Biology subjects

Devinsky, O.

Publications and source records attributed to Devinsky, O..

9 recordsLinked to original sources

bioRxiv2018

Resting state functional connectivity patterns associated with pharmacological treatment resistance in temporal lobe epilepsy

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.\n\nSummaryResting State functional magnetic resonance imaging (Rs-fMRI), previously utilized to predict lateralization of seizure foci in temporal lobe epilepsy (TLE), is utilized to determine potential mechanisms and biomarkers for treatment-resistant and well-controlled unilateral TLE. We found significant differences in thalamo-hippocampal functional connectivity between treatment-resistant and well-controlled TLE patients. Differences in functional connectivity were focused to thalamo-hippocampal connections and more pronounced in the hemisphere ipsilateral to seizure foci. Aberrant functional connectivity patterns as measured by Rs-fMRI could thus serve as biomarkers for treatment response in TLE.

neuroscience↗

bioRxiv2018

Two Sides of the Same Coin: The Hippocampus as a Common Neural Substrate for Model-Based Planning and Spatial Memory

Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet, there is limited direct evidence for the link between model-based planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection. We found that both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, planning and place memory covaried with one another, but only in neurologically intact controls, consistent with both functions relying on the same structure in the healthy brain. These findings clarify the scope of hippocampal contributions to behavior and the neural mechanism of model-based planning.

neuroscience↗

bioRxiv2018

Electrocorticographic responses to time-compressed speech vary across the cortical auditory hierarchy

Human listeners understand spoken language across a variety of rates, but when speech is presented three times or more faster than its usual rate, it becomes unintelligible. How the brain achieves such tolerance and why speech becomes unintelligible above certain rates is still unclear. We addressed these questions using electrocorticography (ECoG) recordings in 7 epileptic patients (two female). Patients rated the intelligibility of sentences presented at the original rate (100%), speeded rates (33% or 66% of the original sentence duration) and a slowed rate (150%). We then examined which parameters of the neural response covary with the transition from intelligible to unintelligible speech. Specifically, we asked whether neural responses: 1) track the acoustic envelope of the incoming speech; 2) \"scale\" with speech rate, i.e. whether neural responses elicited by slowed and speeded sentences can be linearly scaled to match the responses to the original sentence. Behaviorally, intelligibility was at ceiling for speech rates of 66% and above, but dropped significantly for the 33% rate. At the neural level, Superior Temporal Gyrus regions (STG) in close proximity to A1 ( low-level) tracked the acoustic envelope and linearly scaled with the input across all speech rates, irrespective of intelligibility. In contrast, secondary auditory areas in the STG as well as the inferior frontal gyrus and angular gyrus ( high-level) tracked the acoustic envelope and linearly scaled with input only for intelligible speech. These results help reconcile seemingly contradictory previous findings and provide better understanding of how information processing unfolds along the cortical auditory hierarchy.

neuroscience↗

bioRxiv2018

Hippocampal signature of associative memory measured by chronic ambulatory intracranial EEG

Some patients with medically refractory focal epilepsy are chronically implanted with a brain-responsive neurostimulation device (the RNS(R) System), permitting neurophysiological measurements at millisecond resolution. This clinical device can be adapted to measure hippocampal dynamics time-locked to cognitive tasks. We illustrate the technique with a proof of concept in three patients previously implanted with the RNS System as they engage in an associative memory task, measured months apart. Hippocampal activity measured in successful encoding in RNS System patients mirrors that in surgical patients during intracranial electroencephalography (iEEG), suggesting that chronic iEEG allows sensitive measurements of hippocampal physiology over prolonged timescales.

neuroscience↗

bioRxiv2017

Superficial Slow Rhythms Integrate Cortical Processing in Humans

The neocortex is composed of six anatomically and physiologically specialized layers. It has been proposed that integration of activity across cortical areas is mediated anatomically by associative connections terminating in superficial layers, and physiologically by slow cortical rhythms. However, the means through which neocortical anatomy and physiology interact to coordinate neural activity remains obscure. Using laminar microelectrode arrays in 19 human participants, we found that most EEG activity is below 10-Hz (delta/theta) and generated by superficial cortical layers during both wakefulness and sleep. Cortical surface grid, grid-laminar, and dual-laminar recordings demonstrate that these slow rhythms are synchronous within upper layers across broad cortical areas. The phase of this superficial slow activity is reset by infrequent stimuli and coupled to the amplitude of faster oscillations and neuronal firing across all layers. These findings support a primary role of superficial slow rhythms in generating the EEG and integrating cortical activity.

neuroscience↗

bioRxiv2017

The Generation and Propagation of the Human Alpha Rhythm

IntroductionThe alpha rhythm (7-13 Hz) is the longest studied brain oscillation and has been theorized to play a key role in cognition. Still, substantial uncertainty remains over its physiology. In this study, we used micro and macro electrodes in patients undergoing surgery for epilepsy to measure the intracortical and thalamic generators of the human alpha rhythm. We first found that alpha propagates from higher-order anterosuperior cortex towards the lower-order occipital poles, consistent with alpha effecting top-down processing. This cortical alpha drives thalamic alpha, reversing prevailing theories of a thalamic alpha pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortex, contravening the popular conception of alpha as an infragranular rhythm. Together, these results demonstrate that the alpha rhythm reflects short-range supragranular feedback which propagates from higher-order to lower order cortex and cortex to thalamus. These physiological insights explain how alpha could mediate feedback throughout the thalamocortical system.

neuroscience↗

bioRxiv2017

Replay of large-scale spatio-temporal patterns from waking during subsequent slow-wave sleep in human cortex

Animal studies support the hypothesis that in slow-wave sleep, replay of waking neocortical activity under hippocampal guidance leads to memory consolidation. However, no intracranial electrophysiological evidence for replay exists in humans. We identified consistent sequences of population firing peaks across widespread cortical regions during complete waking periods. The occurrence of these Motifs were compared between sleeps preceding the waking period (Sleep-Pre) when the Motifs were identified, and those following (Sleep-Post). In all subjects, the majority of waking Motifs (most of which were novel) had more matches in Sleep-Post than in Sleep-Pre. In rodents, hippocampal replay occurs during local sharp-wave ripples, and the associated neocortical replay tends to occur during local sleep spindles and down-to-up transitions. These waves may facilitate consolidation by sequencing cell-firing and encouraging plasticity. Similarly, we found that Motifs were coupled to neocortical spindles, down-to-up transitions, theta bursts, and hippocampal sharp-wave ripples. While Motifs occurring during cognitive task performance were more likely to have more matches in subsequent sleep, our studies provide no direct demonstration that the replay of Motifs contributes to consolidation. Nonetheless, these results confirm a core prediction of the dominant neurobiological theory of human memory consolidation.

neuroscience↗

bioRxiv2017

Quantification of autism recurrence risk by direct assessment of paternal sperm mosaicism

De novo genetic mutations represent a major contributor to pediatric disease, including autism spectrum disorders (ASD), congenital heart disease, and muscular dystrophies1,2, but there are currently no methods to prevent or predict them. These mutations are classically thought to occur either at low levels in progenitor cells or at the time of fertilization1,3 and are often assigned a low risk of recurrence in siblings4,5. Here, we directly assess the presence of de novo mutations in paternal sperm and discover abundant, germline-restricted mosaicism. From a cohort of ASD cases, employing single molecule genotyping, we found that four out of 14 fathers were germline mosaic for a putatively causative mutation transmitted to the affected child. Three of these were enriched or exclusively present in sperm at high allelic fractions (AF; 7-15%); and one was recurrently transmitted to two additional affected children, representing clinically actionable information. Germline mosaicism was further assessed by deep (>90x) whole genome sequencing of four paternal sperm samples, which detected 12/355 transmitted de novo single nucleotide variants that were mosaic above 2% AF, and more than two dozen additional, non-transmitted mosaic variants in paternal sperm. Our results demonstrate that germline mosaicism is an underestimated phenomenon, which has important implications for clinical practice and in understanding the basis of human disease. Genetic analysis of sperm can assess individualized recurrence risk following the birth of a child with a de novo disease, as well as the risk in any male planning to have children.

genetics↗

bioRxiv2017

Time-resolved neural reinstatement and separation during memory decisions in human hippocampus

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding would be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar).During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated both with the strength (HFA power) of hippocampal encoding and with the strength of hippocampal retrieval. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.\n\nSignificance StatementOne of the biggest computational challenges the memory systems faces is to disambiguate highly similar experiences while at the same time preserving and reinstating prior memories. Remarkably, hippocampal processes have been implicated in both of these functions. However, how this is accomplished is unknown. Leveraging the spatiotemporal resolution of electrocorticography, we found evidence for memory reinstatement in both the hippocampus and occipitotemporal cortex. Reinstatement was differentiated in time across these two regions with earlier reinstatement evident in occipitotemporal cortex. Interestingly, when a current experience was very similar, but not identical to a prior one, occipitotemporal cortical activity still showed reinstatement of the prior memory but hippocampal activity differentiated or disambiguated these two similar experiences.

neuroscience↗