Biology subjects

Lega, B.

Publications and source records attributed to Lega, B..

18 recordsLinked to original sources

bioRxiv2026

Time cells lead neural reinstatement of episodic memory

The episodic memory system provides humans with a unique ability to form and retrieve rich and detailed memories. This capacity requires representing temporal context at encoding and recovering it at retrieval to drive successful recall. Time cells and ramping cells in human medial temporal cortex have been proposed as substrates of temporal context, but whether they participate in context recovery during retrieval remains unknown. Using microelectrode recordings from neurosurgical patients across two classical episodic paradigms, free recall and serial reconstruction, we identify time sensitive neurons and demonstrate that these neuron populations participate in neuronal assemblies and organized sequences on gamma and theta time scales respectively. Consistent with recovery of temporal context predicted by behavioral models of episodic processing, time cell firing precedes the broader assembly population and initiates sequential activation retrieval. These properties predict contextually-mediated recall behavior. We also identify phase coding by complementary populations as convergent mechanisms whose recruitment depends on task demands. Finally, we demonstrate the emergence of context-sensitive neurons in a naturalistic viewing dataset lacking the predictable temporal scaffold of canonical assays. These findings identify cellular mechanisms by which the human medial temporal cortex represents temporal context during episodic encoding and recovers it during retrieval.

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bioRxiv2026

The genetic signature of memory encoding along the human hippocampal axis

Episodic memory formation engages hippocampal oscillations that vary along the anterior-posterior axis, but the molecular programs supporting this physiological specialization remain unclear. Here, we leveraged a rare neurosurgical dataset in which patients performed verbal episodic memory tasks during intrahippocampal intracranial EEG recordings prior to en bloc hippocampal resection, enabling integration of encoding-related oscillatory signatures with matched cell-type-resolved transcriptomics from the same individuals. Subsequent memory effects (SMEs) spanned delta/theta, gamma, and hippocampal ripple activity across anterior and posterior hippocampus. Single-nucleus RNA sequencing from anatomically matched anterior and posterior tissue revealed longitudinal transcriptional gradients, most prominent in excitatory neurons. Spatial transcriptomic maps validated axis-enriched transcripts and their localization. Linking subject-specific SMEs to gene expression identified distinct molecular programs: anterior low frequency SMEs associated with synaptic and chromatin-regulatory pathways, and posterior high-frequency SMEs associated with metabolic and protein synthesis processes. Gene regulatory network inference further revealed axis-specific hub architectures. Together, these results define a cell-type-specific genetic architecture linking longitudinal molecular specialization to the human hippocampal encoding dynamics.

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bioRxiv2025

Stimulation modulates cell assemblies linked with gene networks in the human temporal cortex ex vivo

Deep brain stimulation of the temporal cortex can enhance learning and memory in the face of cognitive impairment. Despite the potential of such therapies, the neural and genetic mechanisms underlying the effect of stimulation on human brain circuits are not understood. To explicate direct mechanisms of neural modulation elicited by brain stimulation, we developed an ex vivo approach utilizing microelectrode array stimulation and recording of resected temporal cortex from neurosurgical patients. We find that stimulation preferentially increases firing rates in pyramidal cells compared to interneurons and also strengthens cell assemblies. Using single cell multiomics, we link the observed physiological changes to cell type-specific gene expression patterns. We detail gene regulatory networks that indicate preferential involvement of specific excitatory neuron subtypes and the response of non-neurons. We conclude that the overall impact of stimulation on the human temporal cortex is activation of specific excitatory neurons and enhanced cell assembly activity, and that these changes are supported by gene networks involving immediate early, synaptic, and ion channel genes. Our findings establish a foundation to identify targetable cell type-specific genetic signatures that may be harnessed for therapeutic benefit in future neuromodulation strategies.

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bioRxiv2025

Cholinergic blockade reveals role for human hippocampal theta in encoding but not retrieval

Cholinergic dysfunction is a hallmark of Alzheimers disease and other memory disorders. Yet, the neurophysiological mechanisms linking cholinergic signaling to memory remain poorly understood. In this study, we administered scopolamine, a muscarinic cholinergic antagonist, to neurosurgical patients with intracranial electrodes as they performed an associative recognition memory task. When scopolamine was present at encoding, we observed disruptions to hippocampal slow theta oscillations (2-4 Hz), with selective impairments to recollection-based memory. However, when scopolamine was present during retrieval alone, we observed disruptions to slow theta without impaired memory performance. These disruptions included dose-dependent reductions in theta power, theta phase reset, and encoding-retrieval pattern reinstatement. Together, our results challenge the notion that theta oscillations are necessary for memory retrieval, and instead suggest that theta universally reflects an encoding-related neural state. These findings motivate updates to current models of acetylcholines role in memory and may inform future therapies targeting rhythmic biomarkers of memory dysfunction.

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bioRxiv2024

Differences and similarities between human hippocampal low-frequency oscillations during navigation and mental simulation

Low frequency oscillations in the hippocampus emerge during by both spatial navigation and episodic memory function in humans. We have recently shown that in humans, memory-related processing is a stronger driver of low frequency oscillations than navigation. These findings and others support the idea that low-frequency oscillations are more strongly associated with a general memory function than with a specific role in spatial navigation. However, whether the low-frequency oscillations that support episodic memory and those during navigation could still share some similar functional roles remains unclear. In this study, patients undergoing intracranial electroencephalography (iEEG) monitoring performed a navigation task in which they navigated and performed internally directed route replay, similar to episodic memory. We trained a random forest classification model to use patterns in low-frequency power (2-12 Hz) to learn the position during navigation and subsequently used the same model to successfully decode position during mental simulation. We show that removal of background differences in power between navigation and mental simulation is critical to detecting the overlapping patterns. These results suggest that the low-frequency oscillations that emerge during navigation are more associated with a role in memory than specifically with a navigation related function.

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bioRxiv2023

Study-Phase Reinstatement: Encoding Spontaneous Thoughts as Memories

Can the brain improve the retrievability of an experience after it has occurred? Systems consolidation theory proposes that item-specific cortical reactivation during post-encoding rest periods facilitates the formation of stable memory representations, a prediction supported by neural evidence in humans and animals. Such reactivation may also occur on shorter time scales, offering a potential account of classic list memory phenomena but lacking in support from neural data. Leveraging the high-temporal specificity of intracranial electroencephalography (iEEG), we investigate spontaneous reactivation of previously experienced items during brief intervals between individual encoding events. Across two large-scale free recall experiments, we show that reactivation during these periods, measured by spectral iEEG similarity, predicts subsequent recall. In a third experiment, we show that the same methodology can identify post-encoding reactivation that correlates with subsequent memory, consistent with previous results. Thus, spontaneous study-phase reinstatement reliably predicts memory behavior, linking psychological accounts to neural mechanisms and providing evidence for rapid consolidation processes during encoding.

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bioRxiv2021

Boundary cells in the representation of episodes in the human hippocampus

The representation of episodes is a fundamental requirement for forming episodic memories, but the specific electrophysiological mechanisms supporting episode construction in the human hippocampus remain unknown. Experiments in rodent models indicate that a population of neurons sensitive to edges of an environment, termed border or boundary neurons in spatial navigation, fulfills a role analogous to episode demarcation. We hypothesized that such boundary neurons could be identified in the human mesial temporal lobe, with firing rates sensitive specifically to the beginning and end of mnemonically-relevant episodes in the free recall task. Using a generalized linear model to control for factors such as encoding success and item onset times along with other variables, we found 44 Boundary neurons out of a total 736 single neurons recorded across 27 subjects. We distinguish boundary neurons from a separate population of ramping neurons, which are time-sensitive neurons whose activity provides complementary but distinct information during episodic representation. We also describe evidence that the firing of boundary neurons within the preferred windows (at the beginning and end of episodes) is organized by hippocampal theta oscillations, using spike-field coherence metrics.

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bioRxiv2021

Flexibility of Functional Neuronal Assemblies Supports Human Memory

Summary ParagraphEpisodic memories, or consciously accessible memories of unique events, represent a key aspect of human cognition. Evidence from rodent models suggests that the neural representation of these complex memories requires cooperative firing of groups of neurons on short time scales1, organized by gamma oscillations2, 3. These co-firing groups, termed "neuronal assemblies,"4 represent a fundamental neurophysiological unit supporting memory. Using microelectrode data from neurosurgical patients5, we identify neuronal assemblies in the human MTL and show that they exhibit consistent organization in their firing pattern based on gamma phase information. We connect these properties to memory performance across recording sessions. Finally, we describe how human neuronal assemblies flexibly adjust6-9 over longer time scales. Our findings provide key evidence linking assemblies to human episodic memory for the first time.

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bioRxiv2020

Biomarkers of Memory Variability in Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of cognitive disability and is often associated with significant impairment in episodic memory. In TBI survivors, as in healthy controls, there is marked variability between individuals in memory ability. Using recordings from indwelling electrodes, we characterized and compared the oscillatory biomarkers of mnemonic variability in two cohorts of epilepsy patients: a group with a history of moderate-to-severe TBI (n = 37) and a group of non-TBI controls (n = 111) closely matched for demographics and electrode coverage. Analysis of these recordings demonstrated that increased high frequency power and decreased theta power across a broad set of brain regions mark periods of successful memory formation in both groups. As features in a logistic-regression classifier, spectral power biomarkers effectively predicted recall probability, with little difference between TBI and non-TBI controls. The two groups also displayed similar patterns of theta-frequency connectivity during successful encoding periods. These biomarkers of successful memory, highly conserved between TBI patients and controls, could serve as the basis for novel therapies that target disordered memory across diverse forms of neurological disease.

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bioRxiv2020

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

The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, recent evidence suggests that temporal information is encoded by a population of "time cells." We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of episodic memories. A significant portion of these cells exhibits phase precession, a key phenomenon not previously seen in human recordings. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.

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bioRxiv2019

Intracranial EEG reveals bihemispheric parietal and extra parietal brain networks supporting mental arithmetic

Mathematical reasoning is central to everyday life. Lesion data and functional MRI studies suggest that even simple arithmetic involves the coordination of multiple spatially diverse brain regions, but to date, math processing has not been well characterized using direct brain recordings, especially outside of the parietal cortex. To address this, we utilized an unparalleled data set of 310 subjects implanted with intracranial electrodes to investigate the spatial and temporal dynamics of arithmetic reasoning. Our data support the importance of regions previously implicated in numerosity such as the superior parietal lobule and intraparietal sulcus. However, we also identify contributions to arithmetic processing from regions such as the entorhinal cortex and temporal pole. Using the excellent bihemispheric coverage afforded by our data set and the precise temporal resolution of intracranial recordings, we characterize in detail the spatial and temporal characteristics of an arithmetic processing network, quantifying subtle hemispheric differences for selected regions. We also examine how activity in these regions predicts arithmetic ability and look for gender differences in the pattern of network activation. Our findings further define the complex network of regions involved in human arithmetical reasoning.

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bioRxiv2018

Stimulation of the posterior cingulate impairs episodic memory encoding

Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory processing, making it a potential target for responsive neuromodulation strategies outside of the hippocampal network. However, causal evidence for the role PCC plays in memory encoding is lacking. In patients undergoing seizure mapping, we investigated functional properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography (stereo EEG). These techniques allow precise targeting of deep cortical structures including the PCC, and simultaneous acquisition of oscillatory recordings from neighboring regions such as the hippocampus. We used a free recall experiment in which PCC was stimulated during item encoding period of half of the study lists, while no stimulation was applied during encoding period of the remaining lists. We evaluated if stimulation affected memory and/or modulated hippocampal activity. Results revealed four main findings. (i) Stimulation during encoding impaired memory for early items on the study lists. (ii) Stimulation increased hippocampal gamma band power. (iii) Stimulation-induced gamma power predicted memory impairment. (iv) Functional connectivity between the hippocampus and PCC predicted the degree of stimulation effect on memory. Our findings offer the first causal evidence implicating the PCC in episodic memory encoding. Importantly, results highlight that stimulation targeted outside of the temporal lobe can modulate hippocampal activity with implications on behavior. Furthermore, a-priori measures of connectivity between brain regions within a functional network can be informative in predicting behavioral effects of stimulation. Our findings have significant implications for developing therapie to treat diseases of memory loss and cognitive impairment using DBS.\n\nSignificance StatementCognitive impairment and memory loss are critical public health challenges. Deep brain stimulation (DBS) is a promising tool for developing strategies to ameliorate memory disorders by targeting brain regions involved in mnemonic processing. Using DBS, our study sheds light on the lesser-known role of the posterior cingulate cortex (PCC) in memory encoding. Stimulating the PCC during encoding impairs subsequent recall memory. The degree of impairment is predictedby stimulation-induced hippocampal gamma oscillations and functional connectivity between PCC and hippocampus. Our findings provide the first causal evidence implicating PCC in memory encoding and highlight the PCC as a favorable target for neuromodulation strategies, using a-priori connectivity measures to predict stimulation effects. This has significant implications for developing therapies for memory diseases.

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bioRxiv2018

Functionally distinct high and low theta oscillations in the human hippocampus

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10-Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in thetas function. To characterize human hippocampal theta, we examined the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observed hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displayed oscillations at ~8-Hz and the precise frequency of these oscillations correlated with the speed of movement, implicating these signals in spatial navigation. We also observed slower ~3-Hz oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency did not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.

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bioRxiv2018

Single neurons in the human entorhinal cortex remap to distinguish individual spatial memories

The entorhinal cortex (EC) is known to play a key role in both memory and spatial navigation. Despite this overlap in spatial and mnemonic circuits, it is unknown how spatially responsive neurons contribute to our ability to represent and distinguish past experiences. Recording from medial temporal lobe (MTL) neurons in subjects performing cued recall of object-location memories in a virtual-reality environment, we identified \"trace cells\" in the EC that remap their spatial fields to locations subjects were cued to recall on each trial. In addition to shifting its firing field according to the memory cue, this neuronal activity exhibited a firing rate predictive of the cued memorys content. Critically, this memory-specific neuronal activity re-emerged when subjects were cued for recall without entering the environment, indicating that trace-cell memory representations generalized beyond navigation. These findings suggest a general mechanism for memory retrieval via trace-cell activity and remapping in the EC.

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bioRxiv2018

MTL functional connectivity predicts stimulation-induced theta power

Abstract/SummaryFocal electrical stimulation of the brain incites a cascade of neural activity that propagates from the stimulated region to both nearby and remote areas, offering the potential to control the activity of brain networks. Understanding how exogenous electrical signals perturb such networks in humans is key to its clinical translation. To investigate this, we applied electrical stimulation to subregions of the medial temporal lobe in 26 neurosurgical patients fitted with indwelling electrodes. Networks of low-frequency (5-13 Hz) spectral coherence predicted stimulation-evoked changes in theta (5-8 Hz) power, but only when stimulation was applied in or adjacent to white matter. Furthermore, these power changes aligned with control-theoretic predictions of how exogenous stimulation flows through complex networks, such as a dispersal of induced activity when functional hubs are targeted. Our results demonstrate that functional connectivity is predictive of causal changes in the brain, but that access to structural connections is necessary to observe such effects.

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bioRxiv2018

Functional wiring of the human medial temporal lobe

The medial temporal lobe (MTL) is a locus of episodic memory in the human brain. It is comprised of cytologically distinct subregions that, in concert, give rise to successful encoding and retrieval of context-dependent memories. However, the functional connections between these subregions are poorly understood. To determine functional connectivity among MTL subregions, we had 126 subjects fitted with indwelling electrodes perform a verbal memory task, and asked how encoding or retrieval correlated with interregional synchronization. Using phase-based measures of connectivity, we found that synchronous theta (4-8 Hz) activity underlies successful episodic memory, whereas high-frequencies exhibit desynchronization. Moreover, theta functional connectivity during encoding aligned with key anatomic connections, including critical links between the entorhinal cortex, dentate gyrus, and CA1 of the hippocampus. Retrieval-associated networks demonstrated enhanced involvement of the subiculum, reflecting a substantial reorganization of the encoding-associated network. We posit that coherent theta activity within the MTL marks periods of successful memory, but distinct patterns of connectivity dissociate key stages of memory processing.\n\nSignificance StatementThe brain functions through the interaction of its distinct parts, but little is known about how such connectivity dynamics relate to learning and memory. We used a large dataset of 126 human subjects with intracranial electrodes to assess patterns of electrical connectivity within the medial temporal lobe - a key region for memory processing - as they performed a memory task. We discovered that unique networks of time-varying, low-frequency interactions correlate with memory encoding and retrieval, specifically in the theta band. Simultaneously, we observed elevated spectral power at high frequencies in these same regions. The result is a complete map of physiological dynamics within the MTL, highlighting how a reorganization of theta networks support distinct memory operations.

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bioRxiv2017

Electrophysiological signatures of spatial boundaries in the human subiculum

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly-related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. While studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. Here we present direct intracranial recordings from the hippocampal formation of surgical epilepsy patients while they performed a virtual spatial navigation task. Our results suggest that encoding target locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, or movement. These findings provide the first direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homologue of the hippocampal subregion in which most rodent boundary cells are found.\n\nSignificance StatementSpatial computations using environmental boundaries are an integral part of the brains spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to fMRI studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions we identified, for the first time in humans, a neural marker of boundary representation in the subiculum.

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bioRxiv2017

The medial temporal lobe organizes memory across time and space: Causal evidence from brain stimulation

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects abilities to remember items using view-independent (allocentric) navigation strategies. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.\n\nSignificance StatementNumerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

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