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1.  Increased resting functional connectivity in spike-wave epilepsy in WAG/Rij rats 
Epilepsia  2013;54(7):1214-1222.
Purpose: Functional magnetic resonance imaging (fMRI)-based resting functional connectivity is well suited for measuring slow correlated activity throughout brain networks. Epilepsy involves chronic changes in normal brain networks, and recent work demonstrated enhanced resting fMRI connectivity between the hemispheres in childhood absence epilepsy. An animal model of this phenomenon would be very valuable for investigating fundamental mechanisms and testing therapeutic interventions. Methods: We used fMRI-based resting functional connectivity for studying brain networks involved in absence epilepsy. Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit spontaneous episodes of staring and unresponsiveness accompanied by spike-wave discharges (SWD) resembling human absence seizures in behavior and electroencephalography (EEG). Simultaneous EEG–fMRI data in epileptic WAG/Rij rats in comparison to non-epileptic Wistar controls were acquired at 9.4 T. Regions showing cortical fMRI increases during SWDs were used to define reference regions for connectivity analysis to investigate whether chronic seizure activity is associated with changes in network resting functional connectivity. Key findings: We observed high degrees of cortical-cortical correlations in all WAG/Rij rats at rest (when no SWD were present), but not in non-epileptic controls. Strongest connectivity was seen between regions most intensely involved in seizures, mainly in the bilateral somatosensory and adjacent cortices. Group statistics revealed that resting interhemispheric cortical-cortical correlations were significantly higher in WAG/Rij rats compared to non-epileptic controls. Significance: These findings suggest that activity-dependent plasticity may lead to long-term changes in epileptic networks even at rest. The results show a marked difference between the epileptic and non-epileptic animals in cortical-cortical connectivity, indicating that this may be a useful interictal biomarker associated with the epileptic state.
PMCID: PMC3703864  PMID: 23815571
Resting functional connectivity; spike-wave seizure; fMRI; cortex; thalamus
2.  Should Consciousness be Included in the Classification of Focal (Partial) Seizures? 
Epilepsia  2013;54(6):1125-1130.
The ILAE 2010 report does not classify focal seizures and instead uses “descriptors” to distinguish focal seizures with vs. without impaired consciousness. We recall a recent informal conversation that took place while traveling a back road in Australia (true story), discussing problems with the old terms as well as new biological and practical evidence separating events formerly known as complex partial vs. simple partial seizures. Impaired level of consciousness is a core distinguishing feature of focal seizures, which arises from established physiological mechanisms and can be readily determined based on behavior in most cases. After some debate, we arrive at succinct terms compatible with the old as well as the new ILAE classification report: Focal Impaired Consciousness Seizures (FICS), and Focal Aware Conscious Seizures (FACS). We hope that this discussion will bring impaired consciousness off the back roads of epilepsy classification, and provide useful names for these two very common seizure types.
PMCID: PMC3683876  PMID: 23731397
Epilepsy; Consciousness; Complex partial seizures; Simple partial seizures; Mechanisms
3.  Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat 
PLoS ONE  2014;9(4):e95280.
Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.
PMCID: PMC3991600  PMID: 24748279
4.  Ethosuximide reduces epileptogenesis and behavioural comorbidity in the GAERS model of genetic generalised epilepsy 
Epilepsia  2013;54(4):635-643.
Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has been reported to have disease-modifying anti-epileptogenic activity in the WAG/Rij rat model of genetic generalised epilepsy (GGE) with absence seizures. Here we examined whether chronic treatment with ESX (i) possesses anti-epileptogenic effects in the GAERS model of GGE, (ii) is associated with a mitigation of behavioural comorbidities, and (iii) influences gene expression in the somatosensory cortex region where seizures are thought to originate.
GAERS and Non-Epileptic Control (NEC) rats were chronically treated with ESX (in drinking water) or control (tap water) from 3 to 22 weeks of age. Subsequently, all animals received tap water only for another 12 weeks to assess enduring effects of treatment. Seizure frequency and anxiety-like behaviours were serially assessed throughout the experimental paradigm. Treatment effects on the expression of key components of the epigenetic molecular machinery, the DNA methyltransferase enzymes, were assessed using qPCR.
Key findings
ESX treatment significantly reduced seizures in GAERS during the treatment phase, and this effect was maintained during the 12 weeks post-treatment phase (p<0.05). Further, the anxiety-like behaviours present in GAERS were reduced by ESX treatment (p<0.05). Molecular analysis revealed that ESX treatment was associated with increased expression of DNA methyltransferase enzyme mRNA in cortex.
Chronic ESX treatment has disease-modifying effects in the GAERS model of GGE, with anti-epileptogenic effects against absence seizures and mitigation of behavioural comorbidities. The cellular mechanism for these effects may involve epigenetic modifications.
PMCID: PMC3618492  PMID: 23464801
GAERS; ethosuximide; epileptogenesis; seizures; anxiety; DNA methylation
5.  Analysis of Time and Space Invariance of BOLD Responses in the Rat Visual System 
Cerebral Cortex (New York, NY)  2012;23(1):210-222.
Neuroimaging studies of functional magnetic resonance imaging (fMRI) and electrophysiology provide the linkage between neural activity and the blood oxygenation level–dependent (BOLD) response. Here, BOLD responses to light flashes were imaged at 11.7T and compared with neural recordings from superior colliculus (SC) and primary visual cortex (V1) in rat brain—regions with different basal blood flow and energy demand. Our goal was to assess neurovascular coupling in V1 and SC as reflected by temporal/spatial variances of impulse response functions (IRFs) and assess, if any, implications for general linear modeling (GLM) of BOLD responses. Light flashes induced high magnitude neural/BOLD responses reproducibly from both regions. However, neural/BOLD responses from SC and V1 were markedly different. SC signals followed the boxcar shape of the stimulation paradigm at all flash rates, whereas V1 signals were characterized by onset/offset transients that exhibited different flash rate dependencies. We find that IRFSC is generally time-invariant across wider flash rate range compared with IRFV1, whereas IRFSC and IRFV1 are both space invariant. These results illustrate the importance of measured neural signals for interpretation of fMRI by showing that GLM of BOLD responses may lead to misinterpretation of neural activity in some cases.
PMCID: PMC3513959  PMID: 22298731
calibrated fMRI; local field potential; multiunit activity; neuroenergetics; neurometabolic coupling; transfer function
6.  Prospective assessment of ictal behavior using the revised Responsiveness in Epilepsy Scale (RES-II) 
Epilepsy & behavior : E&B  2012;26(1):25-28.
Impaired consciousness in epilepsy has a significant negative impact on patient quality of life, yet is difficult to study objectively. Here we develop an improved prospective Responsiveness in Epilepsy Scale (RES-II) and report initial results compared to the earlier version of the scale (RES). RES-II is simpler to administer and includes both verbal and nonverbal test items. We evaluated 75 seizures (24 patients) with RES and 34 seizures (11 patients) with RES-II based on video-EEG review. The error rate per seizure by test administrators improved markedly from a mean of 2.01±0.04 with RES to 0.24±0.11 with RES-II. Performance during focal seizures showed a bimodal distribution, corresponding to the traditional complex partial vs. simple partial seizure classification. We conclude that RES-II has improved accuracy and testing efficiency compared to the original RES. Prospective objective testing will ultimately lead to a better understanding of the mechanisms of impaired consciousness in epilepsy.
PMCID: PMC3741052  PMID: 23201609
consciousness; epilepsy; focal seizures; partial seizures; generalized tonic-clonic seizures; behavioral testing
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.  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
9.  Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis 
Epilepsia  2008;50(1):44-55.
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.
PMCID: PMC3741044  PMID: 18637833
epilepsy; kindling; hippocampus; persistent sodium current; LTP
10.  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
11.  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
12.  Statistical parametric mapping demonstrates asymmetric uptake with Tc-99m ECD and Tc-99m HMPAO SPECT in normal brain 
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.
PMCID: PMC3323300  PMID: 21934696
brain asymmetry; brain imaging; SPECT
13.  Development of spike-wave seizures in C3H/HeJ mice 
Epilepsy research  2009;85(1):53-59.
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.
PMCID: PMC3432281  PMID: 19409755
Epilepsy; Electroencephalogram; Rodent; Absence seizure; Petit mal; Epileptogenesis
14.  New strategies for preventing epileptogenesis: Perspective and overview 
Neuroscience letters  2011;497(3):153-154.
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.
PMCID: PMC3432282  PMID: 21354268
Epilepsy; Prevention; Epileptogenesis; Seizures; Development; Traumatic brain injury; Febrile convulsions; Treatment; Anti-epiletogenesis; Comorbidity; Biomarkers; Therapy
15.  Neuroimaging biomarkers of epileptogenesis 
Neuroscience letters  2011;497(3):194-204.
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.
PMCID: PMC3432283  PMID: 21303682
Epileptogenesis; Spike-wave seizure; Neuroimaging; Biomarker
16.  Where fMRI and electrophysiology agree to disagree: corticothalamic and striatal activity patterns in the WAG/Rij rat 
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.
PMCID: PMC3432284  PMID: 22016539
spike-wave seizures; absence seizure; cerebral blood flow; BOLD; thalamus; basal ganglia
17.  Epilepsy and the Consciousness System: Transient Vegetative State? 
Neurologic clinics  2011;29(4):801-823.
PMCID: PMC3432285  PMID: 22032662
Consciousness; Seizures; Absence seizures; Temporal lobe epilepsy; Complex partial seizures; Generalized tonic-clonic seizures; Thalamus; fMRI
18.  Role of Ongoing, Intrinsic Activity of Neuronal Populations for Quantitative Neuroimaging of Functional Magnetic Resonance Imaging–Based Networks 
Brain Connectivity  2011;1(3):185-193.
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.
PMCID: PMC3621320  PMID: 22433047
anesthesiology; brain metabolism; consciousness; magnetic resonance spectroscopic imaging (MRSI); positron emission tomography (PET)
19.  Symptoms of Anxiety and Depression in Childhood Absence Epilepsy 
Epilepsia  2011;52(8):e70-e74.
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.
PMCID: PMC3145036  PMID: 21635244
Childhood Absence Epilepsy; Depression; Anxiety; Seizures; Affective Disorders
20.  Impaired attention and network connectivity in childhood absence epilepsy 
NeuroImage  2011;56(4):2209-2217.
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.
PMCID: PMC3105167  PMID: 21421063
epilepsy; attention; fMRI; networks; connectivity
21.  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
22.  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
23.  Differentiation of Attention-Related Problems in Childhood Absence Epilepsy 
Epilepsy & behavior : E&B  2010;19(1):82-85.
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.
PMCID: PMC2943027  PMID: 20674507
Childhood Absence Epilepsy; Attention; Hyperactivity; Seizures; Behavior
24.  Consciousness and epilepsy: why are patients with absence seizures absent? 
Progress in brain research  2005;150:271-286.
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.
PMCID: PMC3153469  PMID: 16186030
25.  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

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