Dataset Information

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network.

ABSTRACT: Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (G_tonic) of synaptic and extrasynaptic GABA receptors in multiple cells. Here, we monitor extracellular GABA in hippocampal slices using patch-clamp GABA "sniffer" and a novel optical GABA sensor, showing that periodic epileptiform discharges are preceded by transient, region-wide waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to a cycle of GABA-driven network inhibition and disinhibition underpinning this relationship. We test and validate this hypothesis using simultaneous patch-clamp recordings from multiple neurons and selective optogenetic stimulation of fast-spiking interneurons. Critically, reducing GABA uptake in order to decelerate extracellular GABA fluctuations-without affecting synaptic GABAergic transmission or resting GABA levels-slows down rhythmic activity. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA in pacing regenerative rhythmic activity in brain networks.

SUBMITTER: Magloire V

PROVIDER: S-EPMC10615848 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network.

Magloire Vincent V Savtchenko Leonid P LP Jensen Thomas P TP Sylantyev Sergyi S Kopach Olga O Cole Nicholas N Tyurikova Olga O Kullmann Dimitri M DM Walker Matthew C MC Marvin Jonathan S JS Looger Loren L LL Hasseman Jeremy P JP Kolb Ilya I Pavlov Ivan I Rusakov Dmitri A DA

Current biology : CB 20230314 7

Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (G<sub>tonic</sub>) of synaptic and extrasynaptic GABA receptors in multiple cells. Here, we monitor extracellular GABA in h ...[more]

PMID: 36921605

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Project description:ImportanceThe hippocampus is a highly epileptogenic brain region, yet over 90% of hippocampal epileptiform activity (HEA) cannot be identified on scalp electroencephalogram (EEG) by human experts. Currently, detection of HEA requires intracranial electrodes, which limits our understanding of the role of HEA in brain diseases.ObjectiveTo develop and validate a machine learning algorithm that accurately detects HEA from a standard scalp EEG, without the need for intracranial electrodes.Design, setting, and participantsIn this diagnostic study, conducted from 2008 to 2021, EEG data were used from patients with temporal lobe epilepsy (TLE) and healthy controls (HCs) to train and validate a deep neural network, HEAnet, to detect HEA on scalp EEG. Participants were evaluated at tertiary-level epilepsy centers at 2 academic hospitals: Massachusetts General Hospital (MGH) or Brigham and Women's Hospital (BWH). Included in the study were patients aged 12 to 78 years with a clinical diagnosis of TLE and HCs without epilepsy. Patients with TLE and HCs with a history of intracranial surgery were excluded from the study.ExposuresSimultaneous intracranial EEG and/or scalp EEG.Main outcomes and measuresPerformance was assessed using cross-validated areas under the receiver operating characteristic curve (AUC ROC) and precision-recall curve (AUC PR) and additional clinically relevant metrics.ResultsHEAnet was trained and validated using data sets that were derived from a convenience sample of 141 eligible participants (97 with TLE and 44 HCs without epilepsy) whose retrospective EEG data were readily available. Data set 1 included the simultaneous scalp EEG and intracranial electrode recordings of 51 patients with TLE (mean [SD] age, 40.7 [15.9] years; 30 men [59%]) at MGH. An automatically generated training data set with 972 095 positive HEA examples was created, in addition to a held-out expert-annotated testing data set with 22 762 positive HEA examples. HEAnet's performance was validated on 2 independent scalp EEG data sets: (1) data set 2 (at MGH; 24 patients with TLE and 20 HCs; mean [SD] age, 42.3 [16.2] years; 17 men [39%]) and (2) data set 3 (at BWH; 22 patients with TLE and 24 HCs; mean [SD] age, 43.0 [14.4] years; 20 men [43%]). For single-event detection of HEA on data set 1, HEAnet achieved a mean (SD) AUC ROC of 0.89 (0.01) and a mean (SD) AUC PR of 0.39 (0.03). On external validation with data sets 2 and 3, HEAnet accurately distinguished TLE from HC (AUC ROC of 0.88 and 0.95, respectively) and predicted epilepsy lateralization with 100% and 92% accuracy, respectively. HEAnet tracked dynamic changes in HEA in response to seizure medication adjustments and performed comparably with human experts in diagnosing TLE from 1-hour scalp EEG recordings, diagnosing TLE in several individuals that experts missed. Without reducing specificity, addition of HEAnet to human expert EEG review increased sensitivity for diagnosing TLE in humans from 50% to 58% to 63% to 67%.Conclusions and relevanceResults of this diagnostic study suggest that HEAnet provides a novel, noninvasive, quantitative, and clinically relevant biomarker of hippocampal hyperexcitability in humans.

Dataset Information

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network.

Publications

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network.

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