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Blumenfeld, H.

Publications and source records attributed to Blumenfeld, H..

At least 19 recordsLinked to original sources

Measuring conscious tactile perception without report: pupil, blink, and microsaccade signatures of a tactile no-report paradigm

Conscious perception is often inferred from behavioral reports, which conflate awareness-related neural signals with the motor and decision processes required to respond. No-report paradigms address this by using spontaneous physiological signals, such as eye movements, to infer perception. Although our group developed a no-report visual paradigm, we had not applied this approach to touch. We developed a no-report tactile paradigm using the Galileo stimulation system to deliver pneumatic air puffs to non-thumb fingers on both hands while tracking eye movements. Participants reported sensations from the Report hand while receiving threshold-level puffs on both hands; eye metrics were used to infer perception in the No-Report hand. Perceived threshold-level stimuli elicited greater pupil dilation and more post-stimulus blinking than identical unperceived stimuli, with effects lasting 1 - 2 seconds. Microsaccade rate decreased after stimulus onset, but this suppression did not reach statistical significance. A stacked support vector machine trained on the Report eye-tracking measures was applied to classify No-Report trials and successfully separated [Predicted] Perceived from [Predicted] Not Perceived trials (AUC = .92; cross-validated accuracy = 72%; sensitivity = 90% at 80% specificity; label-permutation p < .001). These findings show that eye tracking can detect conscious tactile perception without overt responses and offer a noninvasive, scalable approach for studying tactile perception in patients with self-reported disabilities, including comatose or intubated patients.

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Interruption of rat absence seizures by auditory stimulation

Absence seizures are episodes of impaired consciousness and responsiveness that impact an individuals ability to interact with the world around them. Childhood absence epilepsy, a condition defined by these seizures, can have profound effects on childrens social, educational, and psychological development. Absence seizures are accompanied by a distinctive electrographic signature called a spike-wave discharge. The impairment of consciousness associated with a spike-wave discharge can be variable: some people maintain responsiveness during some absence seizures, and some rodent oscillations resembling spike-wave discharges may not have any behavioral impact. We previously observed that spike-wave discharges in the Genetic Absence Epilepsy Rat from Strasbourg model sometimes terminated shortly after presentation of a conditioned auditory stimulus. In this study we found that these terminations were caused by the stimuli and that they occurred after approximately 50% of stimuli. We also found that the probability of a spike-wave discharge being interrupted depended on stimulus timing, degree of conditioning, and electrographic signal power. These data provide insight into the factors that determine the mechanisms of absence seizure termination, with possible implications for therapy.

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Lateral septal inhibition of nucleus basalis through direct and indirect pathways in focal limbic seizures

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.

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Low and high frequency signatures of impaired consciousness in temporal lobe seizures

Impaired consciousness is a debilitating and unpredictable outcome of mesial temporal lobe seizures whose mechanisms to date remain unclear. Moreover, questions about the relationship between impaired consciousness and lateralization, hemispheric spread and electrophysiological characteristics of seizures are yet to be answered. To address these gaps, we conducted in-depth investigation of behavioral and intracranial EEG data from 186 mesial temporal lobe seizures of 51 patients with intractable mesial temporal lobe epilepsy. We found that bilateral mesial temporal spread of seizures is not a necessary condition for impaired consciousness, although seizures with bilateral mesial temporal involvement were significantly more likely to have impaired consciousness than unilateral seizures. Contrary to prior belief, we found no relationship between the onset side (left vs. right temporal lobe or language dominant vs. non-dominant lobe) of seizures and the probability of impaired consciousness. Lastly, we established that widespread increases in slow-wave activity (delta band) in extratemporal cortical areas, as well as increases in fast activity (beta band) in the temporal lobes were both robust markers of seizures with impaired consciousness and could predict ictal impairment with up to 86% accuracy. Our findings shed new light on networks that underlie impaired consciousness in temporal lobe epilepsy and may help guide deep brain stimulation of such systems (e.g. via thalamic nuclei) as a potential intervention to improve consciousness during seizures.

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Auditory Perception Induces Cortical and Thalamic Event-Related Desynchronization in the Mouse

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 (8-12Hz) and beta (12-30Hz) 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 (30-100Hz) 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 suggest that mice, like humans, process perceptual signals in hierarchically organized corticothalamic networks, and 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. Significance StatementAuditory-induced alpha/beta event-related desynchronizations (ERDs), decreases in cortical activity between 8 and 30Hz following auditory stimulus presentation, are thought to represent systems underlying higher perception and cognition. However, fundamental mechanistic studies are difficult in humans, the dominant organism for studying this phenomenon. In this study we assess mice as a potential alternative model organism. Our results demonstrate that mice exhibit auditory-induced alpha/beta ERDs, that this response is also present in subcortical regions of the mouse brain, and that the cortical ERD is largest and most strongly related to auditory stimulus amplitude in association cortex rather than in primary auditory cortex. These results support the efficacy of mice as an ideal model organism for further examination of alpha/beta ERDs.

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Widespread brain activity increases in frontal lobe seizures with impaired consciousness

Impaired consciousness is a serious clinical manifestation of epilepsy with negative consequences on quality of life. Little work has investigated impaired consciousness in frontal lobe seizures, a common form of focal epilepsy. In temporal lobe seizures, previous studies showed widespread cortical slow waves associated with depressed subcortical arousal and impaired consciousness. However, in frontal lobe epilepsy, it is not known whether cortical slow waves are present, or whether a very different cortical activity pattern may be related to impaired consciousness. We used intracranial EEG recordings of 65 frontal lobe seizures in 30 patients for quantitative analysis of ictal cortical activity and its relationship to impaired consciousness. Behavioral changes based on blinded review of seizure videos were used to classify focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Changes in intracranial EEG power from preictal baseline were analyzed in different cortical regions and across frequency ranges in these three categories. We found that frontal lobe focal aware seizures showed approximately 40% increases in intracranial EEG power localized to the frontal lobe of seizure onset across frequency ranges, with relatively smaller changes in other cortical regions. Frontal lobe focal impaired awareness seizures showed approximately 50% increases in intracranial EEG power, not significantly different from focal aware seizures in the frontal lobe of seizure onset (P = 1.038), but significantly greater than focal aware seizures in other broad cortical regions (P < 0.001). Importantly, the widespread cortical increases in EEG power observed in focal impaired awareness versus focal aware seizures were seen not just in the frequency range of slow waves, but were also observed across other frequencies including fast activity. However, the widespread cortical increases in focal impaired awareness seizures differed from focal to bilateral tonic-clonic seizures where intracranial EEG power increased to a much higher level by approximately 600%. The large power increases in focal to bilateral tonic-clonic were significantly greater than in focal impaired awareness seizures both in the frontal lobe of seizure onset and in other cortical regions (P < 0.001). Our findings contrast with focal temporal lobe epilepsy, where impaired consciousness is associated with cortical slow waves. We can speculate that different focal seizure types produce impaired consciousness by impacting widespread cortical regions but through different physiological mechanisms. Insights gained by studying mechanisms of impaired consciousness may be the first step towards developing novel treatments to prevent this important negative consequence of epilepsy.

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Shared subcortical arousal systems across sensory modalities during transient modulation of attention

Subcortical arousal systems are known to play a key role in controlling sustained changes in attention and conscious awareness. Recent studies indicate that these systems have a major influence on short-term dynamic modulation of visual attention, but their role across sensory modalities is not fully understood. In this study, we investigated shared subcortical arousal systems across sensory modalities during transient changes in attention using block and event-related fMRI paradigms. We analyzed massive publicly available fMRI datasets collected while 1,561 participants performed visual, auditory, tactile, and taste perception tasks. Our analyses revealed a shared circuit of subcortical arousal systems exhibiting early transient increases in activity in midbrain reticular formation and central thalamus across perceptual modalities, as well as less consistent increases in pons, hypothalamus, basal forebrain, and basal ganglia. Identifying these networks is critical for understanding mechanisms of normal attention and consciousness and may help facilitate subcortical targeting for therapeutic neuromodulation.

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Neural mechanisms of awareness of action

The origins of awareness of action (AoA), the ability to report an action just performed, remain elusive. Differing theories ascribe AoA to pre-action, efferent motor/volitional mechanisms versus post-action, afferent sensory/perceptual neural mechanisms. To study these two types of mechanisms and others, we developed a paradigm where very similar aware and unaware actions occur repeatedly. Aware actions demonstrated larger neurophysiological signals both preceding and following movement. The differences included well-known volitional and perceptual event related potentials (PMP, N140, P300), as well as frontal midline theta, event-related alpha/beta desynchronization, and post-move blink rates. On longer time scales, we identified a novel event related potential preceding unaware moves, and found behavioral and pupillometric evidence for decreased attention and arousal over minutes concurrent with AoA loss. Our findings suggest that both dynamic, individual action-associated volitional and perceptual neural activity, as well as long-term attention and arousal states play a role in maintaining AoA.

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The Neural Basis of Attentional Blink as a Selective Control Mechanism in Conscious Perception

Conscious perception of visual stimuli involves large-scale brain networks with multiple activation-deactivation dynamics. Previous works have shown that early detection networks may be switched off about 200ms to 300ms after presentation of a visual stimulus. We hypothesize that these deactivations represent a selective control mechanism of the brain to conserve resources for post-perceptual processing. To this end, we used attentional blink as a behavioral measure for this mechanism. We showed that attentional blink is more likely to occur when a previous visual stimulus was consciously perceived. Using high-resolution eye-tracking, we found prolonged decrease in pupil diameter and transient decrease in blink probability associated with attentional blink. Using scalp EEG data, we further showed that attentional blink is associated with more pronounced event-related potentials related to visual processing and report. One sentence summaryattentional blink may represent a selective control mechanism of neural processing resources underlying conscious perception.

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An adversarial collaboration to critically evaluate theories of consciousness

Different theories explain how subjective experience arises from brain activity1,2. These theories have independently accrued evidence, yet, confirmation bias and dependence on design choices hamper progress in the field3. Here, we present an open science adversarial collaboration which directly juxtaposes Integrated Information Theory (IIT)4,5 and Global Neuronal Workspace Theory (GNWT)6-10, employing a theory-neutral consortium approach11,12. We investigate neural correlates of the content and duration of visual experience. The theory proponents and the consortium developed and preregistered the experimental design, divergent predictions, expected outcomes, and their interpretation12. 256 human subjects viewed suprathreshold stimuli for variable durations while neural activity was measured with functional magnetic resonance imaging, magnetoencephalography, and electrocorticography. We find information about conscious content in visual, ventro-temporal and inferior frontal cortex, with sustained responses in occipital and lateral temporal cortex reflecting stimulus duration, and content-specific synchronization between frontal and early visual areas. These results confirm some predictions of IIT and GNWT, while substantially challenging both theories: for IIT, a lack of sustained synchronization within posterior cortex contradicts the claim that network connectivity specifies consciousness. GNWT is challenged by the general lack of ignition at stimulus offset and limited representation of certain conscious dimensions in prefrontal cortex. Beyond challenging the theories themselves, we present an alternative approach to advance cognitive neuroscience through a principled, theory-driven, collaborative effort. We highlight the challenges to change peoples mind 13 and the need for a quantitative framework integrating evidence for systematic theory testing and building.

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The neural activity of auditory conscious perception

Although recent work has made significant headway in understanding the temporal and spatial dynamics of the neural mechanisms of conscious perception, much of that work has focused on visual paradigms. To determine whether there are shared mechanisms for perceptual consciousness across sensory modalities, here we developed a task to test within the auditory domain. Participants (n=31) completed an auditory perceptual threshold task while undergoing intracranial electroencephalography (icEEG) for intractable epilepsy. Intracranial recordings from over 2,800 grey matter electrodes representing widespread cortical coverage were analyzed for power in the high gamma range (40-115 Hz)--a frequency range that reflects local neural activity. For trials that were perceived, we find activity in early auditory regions which is accompanied by activity in the right caudal middle frontal gyrus, and shortly thereafter by activity in non-auditory thalamus. This is followed by a wave of activity that sweeps through the higher auditory association regions and into parietal and frontal cortices, similar to the wave observed in our visual conscious perception paradigm. However, for not perceived trials, we find that significant activity is restricted to early auditory regions (and areas immediately adjacent to the Sylvian fissure). These findings show that the broad anatomical regions of cortical and subcortical networks involved in auditory perception are similar to the networks observed with vision, suggesting shared general mechanisms for conscious perception.

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Early neural activity changes associated with visual conscious perception

The neural mechanisms of visual conscious perception have been investigated for decades. However, the spatiotemporal dynamics associated with the earliest neural responses following consciously perceived stimuli are still poorly understood. Using a dataset of intracranial EEG recordings, the current study aims to investigate the neural activity changes associated with the earliest stages of visual conscious perception. Subjects (N=10, 1,693 grey matter electrode contacts) completed a continuous performance task in which individual letters were presented in series and subjects were asked to press a button when they saw a target letter. Broadband gamma power (40-115Hz) dynamics were analyzed in comparison to baseline prior to stimulus and contrasted for target trials with button presses and non-target trials without button presses. Regardless of event type, we observed early gamma power changes within 30-150 ms from stimulus onset in a network including increases in bilateral occipital, fusiform, frontal (including frontal eye fields), and medial temporal cortex, increases in left lateral parietal-temporal cortex, and decreases in the right anterior medial occipital cortex. No significant differences were observed between target and non-target stimuli until >150 ms post-stimulus, when we saw greater gamma power increases in left motor and premotor areas, suggesting a possible role of these later signals in perceptual decision making and/or motor responses with the right hand. The early gamma power findings suggest a broadly distributed cortical visual detection network that is engaged at early times tens of milliseconds after signal transduction from the retina.

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More than a feeling: scalp EEG and eye correlates of conscious tactile perception

Understanding the neural basis of consciousness is a fundamental goal of neuroscience. Many of the studies tackling this question have focused on conscious perception, but these studies have been largely vision-centric, with very few involving tactile perception. Therefore, we developed a novel tactile threshold perception task, which we used in conjunction with high-density scalp electroencephalography and eye-metric recordings. Participants were delivered threshold-level vibrations to one of the four non-thumb fingers, and were asked to report their perception using a response box. With false discovery rate (FDR) mass univariate analysis procedures, we found significant event-related potentials (ERP) including bilateral N140 and P300 for perceived vibrations; significant bilateral P100 and P300 were found following vibrations that were not perceived. Significant differences between perceived and not perceived trials were found bilaterally in the N140 and P300. Additionally, we found that pupil diameter and blink rate increased and that microsaccade rate decreased following vibrations that were perceived relative to those that were not perceived. While many of the signals are consistent with similar ERP-findings across sensory modalities, our results indicating a significant P300 in not perceived trials raise more questions regarding P300s perceptual meaning. Additionally, our findings support the use of eye metrics as a measure of physiological arousal as pertains to conscious perception, and may represent a novel path toward the creation of tactile no-report tasks in the future. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/466706v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@e4e7fforg.highwire.dtl.DTLVardef@3b3ed0org.highwire.dtl.DTLVardef@198d517org.highwire.dtl.DTLVardef@cddef3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA novel tactile perceptual threshold task yields robust behavioral results C_LIO_LIEvent-related potentials differ according to perception status C_LIO_LIP300 is observed in both perceived and not perceived trials C_LIO_LIBlink rate, pupil diameter, and microsaccades differ across trial conditions C_LI

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Brain networks in human conscious visual perception

Consciousness is not explained by a single mechanism, rather it involves multiple specialized neural systems overlapping in space and time. We hypothesize that synergistic, large-scale subcortical and cortical attention and signal processing networks encode conscious experiences. To identify brain activity in conscious perception without overt report, we classified visual stimuli as perceived or not using eye measurements. Report-independent event-related potentials and functional magnetic resonance imaging (fMRI) signals both occurred at early times after stimuli. Direct recordings revealed a novel thalamic awareness potential linked to conscious visual perception based on report. fMRI showed thalamic and cortical detection, arousal, attentional salience, task-positive, and default mode networks were involved independent of overt report. These findings identify a specific sequence of neural mechanisms in human conscious visual perception. One-Sentence SummaryHuman conscious visual perception engages large-scale subcortical and cortical networks even without overt report.

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Distinct signatures of loss of consciousness during Focal Impaired Awareness (FIA) versus Focal to Bilateral Tonic-Clonic (FBTC) seizures

Loss of consciousness (LOC) is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany LOC during focal impaired awareness (FIA) seizures, the mechanisms of LOC during focal to bilateral tonic-clonic (FBTC) seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between FIA and FBTC seizures may also help to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies. We quantified clinical signs of LOC and intracranial EEG (iEEG) activity during 129 FIA and 50 FBTC from 41 patients. We characterized iEEG changes both in the seizure onset zone (SOZ) and in areas remote from SOZ with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of iEEG sleep-like activities: slow-wave activity (SWA; 1-4 Hz) and beta/delta ratio (B/D; a validated marker of cortical activation) during FIA vs. FBTC. Second, we quantified differences between FBTC and FIA for a marker validated to detect ictal cross-frequency coupling: phase-locked high-gamma (PLHG; high gamma phased locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index (i.e. the number of channels crossing an energy ratio threshold for high vs. low frequency power). Third, we assessed changes in iEEG activity preceding and accompanying behavioral generalization onset and their correlation with electromyogram (EMG) channels. In addition, we analyzed human cortical multi-unit activity recorded with Utah arrays during three FBTC. Compared to FIA, FBTC seizures were characterized by deeper LOC and by stronger increases in SWA in parieto-occipital cortex. FBTC also displayed more widespread increases in cortical activation (B/D), ictal cross-frequency coupling (PLHG) and ictal recruitment (epileptogenicity index). Even before generalization, FBTC displayed deeper LOC; this early LOC was accompanied by a paradoxical increase in B/D in fronto-parietal cortex. Behavioral generalization coincided with complete loss of responsiveness and a subsequent increase in high-gamma in the whole brain, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of FBTC revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the SOZ. Unlike during FIA, LOC during FBTC is characterized by a paradoxical increase in cortical activation and neuronal firing. These findings suggest differences in the mechanisms of ictal LOC between FIA and FBTC and may account for the more negative prognostic consequences of FBTC.

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A novel mouse model of focal limbic seizures that reproduces behavioral impairment associated with cortical slow wave activity

Patients with focal temporal lobe seizures often experience loss of consciousness. In humans, this loss of consciousness has been shown to be positively correlated with EEG neocortical slow waves, similar to those seen in non-REM sleep. Previous work in rat models of temporal lobe seizures suggests that decreased activity of subcortical arousal systems cause depressed cortical function during seizures. However, these studies were performed under light anesthesia, making it impossible to correlate behavior, and therefore consciousness, to electrophysiologic data. Further, the genetic and molecular toolkits allowing for precise study of the underlying neural circuitry are much more developed in mice than in rats. Here, we describe an awake-behaving, head-fixed mouse model of temporal lobe seizures with both spared and impaired behavior reflecting level of consciousness. Water-restricted mice were head-fixed on a running wheel and trained to associate an auditory stimulus to the delivery of a drop of water from a dispenser. To investigate the effect of seizures on behavior, seizures were electrically induced by stimulating either the left or right hippocampus via a chronically-implanted electrode, while mice were performing the task. Behavior was measured by monitoring lick responses to the auditory stimulus and running speed on the wheel. Further, local field potentials (LFP) signals were simultaneously recorded from hippocampus and orbitofrontal cortex (OFC). Induced focal seizures were 5-30s in duration, and repeatable for several weeks (n=20 animals). Behavioral responses showed a decrease in lick rate to auditory stimulus, and decreased running speed during seizures (p<0.01, n=20 animals). Interestingly, licking response to sound could vary from being impaired to normal during seizures. We found that behavioral impairment is correlated with large amplitude cortical slow-wave activity in frontal cortex, as seen in patients with temporal lobe seizures. These results suggest that induced focal limbic seizures in the mouse can impair consciousness and that the impaired consciousness is correlated with depressed cortical function resembling slow wave sleep. This novel mouse model has similar characteristics with previously studied rat models and human temporal lobe seizures. By leveraging the genetic and molecular techniques available in the mouse, this model can be used to further uncover fundamental mechanisms for loss of consciousness in focal seizures.

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Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

Absence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

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