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1.  Consciousness as a useful concept in epilepsy classification 
Epilepsia  2014;55(8):1145-1150.
Impaired consciousness has important practical consequences for people living with epilepsy. Recent pathophysiologic studies show that seizures with impaired level of consciousness always affect widespread cortical networks and subcortical arousal systems. In light of these findings and their clinical significance, efforts are underway to revise the International League Against Epilepsy (ILAE) 2010 report to include impaired consciousness in the classification of seizures. Lüders and colleagues have presented one such effort, which we discuss here. We then propose an alternative classification of impaired consciousness in epilepsy based on functional neuroanatomy. Some seizures involve focal cortical regions and cause selective deficits in the content of consciousness but without impaired overall level of consciousness or awareness. These include focal aware conscious seizures (FACS) with lower order cortical deficits such as somatosensory or visual impairment as well as FACS with higher cognitive deficits including ictal aphasia or isolated epileptic amnesia. Another category applies to seizures with impaired level of consciousness leading to deficits in multiple cognitive domains. For this category, we believe the terms “dyscognitive” or “dialeptic” should be avoided because they may create confusion. Instead we propose that seizures with impaired level of consciousness be described based on underlying pathophysiology. Widespread moderately severe deficits in corticothalamic function are seen in absence seizures and in focal impaired consciousness seizures (FICS), including many temporal lobe seizures and other focal seizures with impaired consciousness. Some simple responses or automatisms may be preserved in these seizures. In contrast, generalized tonic–clonic seizures usually produce widespread severe deficits in corticothalamic function causing loss of all meaningful responses. Further work is needed to understand and prevent impaired consciousness in epilepsy, but the first step is to keep this crucial practical and physiologic aspect of seizures front-and-center in our discussions.
PMCID: PMC4149314  PMID: 24981294
Epilepsy; Consciousness; Complex partial seizures; Simple partial seizures; Absence seizures; Generalized tonic–clonic seizures; Classification
2.  Consciousness and epilepsy: why are complex-partial seizures complex? 
Progress in brain research  2009;177:147-170.
Why do complex-partial seizures in temporal lobe epilepsy (TLE) cause a loss of consciousness? Abnormal function of the medial temporal lobe is expected to cause memory loss, but it is unclear why profoundly impaired consciousness is so common in temporal lobe seizures. Recent exciting advances in behavioral, electrophysiological, and neuroimaging techniques spanning both human patients and animal models may allow new insights into this old question. While behavioral automatisms are often associated with diminished consciousness during temporal lobe seizures, impaired consciousness without ictal motor activity has also been described. Some have argued that electrographic lateralization of seizure activity to the left temporal lobe is most likely to cause impaired consciousness, but the evidence remains equivocal. Other data correlates ictal consciousness in TLE with bilateral temporal lobe involvement of seizure spiking. Nevertheless, it remains unclear why bilateral temporal seizures should impair responsiveness. Recent evidence has shown that impaired consciousness during temporal lobe seizures is correlated with large-amplitude slow EEG activity and neuroimaging signal decreases in the frontal and parietal association cortices. This abnormal decreased function in the neocortex contrasts with fast polyspike activity and elevated cerebral blood flow in limbic and other subcortical structures ictally. Our laboratory has thus proposed the “network inhibition hypothesis,” in which seizure activity propagates to subcortical regions necessary for cortical activation, allowing the cortex to descend into an inhibited state of unconsciousness during complex-partial temporal lobe seizures. Supporting this hypothesis, recent rat studies during partial limbic seizures have shown that behavioral arrest is associated with frontal cortical slow waves, decreased neuronal firing, and hypometabolism. Animal studies further demonstrate that cortical deactivation and behavioral changes depend on seizure spread to subcortical structures including the lateral septum. Understanding the contributions of network inhibition to impaired consciousness in TLE is an important goal, as recurrent limbic seizures often result in cortical dysfunction during and between epileptic events that adversely affects patients’ quality of life.
PMCID: PMC2901990  PMID: 19818900
cortex; EEG; fMRI; septal nuclei; slow waves; attention; temporal lobe epilepsy; thalamus
3.  Impaired consciousness in temporal lobe seizures: role of cortical slow activity 
Brain  2010;133(12):3764-3777.
Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a ‘network inhibition hypothesis’ in which temporal lobe seizures disrupt brainstem–diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1–2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.
PMCID: PMC2995886  PMID: 21081551
cortex; EEG; seizures; temporal lobe epilepsy; consciousness
4.  Impaired Consciousness in Epilepsy 
Lancet neurology  2012;11(9):814-826.
Consciousness is essential to normal human life. In epileptic seizures consciousness is often transiently lost making it impossible for the individual to experience or respond. This has huge consequences for safety, productivity, emotional health and quality of life. To prevent impaired consciousness in epilepsy it is necessary to understand the mechanisms leading to brain dysfunction during seizures. Normally the “consciousness system”—a specialized set of cortical-subcortical structures—maintains alertness, attention and awareness. Recent advances in neuroimaging, electrophysiology and prospective behavioral testing have shed new light on how epileptic seizures disrupt the consciousness system. Diverse seizure types including absence, generalized tonic-clonic and complex partial seizures converge on the same set of anatomical structures through different mechanisms to disrupt consciousness. Understanding these mechanisms may lead to improved treatment strategies to prevent impaired consciousness and improve quality of life in people with epilepsy.
PMCID: PMC3732214  PMID: 22898735
5.  Impaired consciousness in partial seizures is bimodally distributed 
Neurology  2014;82(19):1736-1744.
To investigate whether impaired consciousness in partial seizures can usually be attributed to specific deficits in the content of consciousness or to a more general decrease in the overall level of consciousness.
Prospective testing during partial seizures was performed in patients with epilepsy using the Responsiveness in Epilepsy Scale (n = 83 partial seizures, 30 patients). Results were compared with responsiveness scores in a cohort of patients with severe traumatic brain injury evaluated with the JFK Coma Recovery Scale–Revised (n = 552 test administrations, 184 patients).
Standardized testing during partial seizures reveals a bimodal scoring distribution, such that most patients were either fully impaired or relatively spared in their ability to respond on multiple cognitive tests. Seizures with impaired performance on initial test items remained consistently impaired on subsequent items, while other seizures showed spared performance throughout. In the comparison group, we found that scores of patients with brain injury were more evenly distributed across the full range in severity of impairment.
Partial seizures can often be cleanly separated into those with vs without overall impaired responsiveness. Results from similar testing in a comparison group of patients with brain injury suggest that the bimodal nature of Responsiveness in Epilepsy Scale scores is not a result of scale bias but may be a finding unique to partial seizures. These findings support a model in which seizures either propagate or do not propagate to key structures that regulate overall arousal and thalamocortical function. Future investigations are needed to relate these behavioral findings to the physiology underlying impaired consciousness in partial seizures.
PMCID: PMC4032205  PMID: 24727311
6.  The default mode network and altered consciousness in epilepsy 
Behavioural neurology  2011;24(1):55-65.
The default mode network has been hypothesized following the observation that specific regions of the brain are consistently activated during the resting state and deactivated during engagement with task. The primary nodes of this network, which typically include the precuneus / posterior cingulate, the medial frontal and lateral parietal cortices, are thought to be involved in introspective and social cognitive functions. Interestingly, this same network has been shown to be selectively impaired during epileptic seizures associated with loss of consciousness. Using a wide range of neuroimaging and electrophysiological modalities, decreased activity in the default state has been confirmed during complex partial, generalized tonic-clonic, and absence seizures. In this review we will discuss these three seizure types and will focus on possible mechanisms by which decreased default mode network activity occurs. Although the specific mechanisms of onset and propagation differ considerably across these seizure types, we propose that the resulting loss of consciousness in all three types of seizures is due to active inhibition of subcortical arousal systems that normally maintain default mode network activity in the awake state. Further, we suggest that these findings support a general “network inhibition hypothesis,” by which active inhibition of arousal systems leads to cortical deactivation resembling other states of reduced consciousness.
PMCID: PMC3150226  PMID: 21447899
Epilepsy; Consciousness; Default Mode Network
7.  Testing for Minimal Consciousness in Complex Partial and Generalized Tonic-Clonic Seizures 
Epilepsia  2012;53(10):e180-e183.
Impaired consciousness in epilepsy has a major negative impact on quality of life. Prior work suggests that complex partial seizures (CPS) and generalized tonic-clonic seizures (GTCS), which both cause loss of consciousness, affect similar fronto-parietal networks. Milder involvement in CPS than in GTCS may spare some simple behavioral responses, resembling the minimally conscious state. However, this difference in responses has not been rigorously tested previously. During video/EEG monitoring, we administered a standardized prospective testing battery including responses to questions and commands, as well as tests for reaching/grasping a ball and visual tracking in 27 CPS (14 patients) and 7 GTCS (6 patients). Behavioral results were analyzed in the ictal and post-ictal periods based on video review. During both CPS and GTCS, patients were unable to respond to questions or commands. However, during CPS patients often retain minimally conscious ball grasping and visual tracking responses. Patients were able to successfully grasp a ball in 60% or to visually track in 58% of CPS, and could carry out both activities in 52% of CPS. In contrast, during GTCS preserved ball grasp (10%), visual tracking (11%) or both (7%) were all significantly less than in CPS. Post-ictal ball grasping and visual tracking were also somewhat better following CPS than GTCS. These findings suggest that impaired consciousness in CPS is more similar to minimally conscious state than to coma. Further work may elucidate the specific brain networks underlying relatively spared functions in CPS, ultimately leading to improved treatments aimed at preventing impaired consciousness.
PMCID: PMC3463733  PMID: 22931210
Consciousness; Epilepsy; Complex Partial Seizures; Generalized Tonic-Clonic Seizures; Visual Tracking; Minimally Conscious State; Vegetative State
8.  Impaired consciousness in epilepsy investigated by a prospective responsiveness in epilepsy scale (RES) 
Epilepsia  2011;53(3):437-447.
Impaired consciousness in epileptic seizures has a major negative impact on patient quality of life. Prior work on epileptic unconsciousness has mainly used retrospective and nonstandardized methods. Our goal was to validate and to obtain initial data using a standardized prospective testing battery.
The responsiveness in epilepsy scale (RES) was used on 52 patients during continuous video/EEG monitoring. RES begins with higher-level questions and commands, and switches adaptively to more basic sensorimotor responses depending on patient performance. RES continues after seizures and includes postictal memory testing. Scoring was conducted based on video review.
Key Findings
Testing on standardized seizure simulations yielded good intra-rater and inter-rater reliability. We captured 59 seizures from 18 patients (35% of participants) during 1420 hours of RES monitoring. RES impairment was greatest during and after tonic-clonic seizures, less in partial seizures, and minimal in auras and subclinical seizures. In partial seizures, ictal RES impairment was significantly greater if EEG changes were present. Maximum RES impairment (lowest ictal score) was also significantly correlated with long postictal recovery time, and poor postictal memory.
We found that prospective testing of responsiveness during seizures is feasible and reliable. RES impairment was related to EEG changes during seizures, as well as to postictal memory deficits and recovery time. With a larger patient sample it is hoped that this approach can identify brain networks underlying specific components of impaired consciousness in seizures. This may allow the development of improved treatments targeted at preventing dysfunction in these networks.
PMCID: PMC3741051  PMID: 22150524
Consciousness; Seizure; Behavior; Testing battery; Electroencephalography; Video/EEG monitoring
9.  Is There a Relation between EEG-Slow Waves and Memory Dysfunction in Epilepsy? A Critical Appraisal 
Is there a relationship between peri-ictal slow waves, loss of consciousness, memory, and slow-wave sleep, in patients with different forms of epilepsy? We hypothesize that mechanisms, which result in peri-ictal slow-wave activity as detected by the electroencephalogram, could negatively affect memory processes. Slow waves (≤4 Hz) can be found in seizures with impairment of consciousness and also occur in focal seizures without impairment of consciousness but with inhibited access to memory functions. Peri-ictal slow waves are regarded as dysfunctional and are probably caused by mechanisms, which are essential to disturb the consolidation of memory entries in these patients. This is in strong contrast to physiological slow-wave activity during deep sleep, which is thought to group memory-consolidating fast oscillatory activity. In patients with epilepsy, slow waves may not only correlate with the peri-ictal clouding of consciousness, but could be the epiphenomenon of mechanisms, which interfere with normal brain function in a wider range. These mechanisms may have transient impacts on memory, such as temporary inhibition of memory systems, altered patterns of hippocampal–neocortical interactions during slow-wave sleep, or disturbed cross-frequency coupling of slow and fast oscillations. In addition, repeated tonic–clonic seizures over the years in uncontrolled chronic epilepsy may cause a progressive cognitive decline. This hypothesis can only be assessed in long-term prospective studies. These studies could disentangle the reversible short-term impacts of seizures, and the impacts of chronic uncontrolled seizures. Chronic uncontrolled seizures lead to irreversible memory impairment. By contrast, short-term impacts do not necessarily lead to a progressive cognitive decline but result in significantly impaired peri-ictal memory performance.
PMCID: PMC4463866  PMID: 26124717
epilepsy; memory; slow waves; consciousness; sleep; seizure
10.  Spectral and spatial shifts of post-ictal slow waves in temporal lobe seizures 
Brain  2012;135(10):3134-3143.
Temporal lobe seizures have a significant chance to induce impairment of normal brain functions. Even after the termination of ictal discharges, during the post-ictal period, loss of consciousness, decreased responsiveness or other cognitive dysfunctions can persist. Previous studies have found various anatomical and functional abnormalities accompanying temporal lobe seizures, including an abnormal elevation of cortical slow waves. Intracranial electroencephalography studies have shown a prominent increase of lower frequency components during and following seizures that impair (complex partial seizures) but not those that preserve (simple partial seizures) normal consciousness and responsiveness. However, due to the limited spatial coverage of intracranial electroencephalography, the investigation of cortical slow waves cannot be easily extended to the whole brain. In this study, we used scalp electroencephalography to study the spectral features and spatial distribution of post-ictal slow waves with comprehensive spatial coverage. We studied simple partial, complex partial and secondarily generalized seizures in 28 patients with temporal lobe seizures. We used dense-array electroencephalography and source imaging to reconstruct the post-ictal slow-wave distribution. In the studied cohort, we found that a ‘global’ spectral power shift to lower frequencies accompanied the increased severity of seizures. The delta spectral power relative to higher frequency bands was highest for secondarily generalized seizures, followed by complex partial seizures and lastly simple partial seizures. In addition to this ‘global’ spectral shift, we found a ‘regional’ spatial shift in slow-wave activity. Secondarily generalized seizures and complex partial seizures exhibited increased slow waves distributed to frontal areas with spread to contralateral temporal and parietal regions than in simple partial seizures. These results revealed that a widespread cortical network including temporal and fronto-parietal cortex is involved in abnormal slow-wave activity following temporal lobe seizures. The differential spectral and spatial shifts of post-ictal electroencephalography activity in simple partial, complex partial and secondarily generalized seizures suggest a possible connection between cortical slow waves and behavioural and cognitive changes in a human epilepsy model.
PMCID: PMC3470709  PMID: 22923634
cortical slowing; temporal lobe seizure; post-ictal state; consciousness; responsiveness
11.  Simultaneous EEG, fMRI, and Behavior in Typical Childhood Absence Seizures 
Epilepsia  2010;51(10):2011-2022.
Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3–4 Hz spike-wave discharges (SWD) on EEG. Prior EEG-fMRI studies of SWD have shown a network of cortical and subcortical changes during these electrical events. However, fMRI during typical childhood absence seizures with confirmed impaired consciousness has not been previously investigated.
We performed EEG-fMRI with simultaneous behavioral testing in 37 children with typical childhood absence epilepsy. Attentional vigilance was evaluated by a continuous performance task (CPT), and simpler motor performance was evaluated by a repetitive tapping task (RTT).
SWD episodes were obtained during fMRI scanning from 9 patients among the 37 studied. fMRI signal increases during SWD were observed in the thalamus, frontal cortex, primary visual, auditory, somatosensory, and motor cortex, and fMRI decreases were seen in the lateral and medial parietal cortex, cingulate gyrus, and basal ganglia. Omission error rate (missed targets) with SWD during fMRI was 81% on CPT and 39% on RTT. For those seizure epochs during which CPT performance was impaired, fMRI changes were seen in cortical and subcortical structures typically involved in SWD, while minimal changes were observed for the few epochs during which performance was spared.
These findings suggest that typical absence seizures involve a network of cortical-subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in childhood absence epilepsy, and help guide development of new therapies for this disorder.
PMCID: PMC2953613  PMID: 20608963
epilepsy; attention; consciousness; thalamus; BOLD; spike-wave
12.  Cortical deactivation induced by subcortical network dysfunction in limbic seizures 
Normal human consciousness may be impaired by two possible routes: direct reduced function in widespread cortical regions, or indirect disruption of subcortical activating systems. The route through which temporal lobe limbic seizures impair consciousness is not known. We recently developed an animal model which, like human limbic seizures, exhibits neocortical deactivation including cortical slow waves and reduced cortical cerebral blood flow (CBF). We now find through functional MRI (fMRI) that electrically-stimulated hippocampal seizures in rats cause increased activity in subcortical structures including the septal area and mediodorsal thalamus, along with reduced activity in frontal, cingulate, and retrosplenial cortex. Direct recordings from the hippocampus, septum, and medial thalamus demonstrated fast poly-spike activity associated with increased neuronal firing and CBF, while frontal cortex showed slow oscillations with decreased neuronal firing and CBF. Stimulation of septal area, but not hippocampus or medial thalamus, in the absence of a seizure resulted in cortical deactivation with slow oscillations and behavioral arrest, resembling changes seen during limbic seizures. Transecting the fornix, the major route from hippocampus to subcortical structures, abolished the negative cortical and behavioral effects of seizures. Cortical slow oscillations and behavioral arrest could be reconstituted in fornix-lesioned animals by inducing synchronous activity in the hippocampus and septal area, implying involvement of a downstream region converged upon by both structures. These findings suggest that limbic seizures may cause neocortical deactivation indirectly, through impaired subcortical function. If confirmed, subcortical networks may represent a target for therapies aimed at preserving consciousness in human temporal lobe seizures.
PMCID: PMC2778759  PMID: 19828814
consciousness; fMRI; fornix; hippocampus; slow oscillations; septum; temporal lobe epilepsy
13.  Cortical and subcortical networks in human secondarily generalized tonic–clonic seizures 
Brain  2009;132(4):999-1012.
Generalized tonic–clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the ‘default mode’ regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic–clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic–clonic seizures. Understanding the networks involved in generalized tonic–clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.
PMCID: PMC2724910  PMID: 19339252
default mode; cerebellum; thalamus; SPECT; epilepsy
14.  Dynamic timecourse of typical childhood absence seizures: EEG, behavior and fMRI 
Absence seizures are 5–10 second episodes of impaired consciousness accompanied by 3–4Hz generalized spike-and-wave discharge on electroencephalography (EEG). The timecourse of functional magnetic resonance imaging (fMRI) changes in absence seizures in relation to EEG and behavior is not known. We acquired simultaneous EEG-fMRI in 88 typical childhood absence seizures from 9 pediatric patients. We investigated behavior concurrently using a continuous performance task (CPT) or simpler repetitive tapping task (RTT). EEG time-frequency analysis revealed abrupt onset and end of 3–4 Hz spike-wave discharges with a mean duration of 6.6 s. Behavioral analysis also showed rapid onset and end of deficits associated with electrographic seizure start and end. In contrast, we observed small early fMRI increases in the orbital/medial frontal and medial/lateral parietal cortex >5s before seizure onset, followed by profound fMRI decreases continuing >20s after seizure end. This timecourse differed markedly from the hemodynamic response function (HRF) model used in conventional fMRI analysis, consisting of large increases beginning after electrical event onset, followed by small fMRI decreases. Other regions, such as the lateral frontal cortex, showed more balanced fMRI increases followed by approximately equal decreases. The thalamus showed delayed increases after seizure onset followed by small decreases, most closely resembling the HRF model. These findings reveal a complex and long lasting sequence of fMRI changes in absence seizures, which are not detectible by conventional HRF modeling in many regions. These results may be important mechanistically for seizure initiation and termination and may also contribute to changes in EEG and behavior.
PMCID: PMC2946206  PMID: 20427649
EEG-fMRI; Thalamus; Absence epilepsy; HRF; Attention; Orbitofrontal cortex
15.  Remote effects of focal hippocampal seizures on the rat neocortex 
Seizures have both local and remote effects on nervous system function. While propagated seizures are known to disrupt cerebral activity, little work has been done on remote network effects of seizures that do not propagate. Human focal temporal lobe seizures demonstrate remote changes including slow waves on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. Ictal neocortical slow waves have been interpreted as seizure propagation, however we hypothesize that they reflect a depressed cortical state resembling sleep or coma. To investigate this hypothesis, we performed multi-modal studies of partial and secondarily-generalized limbic seizures in rats. Video/EEG monitoring of spontaneous seizures revealed slow waves in the frontal cortex during behaviorally mild partial seizures, contrasted with fast poly-spike activity during convulsive generalized seizures. Seizures induced by hippocampal stimulation produced a similar pattern, and were used to perform functional magnetic resonance imaging (fMRI) weighted for blood oxygenation (BOLD) and blood volume (CBV), demonstrating increased signals in hippocampus, thalamus and septum, but decreases in orbitofrontal, cingulate, and retrosplenial cortex during partial seizures; and increases in all these regions during propagated seizures. Combining these results with neuronal recordings and CBF measurements, we related neocortical slow waves to reduced neuronal activity and cerebral metabolism during partial seizures, but found increased neuronal activity and metabolism during propagated seizures. These findings suggest that ictal neocortical slow waves represent an altered cortical state of depressed function, not propagated seizure activity. This remote effect of partial seizures may cause impaired cerebral functions, including loss of consciousness.
PMCID: PMC2590649  PMID: 18768701
consciousness; BOLD decreases; cortex; fMRI; slow oscillations; temporal lobe epilepsy
16.  Association of Human Herpesvirus-6B with Mesial Temporal Lobe Epilepsy 
PLoS Medicine  2007;4(5):e180.
Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)–positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.
Methods and Findings
HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive—the first demonstration of an ex vivo HHV-6–infected astrocyte culture isolated from HHV-6–positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.
Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.
Steve Jacobson and colleagues report finding human herpesvirus-6B DNA in brain resections from 11 of 16 patients with mesial temporal lobe epilepsy, strengthening the evidence for a role for this virus in this condition.
Editors' Summary
Epilepsy is a common brain disorder caused by a sudden, excessive electrical discharge in a cluster of neurons—the cells that transmit electrical messages between the body and the brain. Its symptoms depend on which part of the brain is affected by this electrical firestorm and how far the disturbance spreads. When only part of the brain is affected (a partial seizure or fit), patients may see or smell strange things, recall forgotten memories, or have part of their body jerk uncontrollably. When the electrical disturbance spreads across the whole brain (a generalized seizure), there may be loss of consciousness and/or the whole body may become rigid or jerk. Epilepsy is usually controlled with anti-epileptic drugs or, in very severe focal cases, surgery to the area of the brain where the seizure starts. Although head injuries or brain tumors can trigger epilepsy, the cause of most cases of epilepsy is unknown.
Why Was This Study Done?
Knowing what causes epilepsy might lead to better treatments for it. One possibility is that infections trigger epilepsy. The researchers in this study asked whether infections with human herpesvirus 6B (HHV-6B) are associated with a common type of epilepsy called mesial temporal lobe epilepsy (MTLE). Patients with MTLE often have extensive scarring in the hippocampus, a brain region responsible for memory that lies deep within a bigger region called the temporal lobe. Hippocampal scarring and MTLE are associated with a history of fever-induced fits, and HHV-6B infection can cause such fits in young children. Most people become infected with HHV-6B (or the closely related HHV-6A) early in life. The virus then remains latent for years within the brain and elsewhere. Given these facts and a previous investigation that showed that brain tissue from several patients with MTLE contained HHV-6B, the researchers reasoned that it was worth investigating HHV-6B as a cause of MTLE.
What Did the Researchers Do and Find?
The researchers first looked for HHV-6B DNA in brain tissue surgically removed from patients with MTLE or another type of epilepsy. Tissue from 11 of 16 patients with MTLE (but from 0 of 7 control patients) contained HHV-6B DNA. When the researchers grew astrocytes (a type of brain cell) from some of these samples, only those from HHV-6B DNA-positive samples from patients with MTLE expressed an HHV-6-specific protein. Next, the researchers investigated in detail a patient with MTLE who had four sequential operations to control his epilepsy. This patient's hippocampus, which was removed in his first operation, contained a higher level of HHV-6B DNA than the tissues removed in later operations. After the fourth operation (which removed half of his brain and cured his epilepsy), astrocytes grown from the temporal lobe and the frontal/parietal lobe (a brain region next to the temporal lobe) but not the frontal and occipital lobes contained HHV-6B DNA and expressed a viral protein. The researchers also measured the production by these various astrocytes of a substance that moves glutamate (an amino acid that also acts as a neurotransmitter) across cell membranes—MTLE has been associated with a glutamate transporter deficiency. Consistent with this, astrocytes from the patient's temporal lobe made no glutamate transporter mRNA (mRNA is an essential precursor for protein to be produced). Finally, infection of astrocytes isolated from a patient without MTLE with HHV-6B greatly reduced expression of glutamate transporter in these astrocytes.
What Do These Findings Mean?
These findings, together with those from the previous study, reveal that nearly two-thirds of patients with MTLE (but no patients with other forms of epilepsy) have an active HHV-6B infection in the brain region where their epilepsy originates. Overall, they provide strong support for the idea that HHV-6B infections might cause MTLE, particularly given the results obtained from the patient whose condition only improved after multiple brain operations had removed all the virally infected material. Furthermore, the demonstration that HHV-6B infection reduces glutamate transporter expression in astrocytes suggests that HHV-6B infection might cause astrocyte dysfunction. This dysfunction could lead to injury of the sensitive neurons in the hippocampus and trigger MTLE. Additional patients now need to be studied both to confirm the association between HHV-6B infection and MTLE and to discover exactly how this virus triggers epilepsy.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia page on epilepsy (in English and Spanish)
World Health Organization fact sheet on epilepsy (in English, French, Spanish, Russian, Arabic, and Chinese)
US National Institute for Neurological Disorders and Stroke epilepsy information page (in English and Spanish)
UK National Health Service Direct information for patients on epilepsy (in several languages)
Neuroscience for kids, an educational Web site prepared by Eric Chudler (University of Washington, Seattle, Washington, United States), who also has a site that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
A short scientific article on human herpes virus 6 in the journal Emerging Infectious Diseases
PMCID: PMC1880851  PMID: 17535102
17.  Animal models of epilepsy: use and limitations 
Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Comprehension of the complex mechanisms underlying epileptogenesis and seizure generation in temporal lobe epilepsy and other forms of epilepsy cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Some of these models replicate the natural history of symptomatic focal epilepsy with an initial epileptogenic insult, which is followed by an apparent latent period and by a subsequent period of chronic spontaneous seizures. Seizures are a combination of electrical and behavioral events that are able to induce chemical, molecular, and anatomic alterations. In this review, we summarize the most frequently used models of chronic epilepsy and models of acute seizures induced by chemoconvulsants, traumatic brain injury, and electrical or sound stimuli. Genetic models of absence seizures and models of seizures and status epilepticus in the immature brain were also examined. Major uses and limitations were highlighted, and neuropathological, behavioral, and neurophysiological similarities and differences between the model and the human equivalent were considered. The quest for seizure mechanisms can provide insights into overall brain functions and consciousness, and animal models of epilepsy will continue to promote the progress of both epilepsy and neurophysiology research.
PMCID: PMC4164293  PMID: 25228809
epilepsy; animal model; pilocarpine; kindling; neurodevelopment
18.  On the Neural Mechanisms Subserving Consciousness and Attention 
Consciousness, as described in the experimental literature, is a multi-faceted phenomenon, that impinges on other well-studied concepts such as attention and control. Do consciousness and attention refer to different aspects of the same core phenomenon, or do they correspond to distinct functions? One possibility to address this question is to examine the neural mechanisms underlying consciousness and attention. If consciousness and attention pertain to the same concept, they should rely on shared neural mechanisms. Conversely, if their underlying mechanisms are distinct, then consciousness and attention should be considered as distinct entities. This paper therefore reviews neurophysiological facts arguing in favor or against a tight relationship between consciousness and attention. Three neural mechanisms that have been associated with both attention and consciousness are examined (neural amplification, involvement of the fronto-parietal network, and oscillatory synchrony), to conclude that the commonalities between attention and consciousness at the neural level may have been overestimated. Last but not least, experiments in which both attention and consciousness were probed at the neural level point toward a dissociation between the two concepts. It therefore appears from this review that consciousness and attention rely on distinct neural properties, although they can interact at the behavioral level. It is proposed that a “cumulative influence model,” in which attention and consciousness correspond to distinct neural mechanisms feeding a single decisional process leading to behavior, fits best with available neural and behavioral data. In this view, consciousness should not be considered as a top-level executive function but should rather be defined by its experiential properties.
PMCID: PMC3253412  PMID: 22291674
attention; consciousness; vision; imaging; MEG; electrophysiology; fMRI; review
19.  Functional Neuroimaging of Spike-Wave Seizures 
Generalized spike-wave seizures are typically brief events associated with dynamic changes in brain physiology, metabolism, and behavior. Functional magnetic resonance imaging (fMRI) provides a relatively high spatio-temporal resolution method for imaging cortical-subcortical network activity during spike-wave seizures. Patients with spike-wave seizures often have episodes of staring and unresponsiveness which interfere with normal behavior. Results from human fMRI studies suggest that spike-wave seizures disrupt specific networks in the thalamus and fronto-parietal association cortex which are critical for normal attentive consciousness. However, the neuronal activity underlying imaging changes seen during fMRI is not well understood, particularly in abnormal conditions such as seizures. Animal models have begun to provide important fundamental insights into the neuronal basis for fMRI changes during spike-wave activity. Work from these models including both fMRI and direct neuronal recordings suggest that, like in humans, specific cortical-subcortical networks are involved in spike-wave, while other regions are spared. Regions showing fMRI increases demonstrate correlated increases in neuronal activity in animal models. The mechanisms of fMRI decreases in spike-wave will require further investigation. A better understanding of the specific brain regions involved in generating spike-wave seizures may help guide efforts to develop targeted therapies aimed at preventing or reversing abnormal excitability in these brain regions, ultimately leading to a cure for this disorder.
PMCID: PMC3749239  PMID: 18839093
20.  Spectral Signatures of Reorganised Brain Networks in Disorders of Consciousness 
PLoS Computational Biology  2014;10(10):e1003887.
Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment.
Author Summary
What are the neural signatures of consciousness? This is an elusive yet fascinating challenge to current cognitive neuroscience, but it takes on an immediate clinical and societal significance in patients diagnosed as vegetative and minimally conscious. In these patients, it leads us to ask whether we can test for the presence of these signatures in the absence of any external signs of awareness. Recent conceptual advances suggest that consciousness requires a dynamic balance between integrated and differentiated networks of information exchange between brain regions. Here we apply this insight to study such networks in patients and compare them to healthy adults. Using the science of graph theory, we show that the rich and diversely connected networks that support awareness are characteristically impaired in patients, lacking the ability to efficiently integrate information across disparate regions via well-connected hubs. We find that the quality of patients' networks also correlates well with their degree of behavioural responsiveness, and some vegetative patients who show signs of hidden awareness have remarkably well-preserved networks similar to healthy adults. Overall, our research highlights distinctive network signatures of pathological unconsciousness, which could improve clinical assessment and help identify patients who are aware despite being uncommunicative.
PMCID: PMC4199497  PMID: 25329398
21.  Spatiotemporal Neuronal Correlates of Seizure Generation in Focal Epilepsy 
Epilepsia  2012;53(5):807-816.
Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathological brain. Resective surgery targeting this focus is an effective treatment in carefully selected patients, but not all. While in vivo recordings of single-neuron (i.e., “unit”) activity in patients with epilepsy have a long history, no studies have examined long–term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure onset zone.
Microelectrode arrays recorded action potentials from neurons in mesial temporal structures (often including contralateral mesial temporal structures) in seven patients with mesial temporal lobe epilepsy.
Key Findings
Only 7.6% of microelectrode recordings showed increased firing rates prior to seizure onset and only 32.4% of microelectrodes showed any seizure-related activity changes. Surprisingly, firing rates on the majority of microelectrodes (67.6%) did not change throughout the seizure, including some microelectrodes located within the seizure onset zone. Furthermore, changes in firing rate prior to and at seizure onset were observed on microelectrodes located outside the seizure onset zone and even in contralateral mesial temporal lobe. These early changes varied from seizure to seizure, demonstrating the heterogeneity of ensemble activity underlying the generation of focal seizures. Increased neuronal synchrony was primarily observed only following seizure onset.
These results suggest that cellular correlates of seizure initiation and sustained ictal discharge in mesial temporal lobe epilepsy involve a small subset of the neurons within and outside the seizure onset zone. These results further suggest that the “epileptic ensemble or network” responsible for seizure generation are more complex and heterogeneous than previously thought and that future studies may find mechanistic insights and therapeutic treatments outside the clinical seizure onset zone.
PMCID: PMC3339564  PMID: 22352423
multi-unit; ictogenesis; ensemble; microelectrode; electrophysiology; mesial temporal lobe
22.  Brain CT scan results in Epileptic patients referred to neurologic clinics in Kermanshah in 1375-86 
Journal of Injury and Violence Research  2012;4(3 Suppl 1): Paper No. 77.
The analysis of the brain CT Scan results in patients with epilepsy referred to the neurology clinic of Kermanshah during 1996-2007. Epilepsy is a transient disorder of the nervous system due to sudden discharge of brain neurons. The sudden and abnormal neuronal discharge may lead to consciousness level reduction, changes in perception or mental dysfunction of seizure movements, sensorineural disorders or a combination of these symptoms.
This was a descriptive-cross sectional study. Patients with epilepsy referred to the neurology clinic in Kermanshah (Iran) who were studied by Brain CT scan during 1996-2007 were investigated. After confirming the epilepsy of patients by neurosurgery experts and removal of the seizure of consciousness loss due to other causes such as syncope, 931 patients were enrolled in our study.
Among 931 patients, only 905 patients had undergone Brain CT of which 464 were female and the rest were male. 325 patients suffered from focal motor epilepsy, patients referred with temporal epilepsy, 473 patients with Grand Mal epilepsy, 12 patients with absence epilepsy, 54 patients with myoclonic epilepsy, and 7 patients suffered from other types of epilepsy. The greatest Brain CT disorder was related to focal epilepsy. Among 125 patients with abnormal Brain CT, the greatest disorder was associated with cerebrovascular disorders (58 cases). In this study, the age range of samples was 1-89 years old. The lowest disorder was found in the age group of 10-19 and 20-39 years old (8.7% and 12.4%, respectively). The greatest disorder was observed in patients over 60 years old (38.3%). It should be noted that no Brain CT disorder was found in patients with youth myoclonic and absence epilepsy.
The results of the present study can be helpful for proper use of brain imaging in patients with epilepsy.
Epilepsy, Brain CT, Neurology Clinic, Mayoclonic epilepsy
PMCID: PMC3571603
23.  An information integration theory of consciousness 
BMC Neuroscience  2004;5:42.
Consciousness poses two main problems. The first is understanding the conditions that determine to what extent a system has conscious experience. For instance, why is our consciousness generated by certain parts of our brain, such as the thalamocortical system, and not by other parts, such as the cerebellum? And why are we conscious during wakefulness and much less so during dreamless sleep? The second problem is understanding the conditions that determine what kind of consciousness a system has. For example, why do specific parts of the brain contribute specific qualities to our conscious experience, such as vision and audition?
Presentation of the hypothesis
This paper presents a theory about what consciousness is and how it can be measured. According to the theory, consciousness corresponds to the capacity of a system to integrate information. This claim is motivated by two key phenomenological properties of consciousness: differentiation – the availability of a very large number of conscious experiences; and integration – the unity of each such experience. The theory states that the quantity of consciousness available to a system can be measured as the Φ value of a complex of elements. Φ is the amount of causally effective information that can be integrated across the informational weakest link of a subset of elements. A complex is a subset of elements with Φ>0 that is not part of a subset of higher Φ. The theory also claims that the quality of consciousness is determined by the informational relationships among the elements of a complex, which are specified by the values of effective information among them. Finally, each particular conscious experience is specified by the value, at any given time, of the variables mediating informational interactions among the elements of a complex.
Testing the hypothesis
The information integration theory accounts, in a principled manner, for several neurobiological observations concerning consciousness. As shown here, these include the association of consciousness with certain neural systems rather than with others; the fact that neural processes underlying consciousness can influence or be influenced by neural processes that remain unconscious; the reduction of consciousness during dreamless sleep and generalized seizures; and the time requirements on neural interactions that support consciousness.
Implications of the hypothesis
The theory entails that consciousness is a fundamental quantity, that it is graded, that it is present in infants and animals, and that it should be possible to build conscious artifacts.
PMCID: PMC543470  PMID: 15522121
24.  Altered network properties of the fronto-parietal network and the thalamus in impaired consciousness☆ 
NeuroImage : Clinical  2013;4:240-248.
Recovery of consciousness has been associated with connectivity in the frontal cortex and parietal regions modulated by the thalamus. To examine this model and to relate alterations to deficits in cognitive functioning and conscious processing, we investigated topological network properties in patients with chronic disorders of consciousness recovered from coma.
Resting state fMRI data of 34 patients with unresponsive wakefulness syndrome and 25 in minimally conscious state were compared to 28 healthy controls. We investigated global and local network characteristics. Additionally, behavioral measures were correlated with the local metrics of 28 regions within the fronto-parietal network and the thalamus.
In chronic disorders of consciousness, modularity at the global level was reduced suggesting a disturbance in the optimal balance between segregation and integration. Moreover, network properties were altered in several regions which are associated with conscious processing (particularly, in medial parietal, and frontal regions, as well as in the thalamus). Between minimally conscious and unconscious patients the local efficiency of medial parietal regions differed. Alterations in the thalamus were particularly evident in non-conscious patients. Most of the regions affected in patients with impaired consciousness belong to the so-called ‘rich club’ of highly interconnected central nodes. Disturbances in their topological characteristics have severe impact on information integration and are reflected in deficits in cognitive functioning probably leading to a total breakdown of consciousness.
•We investigated network properties in patients with a disorder of consciousness.•Patients showed reduced global modularity.•Alterations in regions of the rich club were related to impaired consciousness.•These alterations have severe impact on information integration and segregation.•Disturbances in overall integration may lead to breakdown of consciousness.
PMCID: PMC3895618  PMID: 24455474
DOC, disorders of consciousness; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; MCS, minimally conscious state; VS/UWS, vegetative state/unresponsive wakefulness syndrome; Consciousness; Vegetative state; Network; Graph theory; Connectivity; Small world
25.  The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes 
eLife  2014;3:e01267.
The mechanisms generating epileptic neuronal networks following insults such as severe seizures are unknown. We have previously shown that interfering with the function of the neuron-restrictive silencer factor (NRSF/REST), an important transcription factor that influences neuronal phenotype, attenuated development of this disorder. In this study, we found that epilepsy-provoking seizures increased the low NRSF levels in mature hippocampus several fold yet surprisingly, provoked repression of only a subset (∼10%) of potential NRSF target genes. Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked. Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels. Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function. Thus, dynamic, selective regulation of NRSF target genes may play a role in influencing neuronal properties in pathological and physiological contexts.
eLife digest
Epilepsy is a common brain disease that can cause disabling seizures. During a seizure, brain cells send out abnormal signals, which can mean that people having seizures may be unaware of their surroundings and may fall or otherwise injure themselves.
Individuals with epilepsy develop changes in their brain cells and in the circuits that connect these cells together. Some people develop epilepsy because they have mutations in genes. Others develop the condition after an injury or a long seizure, which leads to changes in gene expression and therefore changes to the brain's cells and circuits.
In 2011, researchers found that a protein that normally switches off the expression of certain genes during brain development, but which is almost absent in the adult brain, may run amok after a seizure. The level of this protein—a transcription factor called NRSF—increased in the brains of rats that had been caused to have a seizure. A long provoked seizure caused many of the rats to develop epilepsy. But, if NRSF was blocked after the original seizure, the rats were less likely to have further seizures later on. Now McClelland et al., including several of the researchers involved in the 2011 work, have examined what normally happens to the expression of genes after a seizure and what happens when the NRSF transcription factor is blocked.
McClelland et al. found that only a small subset—about 10%—of the genes that can theoretically be silenced by NRSF are switched off in the brain when this protein's levels increase after a seizure. The increased NRSF levels, unexpectedly, did not affect the genes that bind tightly to this transcription factor. Nor did NRSF affect genes that bind loosely. Instead, the genes that the transcription factor binds to with an intermediate strength were the ones that were switched off. McClelland et al. suggest that this ‘mid-range binding’ to NRSF allows the expression of these genes to be increased or decreased in response to there being more or less NRSF in the cell. Genes that bind tightly to NRSF are likely to already have a lot of NRSF bound and are therefore already switched off; and loosely-binding genes would likely need even more NRSF before they are switched off.
The subset of genes that were switched off by the increased levels of NRSF after a seizure code for a number of proteins that brain cells need to be able to effectively send and receive messages. Blocking the ability of NRSF to bind to these genes and switch them off may help to prevent the brain changes that cause epilepsy.
PMCID: PMC4129437  PMID: 25117540
neuron-restrictive silencing factor; epilepsy; gene set enrichment analysis; rat

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