Biology subjects

Lega, B. C.

Publications and source records attributed to Lega, B. C..

15 recordsLinked to original sources

bioRxiv2025

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth

The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated [~]100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an unexpected function. GAA accumulates in GAMT deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing GABA currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a new mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

cancer biology↗

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

A wireless, 60-channel, AI-enabled neurostimulation platform

ObjectiveClosed-loop neuromodulatory therapies require devices that can both decode ongoing brain states and deliver multi-site stimulation. MethodsWe describe the Smart Neurostimulation System (SNS), a cranially mounted implant with 60 configurable recording/stimulation channels, inductive power, and onboard spectral-feature classification. In three freely-moving sheep we streamed local-field potentials and conducted two parameter sweep experiments. ResultsCross-validated movement classifiers achieved an average AUC > 0.95. Increasing stimulation amplitude and frequency produced post-stimulation elevations in -band (8-12 Hz) and{gamma} -band (78-82 Hz) power at most target locations. ConclusionThe SNS unifies high-density sensing, real-time brain state decoding, and programmable closed-loop stimulation in a single device, demonstrating behavioral-state prediction and parameter-dependent neuromodulation in vivo. SignificanceThese findings establish a preclinical foundation for biomarker-guided stimulation targeting distributed cortical networks underlying memory and cognition. HighlightsO_LIWireless 60-channel implant enables simultaneous sensing and stimulation C_LIO_LIvine study demonstrates reliable classification of movement and stimulation-related modulation of spectral activity C_LIO_LIThe SNS represents a platform for biomarker-guided neuromodulation therapies C_LI

neuroscience↗

bioRxiv2023

Episodic boundaries affect neural features of representational drift in humans

A core feature of episodic memory is representational drift, the gradual change in aggregate oscillatory features that supports temporal association of memory items. However, models of drift overlook the role of episodic boundaries, which indicate a shift from prior to current context states. Our study focuses on the impact of task boundaries on representational drift in the parietal and temporal lobes in 99 subjects during a free recall task. Using intracranial EEG recordings, we show boundary representations reset gamma band drift in the medial parietal lobe, selectively enhancing the recall of early list (primacy) items. Conversely, the lateral temporal cortex shows increased drift for recalled items but lacked sensitivity to task boundaries. Our results suggest regional sensitivity to varied contextual features: the lateral temporal cortex uses drift to differentiate items, while the medial parietal lobe uses drift-resets to associate items with the current context. We propose drift represents relational information tailored to a regions sensitivity to unique contextual elements. Our findings offer a mechanism to integrate models of temporal association by drift with event segmentation by episodic boundaries.

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↗

bioRxiv2021

Distinct neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood-oxygen-level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modelling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70-150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30-70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex. Significance StatementThe blood-oxygen-level-dependent (BOLD) signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in frontal, temporal, and parietal cortex. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.

neuroscience↗

bioRxiv2020

Distinct cortical systems reinstate the content and context of episodic memories

Episodic recall depends upon the reinstatement of cortical activity present during the formation of a memory. We identified dissociable cortical networks via functional connectivity that uniquely reinstated semantic content and temporal context of previously studied stimuli during free recall. Network-specific reinstatement predicted the temporal and semantic organization of recall sequences, demonstrating how specialized cortical systems enable the human brain to target specific memories.

neuroscience↗

bioRxiv2020

Hippocampal theta oscillations support successful associative memory formation

1.Models of memory formation posit that recollection as compared to familiarity-based memory depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected versus those that are recognized on the basis of familiarity should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans results have not been as clear. Here, we employed an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients undergoing intracranial EEG monitoring. We identified a dissociation between 2- 5 Hz and 5-9 Hz theta oscillations, by which 2-5 Hz oscillations uniquely were linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding, distinguished recollected from familiar items at retrieval, and contributed to reinstatement of encoding-related patterns that distinguished these items. Our results provide direct electrophysiological evidence that 2-5 Hz hippocampal theta oscillations support the encoding and retrieval of memories based on recollection but not familiarity. 2. Significance StatementExtensive fMRI evidence suggests that the hippocampus plays a selective role in recollection rather than familiarity, during both encoding and retrieval. However, there is little or no electrophysiological evidence that speaks to whether the hippocampus is selectively involved in recollection. Here, we used intracranial EEG from human participants engaged in an associative recognition paradigm. The findings suggest that oscillatory power and phase reset in the hippocampus are selectively associated with recollection rather than familiarity-based memory judgements. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection than familiarity. Collectively, the findings support a role for hippocampal theta oscillations in human episodic memory.

neuroscience↗

bioRxiv2020

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

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

neuroscience↗

bioRxiv2019

The genomic underpinnings of oscillatory biomarkers supporting successful memory encoding in humans

In humans, brain oscillations are thought to support critical features of memory formation such as coordination of activity across regions, consolidation, and temporal ordering of events. However, understanding the molecular mechanisms underlining this activity in humans remains a major challenge. Here, we measured memory-sensitive oscillations using direct intracranial electroencephalography recordings from the temporal cortex of patients performing an episodic memory task. By then employing transcriptomics on the resected tissue from the same patients, we linked gene expression with brain oscillations, identifying genes correlated with oscillatory signatures of memory formation across six frequency bands. A co-expression analysis isolated biomarker-specific modules associated with neuropsychiatric disorders as well as ion channel activity. Using single-nuclei transcriptomic data from this resected tissue, we further revealed that biomarker-specific modules are enriched for both excitatory and inhibitory neurons. This unprecedented dataset of patient-specific brain oscillations coupled to genomics unlocks new insights into the genetic mechanisms that support memory encoding. By linking brain expression of these genes to oscillatory patterns, our data help overcome limitations of phenotypic methods to uncover genetic links to memory performance.

genomics↗

bioRxiv2019

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

Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results help guide clinicians and researchers when designing stimulation protocols to cause precisely targeted changes in human brain activity.

neuroscience↗

bioRxiv2019

Gamma oscillations during episodic memory processing reveal reversal of information flow between the hippocampus and prefrontal cortex

A critical and emerging question in human episodic memory is how the hippocampus interacts with the prefrontal cortex during the encoding and retrieval of items and their contexts. In the present study, participants performed an episodic memory task (free recall) while intracranial electrodes were simultaneously inserted into the hippocampus and multiple prefrontal locations, allowing the quantification of relative onset times of gamma band activity in the cortex and the hippocampus in the same individual. We observed that in left anterior ventrolateral prefrontal cortex (aVLPFC) gamma band activity onset was significantly later than in the hippocampus during memory encoding, whereas its activity significantly preceded that in the hippocampus during memory retrieval. These findings provide direct evidence to support models of prefrontal-hippocampal interactions derived from studies of rodents, but suggest that in humans, it is the aVLPFC rather than medial prefrontal cortex that demonstrate these reciprocal interactions.

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

Hippocampal theta codes for distances in semantic and temporal spaces

AO_SCPCAPBSTRACTC_SCPCAPThe medial temporal lobe (MTL) is known to support episodic memory and spatial navigation, raising the possibility that its true function is to form \"cognitive maps\" of any kind of information. Studies in humans and animals support the idea that the hippocampal theta rhythm (4-8 Hz) is key to this mapping function, as it has been repeatedly observed during spatial navigation tasks. If episodic memory and spatial navigation are two sides of the same coin, we hypothesized that theta oscillations would also reflect relations between explicitly nonspatial items, such as words. We asked 189 neurosurgical patients to perform a verbal free-recall task, of which 96 had indwelling electrodes placed in the MTL. Subjects were instructed to remember short lists of sequentially-presented nouns. We found that hippocampal theta power and connectivity during item retrieval coded for semantic distances between words, as measured using word2vec-derived subspaces. Additionally, hippocampal theta indexed temporal distances between words after filtering lists on recall performance, to ensure adequate dynamic range in time. Theta effects were only noted for semantic subspaces of 1-dimension, indicating a substantial compression of the possible semantic feature space. These results lend further support to our growing confidence that the MTL forms cognitive maps of arbitrary representational spaces, reconciling longstanding differences between the spatial and episodic memory literatures.

neuroscience↗

bioRxiv2018

Predictive control of electrophysiological network architecture using direct, single-node neurostimulation in humans

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

neuroscience↗