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.
Consciousness; Epilepsy; Complex Partial Seizures; Generalized Tonic-Clonic Seizures; Visual Tracking; Minimally Conscious State; Vegetative State
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.
Central nervous system plasticity is essential for normal function, but can also reinforce abnormal network behavior, leading to epilepsy and other disorders. The role of altered ion channel expression in abnormal plasticity has not been thoroughly investigated. Nav1.6 is the most abundantly expressed sodium channel in the nervous system. Because of its distribution in the cell body and axon initial segment, Nav1.6 is crucial for action potential generation. The goal of the present study was to investigate the possible role of changes in Nav1.6 expression in abnormal, activity-dependent plasticity of hippocampal circuits.
We studied kindling, a form of abnormal activity-dependent facilitation. We investigated: 1. sodium channel protein expression by immunocytochemistry and sodium channel mRNA by in situ hybridization, 2. sodium current by patch clamp recordings, and 3. rate of kindling by analysis of seizure behavior. The initiation, development, and expression of kindling in wild type mice were compared to Nav1.6 +/− medtg mice, which have reduced expression of Nav1.6.
We found that kindling was associated with increased expression of Nav1.6 protein and mRNA, which occurred selectively in hippocampal CA3 neurons. Hippocampal CA3 neurons also showed increased persistent sodium current in kindled animals compared to sham-kindled controls. Conversely, Nav1.6 +/− medtg mice resisted the initiation and development of kindling.
These findings suggest an important mechanism for enhanced excitability, in which Nav1.6 may participate in a self-reinforcing cycle of activity-dependent facilitation in the hippocampus. This mechanism could contribute to both normal hippocampal function, and to epilepsy and other common nervous system disorders.
epilepsy; kindling; hippocampus; persistent sodium current; LTP
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.
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.
Consciousness; Seizure; Behavior; Testing battery; Electroencephalography; Video/EEG monitoring
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.
Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease.
brain asymmetry; brain imaging; SPECT
C3H/HeJ mice have been reported to have relatively early onset of spike-wave discharges (SWD), and a defective AMPA receptor subunit Gria4 as the genetic cause. We investigated the time course of SWD development through serial EEG recordings in C3H/HeJ mice to better characterize this model. We found that at immature postnatal ages of 5–15 days, rare SWD-like events were observed at an average rate of 3 per hour, and with relatively broad spikes, irregular rhythm, slow frequency (5–6 Hz), and short duration (mean 1.75 s). This was followed by a transitional period of increasing SWD incidence, which then stabilized in mature animals at age 26–62 days, with SWD at an average rate of 45 per hour, narrower spike morphology, regular rhythm, higher frequency (7–8 Hz), and longer duration (mean 3.40 s). This sequence of maturational changes in SWD development suggests that effects of early intervention could be tested in C3H/HeJ mice over the course of a few weeks, rather than a few months as in rats, greatly facilitating future research on anti-epileptogenesis.
Epilepsy; Electroencephalogram; Rodent; Absence seizure; Petit mal; Epileptogenesis
Epilepsy is a common disorder with a major negative impact on patient quality of life, yet treatment so far is directed mainly at blocking the symptoms—epileptic seizures, not the underlying cause. In recent years, investigation of epilepsy development or epileptogenesis has yielded new insights into potential therapies that may ultimately prevent epilepsy before it starts. In this special issue of Neuroscience Letters the latest advances in the field are brought together, summarizing: (1) important animal models in both primary and secondary epilepsies, (2) promising biomarkers for monitoring epileptogenesis, (3) cellular and molecular mechanisms which may serve as viable targets for therapy, and (4) translational approaches to human clinical trials. Bringing together these intriguing new approaches to treating epilepsy as a preventable disorder will hopefully soon make symptomatic treatment of epilepsy unnecessary in most patients.
Epilepsy; Prevention; Epileptogenesis; Seizures; Development; Traumatic brain injury; Febrile convulsions; Treatment; Anti-epiletogenesis; Comorbidity; Biomarkers; Therapy
Much progress has been made in the field studying the process of epileptogenesis via neuroimaging techniques. Conventional imaging methods include magnetic resonance imaging with morphometric analysis, magnetic resonance spectroscopy and positron emission tomography. Newer network-based methods such as diffusion tensor imaging and functional magnetic resonance imaging with resting functional connectivity are being developed and applied to clinical use. This review provides a brief summary of the major human and animal studies in both partial and generalized epilepsies that demonstrate the potential of these imaging modalities to serve as biomarkers of epileptogenesis.
Epileptogenesis; Spike-wave seizure; Neuroimaging; Biomarker
The relationship between neuronal activity and hemodynamic changes plays a central role in functional neuroimaging. Under normal conditions and in neurological disorders such as epilepsy it is commonly assumed that increased functional magnetic resonance imaging (fMRI) signals reflect increased neuronal activity, and that fMRI decreases represent neuronal activity decreases. Recent work suggests these assumptions usually hold true in the cerebral cortex. However, less is known about the basis of fMRI signals from subcortical structures such as the thalamus and basal ganglia. We used Wistar Albino Glaxo rats of Rijswijk (WAG/Rij), an established animal model of human absence epilepsy, to perform fMRI studies with blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) contrasts at 9.4 Tesla; as well as laser Doppler cerebral blood flow (CBF), local field potential (LFP), and multiunit activity (MUA) recordings. We found that during spike-wave discharges, the somatosensory cortex and thalamus showed increased fMRI, CBV, CBF, LFP and MUA signals. However, the caudate-putamen showed fMRI, CBV and CBF decreases despite increases in LFP and MUA signals. Similarly, during normal whisker stimulation the cortex and thalamus showed increases in CBF and MUA, while the caudate-putamen showed decreased CBF with increased MUA. These findings suggest that neuroimaging-related signals and electrophysiology tend to agree in the cortex and thalamus, but disagree in the caudate-putamen. These opposite changes in vascular and electrical activity indicate that caution should be applied when interpreting fMRI signals in both health and disease from the caudate-putamen, as well as possibly from other subcortical structures.
spike-wave seizures; absence seizure; cerebral blood flow; BOLD; thalamus; basal ganglia
Consciousness; Seizures; Absence seizures; Temporal lobe epilepsy; Complex partial seizures; Generalized tonic-clonic seizures; Thalamus; fMRI
A primary objective in neuroscience is to determine how neuronal populations process information within networks. In humans and animal models, functional magnetic resonance imaging (fMRI) is gaining increasing popularity for network mapping. Although neuroimaging with fMRI—conducted with or without tasks—is actively discovering new brain networks, current fMRI data analysis schemes disregard the importance of the total neuronal activity in a region. In task fMRI experiments, the baseline is differenced away to disclose areas of small evoked changes in the blood oxygenation level-dependent (BOLD) signal. In resting-state fMRI experiments, the spotlight is on regions revealed by correlations of tiny fluctuations in the baseline (or spontaneous) BOLD signal. Interpretation of fMRI-based networks is obscured further, because the BOLD signal indirectly reflects neuronal activity, and difference/correlation maps are thresholded. Since the small changes of BOLD signal typically observed in cognitive fMRI experiments represent a minimal fraction of the total energy/activity in a given area, the relevance of fMRI-based networks is uncertain, because the majority of neuronal energy/activity is ignored. Thus, another alternative for quantitative neuroimaging of fMRI-based networks is a perspective in which the activity of a neuronal population is accounted for by the demanded oxidative energy (CMRO2). In this article, we argue that network mapping can be improved by including neuronal energy/activity of both the information about baseline and small differences/fluctuations of BOLD signal. Thus, total energy/activity information can be obtained through use of calibrated fMRI to quantify differences of ΔCMRO2 and through resting-state positron emission tomography/magnetic resonance spectroscopy measurements for average CMRO2.
anesthesiology; brain metabolism; consciousness; magnetic resonance spectroscopic imaging (MRSI); positron emission tomography (PET)
Childhood absence epilepsy (CAE) has been recently linked to a number of cognitive, behavioral, and emotional disorders. Identification of affective disorders (anxiety and depression) presents unique challenges in pediatric populations, and successful early intervention may significantly improve long-term developmental outcomes. The current study examined the specific anxiety and depression symptoms CAE children experience, and explored the role of disease factors in the severity of their presentation. Forty-five subjects with CAE and 41 healthy matched controls, ages 6 to 16 participated in the study. The Behavior Assessment System for Children (BASC) was completed by parents, and the Anxiety and Depression subscales were used to characterize problems. Item analysis within the subscales revealed that CAE children demonstrated higher rates of symptoms of anxiety (nervousness and thought rumination) and depression (sadness and crying), as well as more general psychosocial problems including isolation and low self-esteem. Disease duration, intractability, and medication effects were not associated with higher rates of affective problems in this limited patient sample. Screening CAE patients for comorbid psychiatric disorders early by focusing on specific symptom profiles unique to this population may enhance overall treatment and developmental outcomes.
Childhood Absence Epilepsy; Depression; Anxiety; Seizures; Affective Disorders
Patients with childhood absence epilepsy (CAE) often demonstrate impaired interictal attention, even with control of their seizures. No previous study has investigated the brain networks involved in this impairment. We used the Continuous Performance Task (CPT) of attentional vigilance and the Repetitive Tapping Task (RTT), a control motor task, to examine interictal attention in 26 children with CAE and 22 matched healthy controls. Each subject underwent simultaneous 3T functional magnetic resonance imaging-electroencephalography (fMRI-EEG) and CPT/RTT testing. Areas of activation on fMRI during the CPT task were correlated with behavioral performance and used as seed regions for resting functional connectivity analysis. All behavioral measures reflecting inattention were significantly higher in patients. Correlation analysis revealed that impairment on all measures of inattention on the CPT task was associated with decreased medial frontal cortex (MFC) activation during CPT. In addition, analysis of resting functional connectivity revealed an overall decrease within an ‘attention network’ in patients relative to controls. Patients demonstrated significantly impaired connectivity between the right anterior insula/frontal operculum (In/FO) and MFC relative to controls. Our results suggest that there is impaired function in an attention network comprising anterior In/FO and MFC in patients with CAE. These findings provide an anatomical and functional basis for impaired interictal attention in CAE, which may allow the development of improved treatments targeted at these networks.
epilepsy; attention; fMRI; networks; connectivity
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.
cortex; EEG; seizures; temporal lobe epilepsy; consciousness
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.
epilepsy; attention; consciousness; thalamus; BOLD; spike-wave
The current study examined the specific types of attention-related problems CAE children experience and the role of disease factors on the development of attention-related problems. Thirty-eight subjects with CAE and 46 healthy controls, ages 6 to 16 participated in the study. The Behavior Assessment System for Children (BASC) was completed by parents, and the Attention Problems and Hyperactivity subscales were used to characterize CAE children’s problems. Item analysis within the subscales revealed that CAE children demonstrated higher rates of hyperactive (overactivity and fidgetiness) and inattentive (forgetfulness and distractibility) problems, and required more supervision. Within CAE analyses revealed that those who were actively having seizures were more impatient and those with a longer duration of illness were less proficient in completing homework. Children with CAE are at risk for certain inattentive and hyperactive problems, which can differ depending on duration of illness and active seizure status.
Childhood Absence Epilepsy; Attention; Hyperactivity; Seizures; Behavior
Epileptic seizures cause dynamic, reversible changes in brain function and are often associated with loss of consciousness. Of all seizure types, absence seizures lead to the most selective deficits in consciousness, with relatively little motor or other manifestations. Impaired consciousness in absence seizures is not monolithic, but varies in severity between patients and even between episodes in the same patient. In addition, some aspects of consciousness may be more severely involved than other aspects. The mechanisms for this variability are not known. Here we review the literature on human absence seizures and discuss a hypothesis for why effects on consciousness may be variable. Based on behavioral studies, electrophysiology, and recent neuroimaging and molecular investigations, we propose absence seizures impair focal, not generalized brain functions. Imapired consciousness in absence seizures may be caused by focal disruption of information processing in specific corticothalamic networks, while other networks are spared. Deficits in selective and varying cognitive functions may lead to impairment in different aspects of consciousness. Further investigations of the relationship between behavior and altered network function in absence seizures may improve our understanding of both normal and impaired consciousness.
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.
Epilepsy; Consciousness; Default Mode Network
Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy and generalized epilepsy animal models, as well as patients with epilepsy. However, the role and importance of HCN1 downregulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure induction method used. Thus, downregulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor to seizure behavior.
intrinsic excitability; Ih conductance; HCN channels; limbic seizures; kindling; pilocarpine
Current treatments for epilepsy may control seizures, but have no known effects on the underlying disease. We sought to determine whether early treatment in a model of genetic epilepsy would reduce the severity of the epilepsy phenotype in adulthood.
We used Wistar albino Glaxo rats of Rijswijk (WAG/Rij) rats, an established model of human absence epilepsy. Oral ethosuximide was given from age p21 to 5 months, covering the usual period in which seizures develop in this model (age ~3 months). Two experiments were performed: (1) cortical expression of ion channels Nav1.1, Nav1.6, and HCN1 (previously shown to be dysregulated in WAG/Rij) measured by immunocytochemistry in adult treated rats; and (2) electroencephalogram (EEG) recordings to measure seizure severity at serial time points after stopping the treatment.
Early treatment with ethosuximide blocked changes in the expression of ion channels Nav1.1, Nav1.6, and HCN1 normally associated with epilepsy in this model. In addition, the treatment led to a persistent suppression of seizures, even after therapy was discontinued. Thus, animals treated with ethosuximide from age p21 to 5 months still had a marked suppression of seizures at age 8 months.
These findings suggest that early treatment during development may provide a new strategy for preventing epilepsy in susceptible individuals. If confirmed with other drugs and epilepsy paradigms, the availability of a model in which epileptogenesis can be controlled has important implications both for future basic studies, and human therapeutic trials.
Epileptogenesis; Activity-dependent; Prevention; Idiopathic generalized epilepsy; Sodium channels; HCN1
Patients with epilepsy are at risk of traffic accidents when they have seizures while driving. However, driving is an essential part of normal daily life in many communities, and depriving patients of driving privileges can have profound consequences for their economic and social well being. In the current study, we collected ictal performance data from a driving simulator and two other video games in patients undergoing continuous video/EEG monitoring. We captured 22 seizures in 13 patients and found that driving impairment during seizures differed both in terms of magnitude and character, depending on the seizure type. Our study documents the feasibility of the prospective study of driving and other behaviors during seizures through the use of computer-based tasks. This methodology may be applied to further describe differential driving impairment in specific types of seizures and to gain data on anatomical networks disrupted in seizures that impair consciousness and driving safety.
Epilepsy; consciousness; driving; EEG; SPECT; virtual reality; computer games
Generalized tonic-clonic seizures cause widespread physiological changes throughout the cerebral cortex and subcortical structures in the brain. Using combined blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 9.4 T and electroencephalography (EEG) these changes can be characterized with high spatiotemporal resolution. We studied BOLD changes in anesthetized Wistar rats during bicuculline-induced tonic-clonic seizures. Bicuculline, a GABAA receptor antagonist, was injected systemically and seizure activity was observed on EEG as high amplitude, high-frequency polyspike discharges followed by clonic paroxysmal activity of lower frequency, with mean electrographic seizure duration of 349 s. Our aim was to characterize the spatial localization, direction, and timing of BOLD signal changes during the pre-ictal, ictal and post-ictal periods. Group analysis was performed across seizures using paired t-maps of BOLD signal superimposed on high resolution anatomical images. Regional analysis was then performed using volumes of interest to quantify BOLD timecourses. In the pre-ictal period we found focal BOLD increases in specific areas of somatosensory cortex (S1, S2) and thalamus several seconds before seizure onset. During seizures we observed BOLD increases in cortex, brainstem and thalamus and BOLD decreases in the hippocampus. The largest ictal BOLD increases remained in the focal regions of somatosensory cortex showing pre-ictal increases. During the post-ictal period we observed widespread BOLD decreases. These findings support a model in which “generalized” tonic-clonic seizures begin with focal changes before electrographic seizure onset, which progress to non-uniform changes during seizures, possibly shedding light on the etiology and pathophysiology of similar seizures in humans.
tonic-clonic seizure; fMRI; cortex; thalamus; bicuculline; cortical focus theory
Several large and meta-analytic studies have failed to support a consistent relationship between visual or “nonverbal” memory deficits and right mesial temporal lobe changes. However, the Brown Location Test (BLT) is a recently developed dot location learning and memory test that uses a nonsymmetrical array and provides control over many of the confounding variables (e.g., verbal influence and drawing requirements) inherent in other measures of visual memory. In the present investigation, we evaluated the clinical utility of the BLT in patients who had undergone left or right anterior mesial temporal lobectomies. We also provide adult normative data of 298 healthy adults in order to provide standardized scores. Results revealed significantly worse performance on the BLT in the right as compared to left lobectomy group and the healthy adult normative sample. The present findings support a role for the right anterior-mesial temporal lobe in dot location learning and memory.
spatial; visuospatial; lateralization; memory; location; epilepsy
Most epilepsy genes encode ion channels, but the LGI1 gene responsible for Autosomal Dominant Partial Epilepsy with Auditory Features produces a secreted protein. LGI1 is suggested to regulate PSD-95 via ADAM22. However, no unbiased screen of LGI1 action has been conducted. Here, we searched for brain genes supporting high affinity LGI-1 binding. ADAM23 was the only LGI1 interactor identified. The related proteins, ADAM22 and ADAM11, but not ADAM12, bind LGI1. Neither ADAM23 nor ADAM11, nor some forms of ADAM22, contain PDZ-interacting sequences, suggesting PSD-95-independent mechanisms in ADPEAF. Because ADAMs modulate integrins, we examined LGI1 effect on neurite outgrowth. LGI1 increases outgrowth from wild type but not ADAM23-/- neurons. Furthermore, CA1 pyramidal neurons of ADAM23-/- hippocampi have reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures, while ADAM23+/- mice have decreased seizure thresholds. Thus, LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology and altered anatomical patterning contributes to ADPEAF.