Biology subjects

Sheth, S. A.

Publications and source records attributed to Sheth, S. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Electrophysiological dissociation of human posterior cingulate cortex contributions to value- and memory-based decision-making

The human posterior cingulate cortex (PCC) is routinely implicated in cognition and disease, yet its specific functional contributions remain unclear. Historically, human neuroimaging has linked the region to episodic memory and the default mode network, while a distinct non-human primate electrophysiology literature has focused on economic decision-making. Integrating anatomical evidence with these literatures, it has recently been proposed that this divergence reflects subregional organization, with dorsal PCC as a potential convergence site for value-based and memory-based decisions. Here, we recorded local field potentials (LFPs) and single units from human PCC while the same participants performed matched value- and memory-based decision tasks. LFPs in dorsal but not ventral PCC showed sustained engagement across both tasks, with risk sensitivity emerging only after the decision. In contrast, single-unit activity was more temporally circumscribed and could be grouped into response profiles active before or after the decision. Dorsal but not ventral PCC engagement further extended to memory encoding, recognition, and confidence judgments. Together, these findings reveal a consistent functional dissociation, identifying dorsal PCC as a domain-general interface between evaluative and mnemonic systems. In doing so, they align human and non-human primate accounts of PCC function and help orient future targeted studies of its role in cognition and disease.

neuroscience↗

bioRxiv2026

Electrophysiological features of signals recorded from white matter

Intracranial neurophysiology studies have typically ignored signals from electrodes located in white matter (WM), assuming that their information content is artifactual or related to nearby gray matter (GM). Here, we tested the electrophysiological and functional features of signals recorded from different WM locations. Signals were recorded from 19 patients undergoing intracranial monitoring for drug-resistant epilepsy by means of stereo-electroencephalography (sEEG). Each sEEG electrode was classified into WM or GM based on the surrounding tissue. We obtained recordings from a total of 1,717 sEEG electrode contacts, 36% in WM, while the patients were in awake resting state (5 minutes). For each sEEG electrode, we employed a model-based spectral decomposition to separate periodic and aperiodic components, and we computed signal complexity metrics. For a subset of participants, we computed WM structural information from diffusion-weighted magnetic resonance imaging and we evaluated functional signals during a cognitive control task. Our results show that signals recorded from WM have different spectral features and higher complexity than GM. Complexity correlates positively with fractional anisotropy, and modulations related to behavior during the task were detected in WM. Overall, this indicates that WM signals carry information that may reflect signal propagation across WM fiber tracts.

neuroscience↗

bioRxiv2026

Estimation of neuronal tuning for word meaning from passively recorded naturalistic speech

The ability to derive neural-level language coding models holds great scientific and clinical potential. Current approaches are limited by the scale and ethological validity of input data; applications requiring large, rare, or naturalistic samples in particular would benefit from the ability to infer neural coding from incidental everyday speech. Here we present a novel pipeline designed to leverage spontaneous and incidental naturalistic speech. This pipeline performs transcription, segmentation, and video-assisted diarization, as well as alignment and spike detection of neural data. We apply this pipeline to a dataset derived from 21 patients (6+ days each, over 800 hours and 5 million words total). We benchmark both encoding and decoding models against extensive and rare ground-truth control datasets consisting of human-curated word-level temporal alignment and manually sorted spikes. We further validate our approach by quantifying representational drift, effect of dataset size, and differences between six brain areas. Together, these findings demonstrate that incidental natural speech is sufficiently processed in the brain to enable the estimation neural-level embeddings.

neuroscience↗

bioRxiv2026

Conserved fiber topography of the anterior limb of the internal capsule in treatment-resistant psychiatric patients

IntroductionThe anterior limb of the internal capsule (ALIC) is a major white matter highway connecting prefrontal cortical (PFC) regions to the thalamus, brainstem, and subthalamic nucleus. Structural and functional abnormalities within the ALIC circuit have been associated with many neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and depression, and deep brain stimulation (DBS) may provide effective treatment to some of these patients. However, it remains unclear whether the well-characterized topographic organization of the ALIC observed in healthy individuals and preclinical models is preserved in treatment-resistant psychiatric populations. MethodsWe first used diffusion tractography to evaluate the topography of PFC and subcortical fibers through the ALIC in patients with treatment-resistant OCD (n=18) and depression (n=5). In depression patients, we also evaluated ALIC topography using cerebro-cerebral evoked potentials (CCEPs) elicited by single-pulse electrical stimulation (SPES) of DBS leads in the ALIC and recordings in the ventral PFC (vPFC). ResultsThe topographic organization of PFC and subcortical projections is preserved in the ALIC among treatment-resistant psychiatric patients, consistent with patterns observed in healthy individuals and preclinical models. CCEP recordings in the ventral PFC showed a ventral ALIC to medial vPFC/dorsal ALIC to lateral vPFC response pattern in the left hemisphere, but not in the right. ConclusionOur findings confirm that topographic patterns within the ALIC previously identified using preclinical models and healthy controls are preserved in treatment-resistant psychiatric patients. Furthermore, by linking white matter topography to stimulation effects, this work supports more precise and individualized neuromodulatory strategies for neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Distinct tasks engage a shared neural subspace in human hippocampus and anterior cingulate cortex

A hallmark of human cognitive flexibility is the ability to perform a wide range of unrelated tasks. While much is known about how neural circuits support individual tasks, less is understood about how these circuits support multiple tasks. Are neural representations largely task-specific, or do they retain a shared structure across distinct behaviors? To investigate this question, we recorded neural population activity from the hippocampus and anterior cingulate cortex, two regions linked to generalization and cognitive control, in eleven human patients performing three distinct tasks. Using dimensionality reduction, we estimated the neural subspace associated with each task and compared subspace geometry across tasks. We found that task-related subspaces were not independent: across tasks, approximately half of the subspace dimensions were shared, and these were primarily the dimensions containing most of the shared neural covariance. These findings indicate that neural population activity in these regions is not purely task-specific. This suggests a stable, low-dimensional circuit structure may persist even across unrelated behaviors, potentially providing a common substrate for flexible cognition.

neuroscience↗

bioRxiv2025

Neural components underlying successful free recall are specific to episodic memory

AbstractEpisodic memory depends upon activity distributed across the brain. However, the activity underlying memory has largely been examined within single tasks in isolation. Thus it is unclear to what extent prior findings reflect task-general rather than memory-specific cognitive processes. Here we address this question using data from 371 patients recorded intracranially who performed a free recall task with encoding and retrieval phases alongside an arithmetic distractor phase. We ask whether neural decoders fit to predict behavior from one phase transfer to the others. Encoding-retrieval transfer exceeds both arithmetic-encoding and arithmetic-retrieval transfer and therefore cannot be explained solely by processes supporting arithmetic. We further detect transfer between arithmetic and retrieval but not between arithmetic and encoding. The brain-behavioral relations observed in these tasks thus do not merely reflect a single task-general factor of activity. We propose cross-task decoding as a method for identifying the neural factor structure underlying distinct cognitive processes.

neuroscience↗

bioRxiv2025

Attention is all you need (in the brain): semantic contextualization in human hippocampus

Word meanings in language are contextualized by surrounding words. Inspired by the self-attention mechanism in transformer-based large language models (LLMs), we hypothesized that structural composition in the brain arises from combining canonical (non-contextual) word representations with those of nearby words. We analyzed single unit activity in the human hippocampus, a region involved in semantic and contextual processing, while n=10 participants listened to podcasts. We found that hippocampal neurons encoded word position within a clause, using both ordinal and frequency-domain positional encoding. Moreover, neural responses to specific words reflected both the words own lexical semantics and a weighted sum of the embeddings of preceding words. The relative weighting of these contextualizing words correlated with LLM self-attention weights. These findings suggest that contextualization in the brain makes use of vectorial shifts that have a resemblance to attentional reweighting in LLMs, and highlight the role of the mesial temporal lobe within the broader language network.

neuroscience↗

bioRxiv2025

Learning and language in the unconscious human hippocampus

Consciousness is a fundamental component of cognition,1 but the degree to which higher-order pattern recognition relies on it remains disputed.2,3 Here we demonstrate the persistence of oddball discrimination, semantic processing, and online prediction in individuals under general anesthesia-induced loss of consciousness.4,5 Using high-density Neuropixels microelectrodes6 to record both single unit and local field potential neural activity in the human hippocampus while playing a series of tones to anesthetized patients, we found that hippocampal neurons and local oscillations retained some detection of oddball tones. This effect size grew over the course of the experiment ([~]10 minutes), demonstrating representational plasticity. A biologically plausible recurrent neural network model showed that learning and oddball representation are an emergent property of flexible tone discrimination. Moreover, when we played language stimuli, single units and local field potentials carried information about the semantic and grammatical features of natural speech, even predicting semantic information about upcoming words. Together these results indicate that in the hippocampus, which is anatomically and functionally distant from primary sensory cortices,7 complex processing of sensory stimuli occurs even in the unconscious state.

neuroscience↗

bioRxiv2024

Cell type transcriptional identities are maintained in cultured ex vivo human brain tissue

It is becoming more broadly accepted that human-based models are needed to better understand the complexities of the human nervous system and its diseases. The recently developed human brain organotypic culture model is one highly promising model that requires the involvement of neurosurgeons and neurosurgical patients. Studies have investigated the electrophysiological properties of neurons in such ex vivo human tissues, but the maintenance of other cell types within explanted brain remains largely unknown. Here, using single-nucleus RNA sequencing, we systematically evaluate the transcriptional identities of the various cell types found in six patient samples after fourteen days in culture (83,501 nuclei from day 0 samples and 45,738 nuclei from day 14 samples). We used two pediatric temporal lobectomy samples, an adult frontal cortex sample, two IDH wild-type glioblastoma samples, and one medulloblastoma sample. We found remarkably high correlations of day 14 transcriptional identities to day 0 tissue, especially in tumor cells (r = 0.90 to 0.93), though microglia (r = 0.86), oligodendrocytes (r = 0.80), pericytes (r = 0.77), endothelial cells (r = 0.78), and fibroblasts (r = 0.76) showed strong preservation of their transcriptional profiles as well. Astrocytes and excitatory neurons showed more moderate preservation (r = 0.66 and 0.47, respectively). Because the main difficulty with organotypic brain cultures is the acquisition of human tissue, which is readily available to neurosurgeons, this model is easily accessible to neurosurgeon-scientists and neurosurgeons affiliated with research laboratories. Broad uptake of this more representative model should prompt advances in our understanding of many uniquely human diseases, lead to more reliable clinical trial performance, and ultimately yield better therapies for our patients.

neuroscience↗

bioRxiv2024

Proper reference selection and re-referencing to mitigate bias in single pulse electrical stimulation data

Single pulse electrical stimulation experiments produce pulse-evoked potentials used to infer brain connectivity. The choice of recording reference for intracranial electrodes remains non-standardized and can significantly impact data interpretation. When the reference electrode is affected by stimulation or evoked brain activity, it can contaminate the pulse-evoked potentials recorded at all other electrodes and influence interpretation of findings. We highlight this specific issue in intracranial EEG datasets from two subjects recorded at separate institutions. We present several intuitive metrics to detect the presence of reference contamination and offer practical guidance on different mitigation strategies. Either switching the reference electrode or re-referencing to an adjusted common average effectively mitigated the reference contamination issue, as evidenced by increased variability in pulse-evoked potentials across the brain. Overall, we demonstrate the importance of clear quality checks and preprocessing steps that should be performed before analysis of single pulse electrical stimulation data. HighlightsO_LIA reference electrode close to active tissue can contaminate intracranial EEG signals C_LIO_LIInterpretation of pulse-evoked potentials can be biased by reference contamination C_LIO_LILow response variability between channels is indicative of reference contamination C_LIO_LIReference contamination can be resolved through data recollection or re-referencing C_LI

neuroscience↗

bioRxiv2024

Insula uses overlapping codes for emotion in self and others

In daily life, we must recognize others emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

neuroscience↗

bioRxiv2023

Endocisternal interfaces for minimally invasive neural stimulation and recording of the brain and spinal cord

Minimally invasive neural interfaces can be used to diagnose, manage, and treat many disorders with substantially reduced risks of surgical complications. Endovascular neural interfaces implanted in the veins or arteries is one approach, but it requires prescriptions of anti-thrombotic medication and are likely not explantable after endothelialization. More critically, the approach is limited by the small size and location of blood vessels, such that many important cortical, subcortical, spinal targets cannot be reached. Here, we demonstrate a chronic endocisternal neural interface that approaches brain and spinal cord targets through inner and outer cerebral spinal fluid (CSF) spaces. These spaces surround the nervous system and lack the tortuosity of the circulatory system, giving us access to the entire brain convexity, deep brain structures within the ventricles, and the spinal cord from the spinal subarachnoid space. Combined with miniature magnetoelectric-powered bioelectronics, the entire wireless system is deployable through a percutaneous procedure. The flexible catheter electrodes can be freely navigated throughout the body from the spinal to cranial subarachnoid space, and from the cranial subarachnoid space to the ventricles. We show in a large animal model that we can also reposition the recording and stimulation electrodes or explant the neural interface after chronic implantation. This enables applications in therapies that require transient or permanent brain/machine interface such as stroke rehabilitation and epilepsy monitoring and opens a new class of minimally invasive endocisternal bioelectronics.

bioengineering↗

bioRxiv2023

Default mode network spatio-temporal electrophysiological signature and causal role in creativity

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally-directed cognition. It subserves self-referential thinking, recollection of the past, mind wandering, and creativity. Knowledge about the electrophysiology underlying DMN activity is scarce, due to the difficulty to simultaneously record from multiple distant cortical areas with commonly-used techniques. The present study employs stereo-electroencephalography depth electrodes in 13 human patients undergoing monitoring for epilepsy, obtaining high spatiotemporal resolution neural recordings across multiple canonical DMN regions. Our results offer a rare insight into the temporal evolution and spatial origin of theta (4-8Hz) and gamma signals (30-70Hz) during two DMN-associated higher cognitive functions: mind-wandering and alternate uses. During the performance of these tasks, DMN activity is defined by a specific pattern of decreased theta coupled with increased gamma power. Critically, creativity and mind wandering engage the DMN with different dynamics: creativity recruits the DMN strongly during the covert search of ideas, while mind wandering displays the strongest modulation of DMN during the later recall of the train of thoughts. Theta band power modulations, predominantly occurring during mind wandering, do not show a predominant spatial origin within the DMN. In contrast, gamma power effects were similar for mind wandering and creativity and more strongly associated to lateral temporal nodes. Interfering with DMN activity through direct cortical stimulation within several DMN nodes caused a decrease in creativity, specifically reducing the originality of the alternate uses, without affecting creative fluency or mind wandering. These results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in creative thinking. Our findings shed light on the neural constructs supporting creative cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

neuroscience↗

bioRxiv2023

Functional and anatomical connectivity predict brain stimulation's mnemonic effects

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

neuroscience↗

bioRxiv2022

Distinct population and single-neuron selectivity for executive and episodic processing in human dorsal posterior cingulate

Posterior cingulate cortex (PCC) is an enigmatic region implicated in psychiatric and neurological disease, yet its role in cognition remains unclear. Human studies link PCC to episodic memory and default mode network (DMN), while findings from the non-human primate emphasize executive processes more associated with the cognitive control network (CCN) in humans. We hypothesized this difference reflects an important functional division between dorsal (executive) and ventral (episodic) PCC. To test this, we utilized human intracranial recordings of population and single unit activity targeting dorsal PCC during an alternated executive/episodic processing task. Dorsal PCC population responses were significantly enhanced for executive, compared to episodic, task conditions, consistent with the CCN. Single unit recordings, however, revealed four distinct functional types with unique executive (CCN) or episodic (DMN) response profiles. Our findings provide critical electrophysiological data from human PCC, bridging incongruent views within and across species, furthering our understanding of PCC function.

neuroscience↗

bioRxiv2022

Intracranial EEG spectral feature analysis and focal brain stimulation reveal affective specialization within dorsal anterior cingulate cortex

Emotion is represented in several limbic and prefrontal cortical brain areas herein referred to as the Affective Salience Network (ASN). Within this network, less is known about how valence and intensity are processed in the dorsal anterior cingulate (dACC), and how affective processes in dACC compare to activity in other nodes within the ASN. Using a novel spectral feature approach to analyze intracranial electrophysiological data, we discover hemispheric specialization in the dACC such that the right hemisphere is sensitive to intensity while the left hemisphere is sensitive to valence and negative affective bias. We further applied 130 Hz continuous stimulation to the anterior cingulum bundle while patients viewed emotional faces. Faces were rated happier in all patients, an effect modulated by baseline affective bias, suggesting a causal role for the dACC during the processing of external affective stimuli.

neuroscience↗

bioRxiv2021

Spontaneous Neuronal Oscillations in the Human Insula are Hierarchically Organized Traveling Waves

The insula plays a fundamental role in a wide range of adaptive human behaviors, but its electrophysiological dynamics are poorly understood. Here we used human intracranial electroencephalographic recordings to investigate the electrophysiological properties and hierarchical organization of spontaneous neuronal oscillations within the insula. We analyzed the neuronal oscillations of the insula directly and found that rhythms in the theta and beta frequency oscillations are widespread and spontaneously present. These oscillations are largely organized along the anterior-posterior axis of the insula. Both the left and right insula showed anterior-to-posterior decreasing gradients for the power of oscillations in the beta frequency band. The left insula also showed a posterior-to-anterior decreasing frequency gradient and an anterior-to-posterior decreasing power gradient in the theta frequency band. In addition to measuring the power of these oscillations, we also examined the phase of these signals across simultaneous recording channels and found that the insula oscillations in the theta and beta bands are traveling waves. The strength of the traveling waves in each frequency was positively correlated with the amplitude of each oscillation. However, the theta and beta traveling waves were uncoupled to each other in terms of phase and amplitude, which suggested that insula traveling waves in the theta and beta bands operate independently. Our findings provide new insights into the spatiotemporal dynamics and hierarchical organization of neuronal oscillations within the insula, which, given its rich connectivity with widespread cortical regions, indicates that oscillations and traveling waves have an important role in intra- and inter-insula communication.

neuroscience↗

bioRxiv2021

Wireless endovascular nerve stimulation with a millimeter-sized magnetoelectric implant

Implanted bioelectronic devices have the potential to treat disorders that are resistant to traditional pharmacological therapies; however, reaching many therapeutic nerve targets requires invasive surgeries and implantation of centimeter-sized devices. Here we show that it is possible to stimulate peripheral nerves from within blood vessels using a millimeter-sized wireless implant. By directing the stimulating leads through the blood vessels we can target specific nerves that are difficult to reach with traditional surgeries. Furthermore, we demonstrate this endovascular nerve stimulation (EVNS) with a millimeter sized wireless stimulator that can be delivered minimally invasively through a percutaneous catheter which would significantly lower the barrier to entry for neuromodulatory treatment approaches because of the reduced risk. This miniaturization is achieved by using magnetoelectric materials to efficiently deliver data and power through tissue to a digitally-programmable 0.8 mm2 CMOS system-on-a-chip. As a proof-of-principle we show wireless stimulation of peripheral nerve targets both directly and from within the blood vessels in rodent and porcine models. The wireless EVNS concept described here provides a path toward minimally invasive bioelectronics where mm-sized implants combined with endovascular stimulation enable access to a number of nerve targets without open surgery or implantation of battery-powered pulse generators.

bioengineering↗