Biology subjects

Schevon, C. A.

Publications and source records attributed to Schevon, C. A..

10 recordsLinked to original sources

bioRxiv2026

Electrophysiologically Targeted Biopsies Reveal the Transcriptional Landscape of Focal Epilepsy

Up to 30% of patients with epilepsy have intractable seizures, yet the mechanisms of focal ictogenesis remain unclear. Tissue involvement in ictal regions is heterogeneous, with different regions playing distinct roles in ictogenesis, seizure propagation, and resistance to spread. These roles are reflected in electrophysiologic differences between the seizure focus and the ictal penumbra, where evidence of synaptic spread is present but excitatory firing is constrained by largely intact inhibition. Investigation of the disruption of the normal interplay between excitatory and inhibitory activity, thought to underlie ictogenesis across a range of epilepsy etiologies, is limited by network complexity and cellular heterogeneity in human tissue samples. In this study, we relate cellular and molecular alterations to excitatory-inhibitory disruption in network dynamics defined by electrophysiologic features. This work may aid in the identification of clinically relevant tissue biomarkers and support novel preclinical therapeutic approaches for treatment-resistant focal epilepsy disorders. We developed a novel intracranial EEG guided, MRI-localized approach to sample paired biopsies from 11 patients with drug-resistant focal epilepsy with diverse etiologies, which were then studied using single-nucleus RNA sequencing (snRNAseq) and immunohistochemistry (IHC). EEG recorded from stereotactically implanted depth arrays (sEEG) was used to identify regions of epileptic involvement, based on findings from prior simultaneous clinical and microelectrode recordings. This approach addresses the intrinsic heterogeneity due to etiology and cortical architecture through paired, within-patient comparisons. We identified distinct cell-type specific transcriptional signatures that differentiate cellular populations in the seizure focus and ictal penumbra in intractable focal epilepsies. Our findings provide a link between tissue composition and gene expression that correlate with electrographic features in a heterogeneous seizure landscape. Our findings support common pathways of seizure generation and spread that are conserved across disease etiologies. Relative depletion of interneuron populations in the seizure focus supports the hypothesis of disrupted inhibition as a driver of epileptiform activity in the seizure focus. The enrichment of plasticity-associated gene signatures in the penumbra suggests a complex interaction of these regions with the seizure focus, as well as the role of the penumbra in enabling or limiting seizure expansion. This study provides a novel methodology for tissue sampling in epilepsy and uncovers biologically relevant tissue signatures that provide grounds for future work in targeting cellular and molecular alterations present in focal epilepsies.

neuroscience↗

bioRxiv2025

Large Language Models Reveal the Neural Tracking of Linguistic Context in Attended and Unattended Multi-Talker Speech

Large language models (LLMs) capture long-range contextual structure in natural language and have recently been shown to align with the human brains contextualized linguistic encoding. This makes them a promising computational probe for studying how context-dependent linguistic information is represented during natural speech perception. Speech perception often occurs in multi-talker environments, where attention must dynamically select among competing streams, yet how contextual information from attended and unattended speech is neurally encoded remains underexplored. Here, we investigate how auditory attention modulates neural tracking of context-dependent linguistic representations using electrocorticography (ECoG) and stereoelectroencephalography (sEEG) recordings from three epilepsy patients engaged in a two-conversation "cocktail party" paradigm. To model neural responses to attended and unattended speech streams, we used contextual word embeddings generated by large language models. We find that LLM-derived features reliably predict brain activity for the attended stream and that contextual information from the unattended stream also contributes to neural prediction. Importantly, these contributions extend beyond low-level acoustic features and shallow syntactic information, and depend on the surrounding linguistic context. Moreover, neural tracking of the unattended stream reflects shorter-range contextual integration than that of the attended stream. Together, these findings indicate that neural responses to speech reflect context-dependent linguistic representations from multiple concurrent speech streams, with attention modulating the depth and timescale of contextual integration. Our results highlight the utility of LLMs for probing higher-level linguistic representations in complex, naturalistic listening environments.

neuroscience↗

bioRxiv2024

Cell-type specific responses to single-pulse electrical stimulation of the human brain

Neuromodulation techniques, such as deep brain stimulation, intraoperative brain mapping, and responsive neurostimulation, use electricity to alter brain activity. Despite daily clinical use in thousands of patients, it remains fundamentally unknown how human neurons respond to intracranial stimulation. We address this question at a basic level by characterizing neuronal cell-type specific firing rate responses to single pulses of electrical stimulation of the human brain. We carried out broadly distributed stimulation in 30 patients undergoing neuromonitoring for epilepsy while recording from isolated neurons on microwires implanted into the medial temporal and frontal lobes. Out of a total of 228 recorded units, 16.2% (N = 191) were classified as interneurons and 83.8% (N = 37) were classified as principal cells, using a threshold clustering method, based on intrinsic waveshape characteristics. To see how stimulation affected neuronal activation for each cell type, we calculated firing rate change between a pre-stimulation and post-stimulation window and observed that 174 units were significantly modulated with the vast majority (91%) showing firing rate suppression. We then characterized stimulation-evoked changes in firing rate to gain insight into cell type-specific responses. Additionally, in a subset of the units, we observed that firing rate responses were modulated by stimulation distance, where local stimulation (within approximately 40 mm) could evoke instantaneous firing, whereas distant stimulation reliably suppressed firing in the same units. Finally, we analyzed a subset of units within the seizure onset zone, which exhibited unique waveform features and responses to stimulation. This study bridges a gap in the neuromodulation field by examining the single-unit firing rate response to direct electrical stimulation of the human brain and analyzing cell-type specific firing rate responses. We show that low frequency, single-pulse stimulation broadly elicits firing rate suppression, but parameters, such as distance from the unit, can have diverse effects on firing rate responses. This work informs the neuronal basis of CCEP generation and therefore has implications for clinical mapping and informs novel active probing strategies for precision diagnosis and neuromodulation of seizure pathophysiology in surgical cases. Moreover, this research has general implications for understanding neuromodulation via direct brain stimulation. Highlights- Putative principal cell waveform shapes are characterized by longer trough-to-peak and full-width half max durations (s) compared to interneurons. - Monopolar stimulation @ 3 mA generally has a widespread suppressive effect on neuronal firing, lasting approximately 1.5 s. - Principal cells show greater suppression amplitude and longer suppression durations than interneurons. - Stimulation within [~] 40 mm is capable of evoking instantaneous firing, despite general suppression from stimulation at greater distances.

neuroscience↗

bioRxiv2024

Temporal integration in human auditory cortex is predominantly yoked to absolute time, not structure duration

Sound structures such as phonemes and words have highly variable durations. Thus, there is a fundamental difference between integrating across absolute time (e.g., 100 ms) vs. sound structure (e.g., phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. To answer this question, we rescaled the duration of all speech structures using time stretching/compression and measured integration windows in the human auditory cortex using a new experimental/computational method applied to spatiotemporally precise intracranial recordings. We observed significantly longer integration windows for stretched speech, but this lengthening was very small ([~]5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.

neuroscience↗

bioRxiv2024

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via RiboTag, morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

neuroscience↗

bioRxiv2021

Human interictal epileptiform discharges are traveling waves reflecting ictal self-organization

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Though they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.

neuroscience↗

bioRxiv2020

Neuronal firing and waveform alterations through ictal recruitment in humans

AO_SCPLOWBSTRACTC_SCPLOWClinical analyses of neuronal activity during seizures, invariably using extracellular recordings, is greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons (units). To address these analytical difficulties, we developed a novel template-matching based spike sorting method, which enabled identification of 1,239 single units in 27 patients with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing through the ictal transition, which was defined as a transient period of intense tonic firing consistent with previous descriptions of the ictal wavefront. After the ictal transition, neurons displayed increased spike duration (p < 0.001) and reduced spike amplitude (p < 0.001), in keeping with prior animal studies; units in non-recruited territories, by contrast, showed more stable waveforms. All units returned to their pre-ictal waveforms after seizure termination. Waveshape changes were stereotyped across seizures within patients. Our analyses of single neuron firing patterns, at the ictal wavefront, showed widespread intense activation, and commonly involving marked waveshape alteration. We conclude that the distinction between tissue that has been recruited to the seizure versus non-recruited territories is evident at the level of single neurons, and that increased waveform duration and decreased waveform amplitude are hallmarks of seizure invasion that could be used as defining characteristics of local recruitment. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWAnimal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proved difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

neuroscience↗

bioRxiv2019

A theoretical model for focal seizure initiation, propagation, termination, and progression

We developed a neural network model that can account for the major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus and postulates a role for synaptic plasticity in emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure evolution end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this can provide a roadmap and potentially a testbed for future explorations of seizure mechanisms and clinical therapies.

neuroscience↗

bioRxiv2019

Risk of Seizures Induced by Intracranial Research Stimulation: Analysis of 770 Stimulation Sessions

BackgroundPatients 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.\n\nObjectiveWe measured the incidence of research stimulation-associated seizures in a large multi-institutional study on brain stimulations effect on memory in order to determine if brain stimulation was statistically associated with seizure incidence, and identify potential risk factors for stimulation-associated seizures.\n\nMethods188 subjects undergoing iEEG monitoring across 10 institutions participated in 770 research stimulation sessions over 3.5 years. Seizures within 30 minutes 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.\n\nResultsIn 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.\n\nIn 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.\n\nConclusionsThe rarity of stimulation-associated seizures, and 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.

neuroscience↗

bioRxiv2019

Single-neuron representations of spatial memory targets in humans

The hippocampus and surrounding medial-temporal-lobe (MTL) structures are critical for both memory and spatial navigation, but we do not fully understand the neuronal representations used to support these behaviors. Much research has examined how the MTL neurally represents spatial information, such as with \"place cells\" that represent the current location or \"head-direction cells\" that code for the current heading. In addition to behaviors that require an animal to attend to the current spatial location, navigating to remote destinations is a common part of daily life. To examine the neural basis of these behaviors we recorded single-neuron activity from neurosurgical patients playing Treasure Hunt, a virtual-reality spatial-memory task. By analyzing how the activity of these neurons related to behavior in Treasure Hunt, we found that the firing rates of many MTL neurons during navigation significantly changed depending on the position of the current spatial target. In addition, we observed neurons whose firing rates during navigation were tuned to specific heading directions in the environment, and others whose activity changed depending on the timing within the trial. By showing that neurons in our task represent remote locations rather than the subjects own position, our results suggest that the human MTL can represent remote spatial information according to task demands.

neuroscience↗