Absence seizures are 5-10 s episodes of impaired consciousness accompanied by 3-4 Hz generalized spike-and-wave discharge on electroencephalography (EEG). The time course 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 nine pediatric patients. We investigated behavior concurrently using a continuous performance task or simpler repetitive tapping task. EEG timefrequency 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 Ͼ5 s before seizure onset, followed by profound fMRI decreases continuing Ͼ20 s after seizure end. This time course 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 detectable 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.

Purpose-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.Methods-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).Results-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.Discussion-These findings suggest that typical absence seizures involve a network of corticalsubcortical areas necessary for normal attention and primary information processing. Identification

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.

Objective:The fundamental mechanisms by which childhood absence epilepsy (CAE) changes neural networks even between seizures remain poorly understood. During seizures, cortical and subcortical networks exhibit bihemspheric synchronous activity based on prior EEG-fMRI studies. Our aim was to investigate whether this abnormal bisynchrony may extend to the interictal period, using a blood oxygen level-dependent (BOLD) resting functional connectivity approach.Methods: EEG-fMRI data were recorded from 16 patients with CAE and 16 age-and gendermatched controls. Three analyses were performed. 1) Using 16 pairs of seizure-related regions of interest (ROI), we compared the between-hemisphere interictal resting functional connectivity of patients and controls. 2) For regions showing significantly increased interhemispheric connectivity in CAE, we then calculated connectivity to the entire brain. 3) A paired-voxel approach was performed to calculate resting functional connectivity between hemispheres without the constraint of predefined ROIs. Results:We found significantly increased resting functional connectivity between hemispheres in the lateral orbitofrontal cortex of patients with CAE compared to normal controls. Enhanced between-hemisphere connectivity localized to the lateral orbitofrontal cortex was confirmed by all 3 analysis methods.Conclusions: Our results demonstrate abnormal increased connectivity between the hemispheres in patients with CAE in seizure-related regions, even when seizures were not occurring. These findings suggest that the lateral orbitofrontal cortex may play an important role in CAE pathophysiology, warranting further investigation. In addition, resting functional connectivity analysis may provide a promising biomarker to improve our understanding of altered brain function in CAE during the interictal period. Neurology Childhood absence epilepsy (CAE) is increasingly recognized as a disorder characterized by impaired function both during seizures, and in the interictal period.1-4 Notably, 3-4 Hz spikewave discharges (SWD) seen in CAE 5-7 and their associated blood oxygenation level-dependent (BOLD) fMRI changes [8][9][10][11][12][13][14][15][16] are bilateral and fairly symmetric. Evidence from animal models indicates that this bihemispheric synchrony during SWD is mediated by the corpus callosum. 17,18 We hypothesize that abnormal bihemispheric synchrony persists in the interictal period, and may participate in generating abnormal function, including enhanced bilateral excitability. The possible role of abnormal long-range bilateral synchrony during the interictal period in CAE has not been previously investigated.The recent development of the resting functional connectivity approach to fMRI has provided a window to observe intrinsic brain activity in health and disease. This method has been used to

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.

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.

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