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.

For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.T he microscopic review of tissue biopsies frequently remains the sole source of intraoperative diagnostic information, and many important surgical decisions such as the extent of tumor resection are based on this information. This approach is timeconsuming, requiring nearly 30 min between the moment a tissue is biopsied and the time the pathologist's interpretation is communicated back to the surgeon. Even after the report of the final pathologic diagnosis is issued days later, a lot of diagnostic, prognostic, and predictive information is left undiscovered and unexamined within the tissue. Tools that provide more immediate feedback to the surgeon and the pathologist and that also rapidly extract detailed molecular information could transform the management of care for cancer patients.MS offers the possibility for the in-depth analysis of the proteins and lipids that comprise tissues (1, 2). We have recently shown that desorption electrospray ionization (DESI) MS is a powerful methodology for characterizing lipids within tumor specimens (3-6). The intensity profile of lipids ionized from within tumors can be used for classifying tumors and for providing valuable prognostic information such as tumor subtype and grade. Because DESI MS is performed in ambient conditions with minimal pretreatment of the samples (7,8), there is the potential to provide diagnostic information rapidly within the operating room (4, 6, 9). The ability to quickly acquire such valuable diagnostic information from lipids prompted us to determine whether we could use DESI MS to detect additional molecules of diagnostic value within tumors, such as their metabolites.Recently,...

SUMMARYPurpose: 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. Methods: 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.Results: 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. Discussion: 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.

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.