Hal Blumenfeld

Although the brain state preceding and during absence seizures has been well-characterized, the postictal brain state remains largely unexplored due to the prevailing assumption that absence seizures have minimal or no postictal changes. To address this gap, scalp EEG recordings from 55 patients with 3-4 Hz spike-wave discharges across four multi-site cohorts were analyzed. Spectral power was measured relative to each seizure’s preictal baseline, and the postictal period was compared to a time-matched preictal window. Rather than an immediate return to baseline after seizure offset, a significant broadband increase in EEG power was observed in the gamma (>25 Hz) and delta (<4 Hz) frequency bands, followed by a gradual decline over the next 15 s to 30 s. In contrast, no comparable change preceded the seizures. This suggests that recovery from an absence seizure is an active process with a characteristic electrophysiological signature consistent with cortical activation and arousal. Thus, postictal arousal may facilitate exit from the seizure state, and with further work could serve as an electrophysiological marker and therapeutic target for recovery in absence epilepsy.

Despite many years of research, the quest to identify neural correlates of perceptual consciousness (NCC) remains unresolved. One major obstacle lies in methodological limitations: most studies rely on non-invasive neural measures with limited spatial or temporal resolution, making it difficult to disentangle proper NCCs from concurrent cognitive processes. Additionally, the relatively low sensitivity of non-invasive neural measures limits the interpretation of null findings in studies targeting proper NCCs. In this review, we discuss how human intracranial recordings can advance the search for NCCs by offering high spatiotemporal resolution, improved signal sensitivity, and broad cortical and subcortical coverage. We review studies that have examined NCCs at the level of single neurons and populations of neurons, and evaluate their implications on the debates between cognitive and sensory theories of consciousness. Finally, we highlight the limits of current intracranial human recordings and propose future directions based on emerging technologies and novel experimental paradigms.

Despite many years of research, the quest to identify neural correlates of perceptual consciousness (NCC) remains unresolved. One major obstacle lies in methodological limitations: most studies rely on non-invasive neural measures with limited spatial or temporal resolution making it difficult to disentangle proper NCCs from concurrent cognitive processes. Additionally, the relatively low sensitivity of non-invasive neural measures limits the interpretation of null findings in studies targeting proper NCCs. In this review, we discuss how human intracranial recordings can advance the search for NCCs, by offering high spatiotemporal resolution, improved signal sensitivity, and broad cortical and subcortical coverage. We review studies that have examined NCCs at the level of single neurons and populations of neurons, and evaluate their implications on the debates between cognitive and sensory theories of consciousness. Finally, we highlight the limits of current intracranial human recordings and propose future directions based on emerging technologies and novel experimental paradigms.

Awareness of action (AoA), or conscious awareness of an action just performed, is an important part of daily experience with major practical and ethical relevance, yet the neural mechanisms of AoA remain largely unknown. The main barrier to studying AoA is a lack of experimental paradigms to directly compare neural activity in aware versus unaware actions. Borrowing from the field of perceptual awareness, where exciting progress has been made by contrastive analysis of aware versus unaware stimuli, we developed a game where participants repeatedly perform nearly identical moves while engaged in a distractor task, and the participants then report awareness or unawareness of the moves they just performed. We found that on short timescales, aware actions had larger neurophysiological signals both preceding and following movement. The differences included both volitional and perceptual event-related potentials (premovement positivity, N140, and P300), as well as frontal midline theta, event-related alpha/beta desynchronization, and postmove blink rates. On longer time scales, we identified a novel positive event-related potential only preceding unaware moves and found behavioral and pupillometric evidence for decreased attention and arousal over minutes concurrent with AoA loss. Our findings reveal three neural mechanisms that may synergistically contribute to AoA: (i) long-term increases in arousal/attentional state at time of action; (ii) increased action-related motor volitional signals; and (iii) increased action-related sensory perceptual signals. Deeper understanding of AoA may ultimately elucidate the causes of variable AoA in daily life and lead to better treatments for impaired AoA in neuropsychiatric disorders.

Studies of human perception have shown early cortical signals for primary information encoding, and later signals for higher order processing. An important late signal is the cortical event-related desynchronization (ERD) in the alpha (8–12 Hz) and beta (12–30 Hz) frequency band, which has been linked to human perceptual awareness. Detailed mechanistic investigation of the ERD would be greatly facilitated by availability of a suitable animal model. We conducted local field potential recordings in the mouse frontal association cortex (FrA), thalamic intralaminar centrolateral nucleus (CL), primary auditory cortex (A1), and primary visual cortex (V1) during two auditory tasks. Fully audible brief 50 ms stimuli with both tasks produced early broadband gamma (30–100 Hz) frequency activity at 0–250ms, followed by a late cortical alpha/beta ERD 250–750 ms after stimulus onset. The ERD was statistically significant in FrA and A1, but not in V1. Interestingly, a significant ERD was also observed in thalamic CL. The magnitude of the ERD at full stimulus intensity, and the slope of the relationship between stimulus intensity versus ERD magnitude, were both largest in FrA, and smaller in CL and A1. Conversely, for early broadband gamma activity the magnitude at full intensity and slopes were largest in A1, smaller in CL and smaller still in FrA. These findings strongly support mice as a promising platform for further investigation of the ERD to better understand the origin and function of this robust yet understudied electrophysiological phenomenon.

Zusammenfassung: Die Internationale Liga gegen Epilepsie (ILAE) hat die operationale Klassifikation epileptischer Anfälle 2017 auf der Grundlage der damals entwickelten Rahmenbedingungen aktualisiert. In diese Überarbeitung wurden die publizierten Erfahrungen mit der Umsetzung der 2017er-Klassifikation einbezogen. Eine 37 Personen zählende Arbeitsgruppe wurde vom ILAE-Exekutivausschuss eingesetzt. Die internationalen Expertinnen und Experten aus allen ILAE-Regionen wandten ein modifiziertes Delphi-Verfahren an, bei dem für jeden Vorschlag ein Konsens von mehr als zwei Dritteln erforderlich war. Nach Veröffentlichung auf der ILAE-Homepage mit dem Ersuchen, Kommentare zu dem Entwurf einzugeben, ernannte der Exekutivausschuss 7 zusätzliche Sachverständige für die Arbeitsgruppe zur Überarbeitung des Positionspapieres, um die eingegangenen Kommentare zu diskutieren und gegebenenfalls einzubeziehen. Die aktualisierte Klassifikation behält die Hauptklassen von Anfällen bei: fokal, generalisiert, unbekannt (ob fokal oder generalisiert) und nicht klassifiziert. Taxonomische Regeln unterscheiden zwischen Klassifikatoren , die biologische Klassen widerspiegeln und sich direkt auf die klinische Behandlung auswirken, und Deskriptoren , die andere wichtige Anfallsmerkmale angeben. Fokale Anfälle und Anfälle unbekannten Ursprungs werden darüber hinaus nach dem Bewusstseinszustand des Patienten während des Anfalls klassifiziert, je nachdem ob eine Bewusstseinsstörung vorliegt oder nicht. Die Bewertung, ob eine Bewusstseinsstörung vorliegt, wird durch Gewahrsein (engl. „awareness“) und Reaktionsfähigkeit (engl. „responsiveness“) während eines Anfalls und erhaltene Erinnerung (engl. „recall“) nach einem Anfall klinisch operationalisiert. Wenn der Bewusstseinszustand nicht bestimmbar ist, wird der Anfall unter dem übergeordneten Begriff, d. h. der Hauptanfallsklasse (fokaler Anfall oder Anfall unbekannten Ursprungs) klassifiziert. Generalisierte Anfälle werden in Absencen, generalisierte tonisch-klonische Anfälle und andere generalisierte Anfälle eingeteilt, wobei jetzt auch der negative Myoklonus als Anfallstyp beschrieben wird. Anfälle werden in der Grundversion als solche mit oder ohne beobachtbare Manifestationen beschrieben, während eine erweiterte Version die chronologische Abfolge der Anfallssemiologie verwendet. Diese aktualisierte Klassifikation umfasst 4 Hauptklassen und nur noch 21 Anfallstypen (und nicht mehr 63 wie in der 2017 Klassifikation; Anm. d. Übersetzer). Besonderer Wert wurde auf die Übersetzbarkeit in andere Sprachen jenseits von Englisch gelegt. Ziel ist es, eine gemeinsame Sprache für alle im Bereich Epilepsie tätigen Gesundheitsfachkräfte zu schaffen – von ressourcenarmen Gebieten bis hin zu hoch spezialisierten Zentren – und leicht zugängliche Begriffe für Patientinnen und Patienten sowie Betreuungspersonen bereitzustellen.

Withdrawal Statement: bioRxiv has withdrawn this manuscript after being contacted by the current corresponding author because they are unable to access the original data for revisions needed to finalize the preliminary results. If you have any questions, please contact the current corresponding author.

Objective: Interictal epileptiform discharges (IEDs) in people with epilepsy (PWE) can impair cognitive functions and increase reaction time (RT) and the likelihood of missed reactions. These effects are not routinely assessed, because reliable methods for detecting IEDs of variable appearance in real time and suitable tests to measure IED effects do not yet exist. The objective was to assess different IED effects using new artificial intelligence and medical electronics. Methods: The Digital Response Test in Epilepsy (DigRTEpi) consisted of a laptop and electronic circuits in a closed loop. Our model with Markov Transition Fields and a deep neural network (ResNet34) visualized the electroencephalogram (EEG) and classified the resulting images. IED detection triggered stimuli in a driving game or in a new cognitive assessment, the interictal Automated Responsiveness Test (iART). DigRTEpi was validated in a prospective case series with 20 people with focal and generalized epilepsies. During offline analysis, sensitivity, specificity, false‐positive IED detection rate, latency of EEG classification, IED‐induced RT prolongation, virtual crashes, and impaired responses to neuropsychological tasks were determined. Results: The model detected IEDs with 84% sensitivity and 96% specificity in our training dataset. In the prospective study with 20 PWE, median sensitivity was 90% (95% confidence interval [CI] = .81–.95), and false‐positive IED detection rate was 2.8 (95% CI 2.1–5.9). The ongoing EEG was classified window‐by‐window in a median 98.7 ms (95% CI = 98.0–99.4). Median RT prolongation and crash probability due to IEDs were 43.8 ms (95% CI = 20.3–64.7) and .9% (95% CI = 0–6.0) per person, respectively. Two patients (10%) had delays of >100 ms, found to be clinically relevant in our prior publication. IEDs caused four patients (20%) each to respond incorrectly or miss answers to neuropsychological tasks. The median false‐positive IED detection rates were 2.8/min (95% CI = 2.1–5.9; driving game) and 2.1/min (95% CI = 1.5–3.2; iART). Significance: By effectively detecting IEDs of variable morphology in real time, DigRTEpi assessed the severity of IED‐associated transitory impairment of virtual driving and cognition to improve personalized care.

Thalamic stimulation has emerged as a promising neuromodulation target for treating disorders of consciousness. Impaired consciousness, a debilitating outcome in temporal lobe epilepsy (TLE) remains a central problem for patients whose seizures cannot be treated pharmacologically and cannot be stopped with conventional surgery or responsive hippocampal stimulation. Although prior studies suggest an essential role of the thalamic intralaminar central lateral (CL) nucleus in arousal and sleep, evidence for a direct effect of thalamic intralaminar stimulation on human arousal has been limited. To address these gaps, the START (stimulation of the thalamus for arousal restoral in TLE) clinical trial investigated the efficacy of bilateral CL thalamic stimulation to restore consciousness during human sleep and TLE seizures. Five patients with medically refractory mesial temporal lobe epilepsy were implanted with an investigational neurostimulator, the Medtronic Summit RC+S ^TM . Optimal CL stimulation parameters were obtained through individualized titration in slow wave sleep, evaluated through analysis of patient movement from video recordings and electrophysiology from simultaneously recorded scalp and hippocampal electroencephalography (EEG). We found that bilateral CL stimulation led to robust arousal from sleep characterized by increased body movements and decreased low frequency power (2-15 Hz) in both cortical and hippocampal EEG during 5 minute epochs of stimulation compared to baseline slow wave sleep. We evaluated impaired consciousness during seizures using verbal and non-verbal behavioral tests administered automatically by smartwatch, and found significant behavioral impairment in three of five patients during seizures with hippocampal stimulation. Administering CL stimulation in patients with impaired consciousness during TLE seizures showed significant improvement in behavioral outcomes in two of three patients, with one patient reaching their baseline performance comparable to non-seizure times. Overall, we found that stimulation of the thalamic CL in TLE patients increased arousal during both sleep and seizures. These findings demonstrate the potential of CL as a therapeutic target for mitigating impaired consciousness in TLE and can serve as a foundation for additional studies to test generalizability of CL stimulation effects on other disorders of consciousness.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy and is characterized by focal seizures originating from limbic structures, including the hippocampus. Patients with TLE often experience impaired consciousness. A recent awake mouse model study demonstrated decreased cortical cholinergic innervation during focal seizures with impaired consciousness, based on cortical slow wave activity and decreased behavioral responsiveness. But the underlying mechanisms for reduced cortical cholinergic activity are not fully understood. This study employs the same awake mouse model combined with electrophysiology recordings in key network nodes, cell-specific calcium imaging in the lateral septum, and neurotransmitter sensing in one of the major subcortical cholinergic systems, the nucleus basalis of Meynert (NBM). We demonstrate that decreased cortical cholinergic innervation during focal seizures comes from both direct inhibition and indirect de-excitation of the NBM, showing a parallel pathway NBM suppression mechanism from the LS directly and through the paratenial thalamic nucleus indirectly. This work contributes to a deeper understanding of the neural processes involved in impaired consciousness during focal seizures and may open the way to new treatments for this disorder.