms have been used in acoustics and geophysics. We find that interictal discharges co-localize with ictal discharges. Moreover, interictal discharges tend to localize to the resection territory in patients with good surgical outcome and outside of the resection territory in patients with poor outcome. The seizure source may originate at, and also travel to, spatially distinct IED foci. Our data provide evidence that interictal discharges may represent travelling waves of pathological activity that are similar to their ictal counterparts, and that both ictal and interictal discharges emerge from common epileptogenic brain regions. Our findings have important clinical implications, as they suggest that seizure source localizations may be derived from interictal discharges, which are much more frequent than seizures., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

The quality of short-term memory (STM) underlies our ability to recall the exact details of a recent event, yet how the human brain enables this core cognitive function remains poorly understood. Here we use multiple experimental approaches to test the hypothesis that the quality of STM, such as its precision or fidelity, relies on the medial temporal lobe (MTL), a region commonly associated with the ability to distinguish similar information remembered in long-term memory. First, with intracranial recordings, we find that delay-period MTL activity retains item-specific STM content that is predictive of subsequent recall precision. Second, STM recall precision is associated with an increase in the strength of intrinsic MTL-to-neocortical functional connections during a brief retention interval. Finally, perturbing the MTL through electrical stimulation or surgical removal can selectively reduce STM precision. Collectively, these findings provide converging evidence that the MTL is critically involved in the quality of STM representation., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022.)

Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurones treated with low Mg 2+ , a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurones and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The sensory cortices of many mammals are often organized into modules in the form of cortical columns, yet whether modular organization at this spatial scale is a general property of the human neocortex is unknown. The strongest evidence for modularity arises when measures of connectivity, structure, and function converge. Here we use microelectrode recordings in humans to examine functional connectivity and neuronal spiking responses in order to assess modularity in submillimeter scale networks. We find that the human temporal lobe consists of temporally persistent spatially compact modules approximately 1.3mm in diameter. Functionally, the information coded by single neurons during an image categorization task is more similar for neurons belonging to the same module than for neurons from different modules. The geometry, connectivity, and spiking responses of these local cortical networks provide converging evidence that the human temporal lobe is organized into functional modules at the micro scale., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite d-2-hydroxyglutarate (d-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures., Methods: We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis. We utilize micro-electrode arrays for in vitro electrophysiological studies in combination with pharmacological manipulations and biochemical studies to better elucidate the impact of d-2-HG on cortical metabolism and neuronal spiking activity., Results: We demonstrate that d-2-HG leads to increased neuronal spiking activity and promotes a distinct metabolic profile in surrounding neurons, evidenced by distinct metabolomic shifts and increased LDHA expression, as well as upregulation of mTOR signaling. The increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition., Conclusion: Together, our data suggest that metabolic disruptions in the surrounding cortex due to d-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant gliomas., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.)

Object repetition commonly leads to long-lasting improvements in identification speed and accuracy, a behavioral facilitation referred to as "repetition priming". Neuroimaging and non-invasive electromagnetic stimulation studies have most often implicated the involvement of left lateral frontal cortex in repetition priming, although convergent evidence from neuropsychological studies is lacking. In the current study, we examine the impact of surgical resection for the treatment of epilepsy on the magnitude of repetition priming at relatively short-term (30-60 min delay) and long-term (3 months) delays in 41 patients with varying seizure foci and resection locations. Overall, patients exhibited significant repetition priming at both short-term and long-term delays. However, patients with frontal resections (largely anterior and medial frontal) differed significantly from those with right anterior temporal resections in showing fully intact short-term priming but absent long-term priming. In a comparison set of 10 recovered aphasic patients, patients with left lateral frontal damage exhibited impaired short-term priming relative to other frontal damage locations, suggesting the differential involvement of lateral and anteromedial frontal regions in mediating repetition priming at short-lag and long-lag timescales, respectively., (Published by Elsevier Ltd.)

We investigated the association between human herpesvirus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations, and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein, and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV-6 (P < .02). Febrile seizure history was not associated with HHV-6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6-positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Direct brain recordings have provided important insights into how high-frequency activity captured through intracranial EEG (iEEG) supports human memory retrieval. The extent to which such activity is comprised of transient fluctuations that reflect the dynamic coordination of underlying neurons, however, remains unclear. Here, we simultaneously record iEEG, local field potential (LFP), and single unit activity in the human temporal cortex. We demonstrate that fast oscillations within the previously identified 80-120 Hz ripple band contribute to broadband high-frequency activity in the human cortex. These ripple oscillations exhibit a spectrum of amplitudes and durations related to the amount of underlying neuronal spiking. Ripples in the macro-scale iEEG are related to the number and synchrony of ripples in the micro-scale LFP, which in turn are related to the synchrony of neuronal spiking. Our data suggest that neural activity in the human temporal lobe is organized into transient bouts of ripple oscillations that reflect underlying bursts of spiking activity., Competing Interests: AT, AV, JW, SI, KZ No competing interests declared

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 ( P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.

Treatment of patients with drug-resistant focal epilepsy relies upon accurate seizure localization. Ictal activity captured by intracranial EEG has traditionally been interpreted to suggest that the underlying cortex is actively involved in seizures. Here, we hypothesize that such activity instead reflects propagated activity from a relatively focal seizure source, even during later time points when ictal activity is more widespread. We used the time differences observed between ictal discharges in adjacent electrodes to estimate the location of the hypothesized focal source and demonstrated that the seizure source, localized in this manner, closely matches the clinically and neurophysiologically determined brain region giving rise to seizures. Moreover, we determined this focal source to be a dynamic entity that moves and evolves over the time course of a seizure. Our results offer an interpretation of ictal activity observed by intracranial EEG that challenges the traditional conceptualization of the seizure source., (Published by Oxford University Press on behalf of the Guarantors of Brain 2021.)

Objective: Focal cortical dysplasias (FCDs) are a common cause of apparently non-lesional drug-resistant focal epilepsy. Visual detection of subtle FCDs on MRI is clinically important and often challenging. In this study, we implement a set of 3D local image filters adapted from computer vision applications to characterize the appearance of normal cortex surrounding the gray-white junction. We create a normative model to serve as the basis for a novel multivariate constrained outlier approach to automated FCD detection., Methods: Standardized MPRAGE, T 2 and FLAIR MR images were obtained in 15 patients with radiologically or histologically diagnosed FCDs and 30 healthy volunteers. Multiscale 3D local image filters were computed for each MR contrast then sampled onto the gray-white junction surface. Using an iterative Gaussianization procedure, we created a normative model of cortical variability in healthy volunteers, allowing for identification of outlier regions and estimates of similarity in normal cortex and FCD lesions. We used a constrained outlier approach following local normalization to automatically detect FCD lesions based on projection onto the mean FCD feature vector., Results: FCDs as well as some normal cortical regions such as primary sensorimotor and paralimbic regions appear as outliers. Regions such as the paralimbic regions and the anterior insula have similar features to FCDs. Our constrained outlier approach allows for automated FCD detection with 80% sensitivity and 70% specificity., Significance: A normative model using multiscale local image filters can be used to describe the normal cortical variability. Although FCDs appear similar to some cortical regions such as the anterior insula and paralimbic cortices, they can be identified using a constrained outlier detection approach. Our method for detecting outliers and estimating similarity is generic and could be extended to identification of other types of lesions or atypical cortical areas., (Published by Elsevier Inc.)

Our memories enable us to form expectations for our future experiences, yet the precise neural mechanisms underlying how we compare any experience to our memory remain unknown. Here, using intracranial EEG recordings, we show that episodic memories formed after a single visual experience establish expectations for future experience within neocortical-medial temporal lobe circuits. When subsequent experiences violate these expectations, we find a 80-120 Hz prediction error signal that emerges in both visual association areas and the medial temporal lobe. Critically, this error signal emerges in visual association areas first and then propagates to the medial temporal lobe. This error signal is accompanied by alpha coherence between the two regions. Our data therefore suggest that internal models formed from episodic memories are generated throughout the visual hierarchy after just a single exposure, and that these internal models are then used for comparison with future experiences.

Despite large individual differences in memory performance, people remember certain stimuli with overwhelming consistency. This phenomenon is referred to as the memorability of an individual item. However, it remains unknown whether memorability also affects our ability to retrieve associations between items. Here, using a paired-associates verbal memory task, we combine behavioural data, computational modelling and direct recordings from the human brain to examine how memorability influences associative memory retrieval. We find that certain words are correctly retrieved across participants irrespective of the cues used to initiate memory retrieval. These words, which share greater semantic similarity with other words, are more readily available during retrieval and lead to more intrusions when retrieval fails. Successful retrieval of these memorable items, relative to less memorable ones, results in faster reinstatement of neural activity in the anterior temporal lobe. Collectively, our data reveal how the brain prioritizes certain information to facilitate memory retrieval.

Objective: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS)., Background: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies., Design/methods: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B., Results: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results., Interpretation: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies., (Published 2020. This article is a U.S Government work and is in the public domain in the USA. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Direct electrical stimulation of the human brain has been used to successfully treat several neurological disorders, but the precise effects of stimulation on neural activity are poorly understood. Characterizing the neural response to stimulation, however, could allow clinicians and researchers to more accurately predict neural responses, which could in turn lead to more effective stimulation for treatment and to fundamental knowledge regarding neural function., Objective: Here we use a linear systems approach in order to characterize the response to electrical stimulation across cortical locations and then to predict the responses to novel inputs., Methods: We use intracranial electrodes to directly stimulate the human brain with single pulses of stimulation using amplitudes drawn from a random distribution. Based on the evoked responses, we generate a simple model capturing the characteristic response to stimulation at each cortical site., Results: We find that the variable dynamics of the evoked response across cortical locations can be captured using the same simple architecture, a linear time-invariant system that operates separately on positive and negative input pulses of stimulation. We demonstrate that characterizing the response to stimulation using this simple and tractable model of evoked responses enables us to predict the responses to subsequent stimulation with single pulses with novel amplitudes, and the compound response to stimulation with multiple pulses., Conclusion: Our data suggest that characterizing the response to stimulation in an approximately linear manner can provide a powerful and principled approach for predicting the response to direct electrical stimulation., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

We compared resting state (RS) functional connectivity and task-based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra- minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right-sided and left-sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task-based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method., (Published [2020]. This article is a U.S. Government work and is in the public domain in the USA.)

Episodic memory retrieval is thought to rely on the replay of past experiences, yet it remains unknown how human single-unit activity is temporally organized during episodic memory encoding and retrieval. We found that ripple oscillations in the human cortex reflect underlying bursts of single-unit spiking activity that are organized into memory-specific sequences. Spiking sequences occurred repeatedly during memory formation and were replayed during successful memory retrieval, and this replay was associated with ripples in the medial temporal lobe. Together, these data demonstrate that human episodic memory is encoded by specific sequences of neural activity and that memory recall involves reinstating this temporal order of activity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Recent evidence has suggested that coherent neuronal oscillations may serve as a gating mechanism for flexibly modulating communication between brain regions. For this to occur, such oscillations should be robust and coherent between brain regions that also demonstrate time-locked correlations, with time delays that match the phase delays of the coherent oscillations. Here, by analyzing functional connectivity in both the time and frequency domains, we demonstrate that alpha oscillations satisfy these constraints and are well suited for modulating communication over large spatial scales in the human brain. We examine intracranial EEG in the human temporal lobe and find robust alpha oscillations that are coherent between brain regions with center frequencies that are consistent within each individual participant. Regions demonstrating coherent narrowband oscillations also exhibit time-locked broadband correlations with a consistent time delay, a requirement for an efficient communication channel. The phase delays of the coherent alpha oscillations match the time delays of the correlated components, and importantly, both broadband correlations and neuronal spiking activity are modulated by the phase of the oscillations. These results are specific to the alpha band and build upon emerging evidence suggesting that alpha oscillations may play an active role in cortical function. Our data therefore provide evidence that large-scale communication in the human brain may be rhythmically modulated by alpha oscillations., (Published by Elsevier Ltd.)

Objective: Due to variability in the patterns of propagation of interictal epileptiform discharges (IEDs), qualitative definition of the irritative zone has been challenging. Here, we introduce a quantitative approach toward exploration of the dynamics of IED propagation within the irritative zone., Methods: We examined intracranial EEG (iEEG) in nine participants undergoing invasive monitoring for seizure localization. We used an automated IED detector and a community detection algorithm to identify populations of electrodes exhibiting IED activity that co-occur in time, and to group these electrodes into communities., Results: Within our algorithmically-identified communities, IED activity in the seizure onset zone (SOZ) tended to lead IED activity in other functionally coupled brain regions. The tendency of pathological activity to arise in the SOZ, and to spread to non-SOZ tissues, was greater in the asleep state., Conclusions: IED activity, and, by extension, the variability observed between the asleep and awake states, is propagated from a core seizure focus to nearby less pathological brain regions., Significance: Using an unsupervised, computational approach, we show that the spread of IED activity through the epilepsy network varies with physiologic state., (Published by Elsevier B.V.)

Electrical brain stimulation is used clinically to target pathological regions of the brain for treatment of diseases, such as Parkinson's disease, epilepsy and depression. Conventional treatments involve chronic implants that disrupt activity through a fixed periodic train of pulses or bursts of pulses applied to the affected region. However, stimulating one region of the brain necessarily affects other structurally and/or functionally connected areas. Understanding how connected regions of the brain are affected by stimulation at the implant site could improve treatment efficacy by informing optimal placement and stimulation patterns. In this study, we build predictive input-output models from intracranial recordings obtained from 10 epilepsy patients implanted with electrodes. Specific contacts within each subject were electrically stimulated (inputs), and evoked responses were simultaneously captured from all contacts (outputs). From these data, we constructed and compared four different dynamical models that contain causal linear and nonlinear components. All model architectures successfully predicted evoked responses to stimulation with single pulses and sequences of pulses. Results suggest that a linear time-invariant model in series with a quadratic non-linearity best captures the relationship between stimulation amplitudes and evoked responses.

Objectives: Neuroinflammation, implicated in epilepsy, can be imaged in humans with positron emission tomography (PET) ligands for translocator protein 18 kDa (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology., Methods: We studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C] N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA) 713, and 31 healthy volunteers. Seizure foci were identified with structural magnetic resonance imaging (MRI) and ictal video-electroencephalography (EEG) monitoring. Six patients had surgical resections; five had focal cortical dysplasia type 2A or B and one microdysgenesis. Brain regions were delineated using FreeSurfer and T1-weighted MRI. We measured brain radioligand uptake (standardized uptake values [SUVs]) in ipsilateral and contralateral regions, to compare calculated asymmetry indices [AIs; 200% *(ipsilateral - contralateral)/(ipsilateral + contralateral)] between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (V T /f P ) in 9 patients (5 high affinity and 4 medium affinity binders) and 11 age-matched volunteers (5 high-affinity and 6 medium affinity) who had metabolite-corrected arterial input functions measured., Results: Nine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. Three of the nine had normal MRI. There was a nonsignificant trend for patients to have higher binding than volunteers both ipsilateral and contralateral to the focus in the group that had absolute binding measured., Significance: Our study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy. There may be a role for TSPO PET for evaluation of patients with suspected neocortical seizure foci, particularly when other imaging modalities are unrevealing. However, a complex method, inherent variability, and increased binding in regions outside seizure foci will limit applicability., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Episodic memory retrieval relies on the recovery of neural representations of waking experience. This process is thought to involve a communication dynamic between the medial temporal lobe memory system and the neocortex. How this occurs is largely unknown, however, especially as it pertains to awake human memory retrieval. Using intracranial electroencephalographic recordings, we found that ripple oscillations were dynamically coupled between the human medial temporal lobe (MTL) and temporal association cortex. Coupled ripples were more pronounced during successful verbal memory retrieval and recover the cortical neural representations of remembered items. Together, these data provide direct evidence that coupled ripples between the MTL and association cortex may underlie successful memory retrieval in the human brain., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To assess the ability of functional MRI (fMRI) to predict postoperative language decline compared to direct cortical stimulation (DCS) in epilepsy surgery patients., Methods: In this prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline., Results: Four of 17 patients (12 female; median [range] age, 43 [23-59] years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline., Significance: Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability., Method: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance., Results: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r 2  = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality)., Significance: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Memories of experiences that occur around the same time are linked together by a shared temporal context, represented by shared patterns of neural activity. However, shared temporal context may be problematic for selective retrieval of specific memories. Here, we examine intracranial EEG (iEEG) in the human temporal lobe as participants perform a verbal paired associates memory task that requires the encoding of distinct word pairs in memory. We find that the rate of change in patterns of low frequency (3-12 Hz) power distributed across the temporal lobe is significantly related to memory performance. We also find that exogenous electrical stimulation affects how quickly these neural representations of temporal context change with time, which directly affects the ability to successfully form memories for distinct items. Our results indicate that the ability to retrieve distinct episodic memories is related to how quickly neural representations of temporal context change over time during encoding.

We identify a memory-specific attention mechanism in the human anterior temporal lobe, an area implicated in semantic processing and episodic memory formation. Spiking neuron activity is suppressed and becomes more reliable in preparation for verbal memory formation. Intracranial electroencephalography signals implicate this region as a source of executive control for attentional selection. Consistent with this interpretation, its surgical removal causes significant memory impairment for attended words relative to unattended words.

Treatment of medically intractable focal epilepsy (MIFE) by surgical resection of the epileptogenic zone (EZ) is often effective provided the EZ can be reliably identified. Even with the use of invasive recordings, the clinical differentiation between the EZ and normal brain areas can be quite challenging, mainly in patients without MRI detectable lesions. Consequently, despite relatively large brain regions being removed, surgical success rates barely reach 60-65%. Such variable and unfavorable outcomes associated with high morbidity rates are often caused by imprecise and/or inaccurate EZ localization. We developed a localization algorithm that uses network-based data analytics to process invasive EEG recordings. This network algorithm analyzes the centrality signatures of every contact electrode within the recording network and characterizes contacts into susceptible EZ based on the centrality trends over time. The algorithm was tested in a retrospective study that included 42 patients from four epilepsy centers. Our algorithm had higher agreement with EZ regions identified by clinicians for patients with successful surgical outcomes and less agreement for patients with failed outcomes. These findings suggest that network analytics and a network systems perspective of epilepsy may be useful in assisting clinicians in more accurately localizing the EZ.

Memory performance is highly variable among individuals. Most studies examining human memory, however, have largely focused on the neural correlates of successful memory formation within individuals, rather than the differences among them. As such, what gives rise to this variability is poorly understood. Here, we examined intracranial EEG (iEEG) recordings captured from 43 participants (23 male) implanted with subdural electrodes for seizure monitoring as they performed a paired-associates verbal memory task. We identified three separate but related signatures of neural activity that tracked differences in successful memory formation across individuals. High-performing individuals consistently exhibited less broadband power, flatter power spectral density slopes, and greater complexity in their iEEG signals. Furthermore, within individuals across three separate time scales ranging from seconds to days, successful recall was positively associated with these same metrics. Our data therefore suggest that memory ability across individuals can be indexed by increased neural signal complexity. SIGNIFICANCE STATEMENT We show that participants whose intracranial EEG exhibits less low-frequency power, flatter power spectrums, and greater sample entropy overall are better able to memorize associations, and that the same metrics track fluctuations in memory performance across time within individuals. These metrics together signify greater neural signal complexity, which may index the brain's ability to flexibly engage with information and generate separable memory representations. Critically, the current set of results provides a unique window into the neural markers of individual differences in memory performance, which have hitherto been underexplored., (Copyright © 2018 the authors 0270-6474/18/381744-12$15.00/0.)

Intracranial recordings captured from subdural electrodes in patients with drug resistant epilepsy offer clinicians and researchers a powerful tool for examining neural activity in the human brain with high spatial and temporal precision. There are two major challenges, however, to interpreting these signals both within and across individuals. Anatomical distortions following implantation make accurately identifying the electrode locations difficult. In addition, because each implant involves a unique configuration, comparing neural activity across individuals in a standardized manner has been limited to broad anatomical regions such as cortical lobes or gyri. We address these challenges here by introducing a semi-automated method for localizing subdural electrode contacts to the unique surface anatomy of each individual, and by using a surface-based grid of regions of interest (ROIs) to aggregate electrode data from similar anatomical locations across individuals. Our localization algorithm, which uses only a postoperative CT and preoperative MRI, builds upon previous spring-based optimization approaches by introducing manually identified anchor points directly on the brain surface to constrain the final electrode locations. This algorithm yields an accuracy of 2 mm. Our surface-based ROI approach involves choosing a flexible number of ROIs with different spatial resolutions. ROIs are registered across individuals to represent identical anatomical locations while accounting for the unique curvature of each brain surface. This ROI based approach therefore enables group level statistical testing from spatially precise anatomical regions., (© 2017 Wiley Periodicals, Inc.)

When we recall an experience, we rely upon the associations that we formed during the experience, such as those among objects, time, and place [1]. These associations are better remembered when they are familiar and draw upon generalized knowledge, suggesting that we use semantic memory in the service of episodic memory [2, 3]. Moreover, converging evidence suggests that episodic memory retrieval involves the reinstatement of neural activity that was present when we first experienced the event. Therefore, we hypothesized that retrieving associations should also reinstate the neural activity responsible for semantic processing. Indeed, previous studies have suggested that verbal memory retrieval leads to the reinstatement of activity across regions of the brain that include the distributed semantic processing network [4-6], but it is unknown whether and how individual neurons in the human cortex participate in the reinstatement of semantic representations. Recent advances using high-density microelectrode arrays (MEAs) have allowed clinicians to record from populations of neurons in the human cortex [7, 8]. Here we used MEAs to record neuronal spiking activity in the human middle temporal gyrus (MTG), a cortical region supporting the semantic representation of words [9-11], as participants performed a verbal paired-associates task. We provide novel evidence that population spiking activity in the MTG forms distinct representations of semantic concepts and that these representations are reinstated during the retrieval of those words., (Published by Elsevier Ltd.)

Converging evidence suggests that reinstatement of neural activity underlies our ability to successfully retrieve memories. However, the temporal dynamics of reinstatement in the human cortex remain poorly understood. One possibility is that neural activity during memory retrieval, like replay of spiking neurons in the hippocampus, occurs at a faster timescale than during encoding. We tested this hypothesis in 34 participants who performed a verbal episodic memory task while we recorded high gamma (62-100 Hz) activity from subdural electrodes implanted for seizure monitoring. We show that reinstatement of distributed patterns of high gamma activity occurs faster than during encoding. Using a time-warping algorithm, we quantify the timescale of the reinstatement and identify brain regions that show significant timescale differences between encoding and retrieval. Our data suggest that temporally compressed reinstatement of cortical activity is a feature of cued memory retrieval. SIGNIFICANCE STATEMENT We show that cued memory retrieval reinstates neural activity on a faster timescale than was present during encoding. Our data therefore provide a link between reinstatement of neural activity in the cortex and spontaneous replay of cortical and hippocampal spiking activity, which also exhibits temporal compression, and suggest that temporal compression may be a universal feature of memory retrieval., (Copyright © 2017 the authors 0270-6474/17/374472-09$15.00/0.)

Despite many advances in the study of large-scale human functional networks, the question of timing, stability, and direction of communication between cortical regions has not been fully addressed. At the cellular level, neuronal communication occurs through axons and dendrites, and the time required for such communication is well defined and preserved. At larger spatial scales, however, the relationship between timing, direction, and communication between brain regions is less clear. Here, we use a measure of effective connectivity to identify connections between brain regions that exhibit communication with consistent timing. We hypothesized that if two brain regions are communicating, then knowledge of the activity in one region should allow an external observer to better predict activity in the other region, and that such communication involves a consistent time delay. We examine this question using intracranial electroencephalography captured from nine human participants with medically refractory epilepsy. We use a coupling measure based on time-lagged mutual information to identify effective connections between brain regions that exhibit a statistically significant increase in average mutual information at a consistent time delay. These identified connections result in sparse, directed functional networks that are stable over minutes, hours, and days. Notably, the time delays associated with these connections are also highly preserved over multiple time scales. We characterize the anatomic locations of these connections, and find that the propagation of activity exhibits a preferred posterior to anterior temporal lobe direction, consistent across participants. Moreover, networks constructed from connections that reliably exhibit consistent timing between anatomic regions demonstrate features of a small-world architecture, with many reliable connections between anatomically neighbouring regions and few long range connections. Together, our results demonstrate that cortical regions exhibit functional relationships with well-defined and consistent timing, and the stability of these relationships over multiple time scales suggests that these stable pathways may be reliably and repeatedly used for large-scale cortical communication., (Published by Oxford University Press on behalf of the Guarantors of Brain 2017. This work is written by US Government employees and is in the public domain in the United States.)