title: A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy.
abstract: Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.
authors.affiliation: Department of Neurology, Harvard Medical School; Department of Neurology, Beth Israel Deaconess Medical Center; Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center; mshafi@bidmc.harvard.edu.
authors.forename: Mouhsin M
authors.initials: MM
authors.lastname: Shafi
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology.
authors.forename: Susan
authors.initials: S
authors.lastname: Whitfield-Gabrieli
authors.affiliation: Department of Neurology, Harvard Medical School; Department of Neurology, Massachusetts General Hospital.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Chu
authors.affiliation: Department of Neurology, Harvard Medical School; Department of Neurology, Beth Israel Deaconess Medical Center; Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual-Leone
authors.affiliation: Department of Neurology, Harvard Medical School; Department of Neurology, Beth Israel Deaconess Medical Center.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Chang
mesh_terms: D001921:Brain; D001931:Brain Mapping; D004569:Electroencephalography; D004827:Epilepsy / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D064847:Multimodal Imaging; D054091:Periventricular Nodular Heterotopia; D050781:Transcranial Magnetic Stimulation