Case Report Intracranial time–frequency correlates of seizure-related negative BOLD response in the sensory-motor network Stefano Meletti a,⇑ , Anna Elisabetta Vaudano a , Laura Tassi c , Fausto Caruana d , Pietro Avanzini b a Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, NOCSAE Hospital, Modena, Italy b Department of Neuroscience, University of Parma, Parma, Italy c ‘‘C. Munari’’ Epilepsy Surgery Centre, Niguarda Hospital, Milan, Italy d Brain Center for Social and Motor Cognition, Italian Institute of Technology, Parma, Italy The clinical and electrophysiological meaning of the decreased BOLD signal observed during focal seizures has not been elucidated yet. Seizures-related BOLD responses usually show increases (so called positive BOLD response; PBR) in brain regions generating the ictal activity (Tyvaert et al., 2009). Intriguingly, also negative BOLD signal changes (negative BOLD response; NBR) have been observed in most of the patients, usually remote from the EZ (Epileptogenic Zone). While the PBR has been related to an increased neuronal and synaptic activity, the significance of the NBR is less understood (Shmuel et al., 2002; Pittau et al., 2013). The electrophysiological correlates of the deactivation in spe- cific brain structures known as the default-mode network (DMN) during task performance has been elucidated, showing that all DMN areas display transient suppressions of broadband gamma (60–140 Hz) power during performance of a visual search task (Ossandón et al., 2011). Recently, Fahoum et al. (2013) investigated the intracranial neurophysiological correlates of runs of distant interictal epileptic discharges (IED) on DMN. They observed that also during spikes, regions of the DMN showing a decreased BOLD signal had a reduction in gamma frequencies paralleled by an increase in the EEG content of lower (<30 Hz) frequencies. No study has evaluated that a similar relationship, between intracranial EEG and BOLD signal, exists also for the ictal events and in cortical regions not belonging to the DMN. In this work we had the opportunity to investigate this issue by analyzing the intracranial EEG correlates, in terms of spectral frequencies, of the cortical regions showing a PBR/NBR during a EEG–fMRI study. The investigated patient had a drug-resistant frontal lobe epi- lepsy with negative motor seizures (Matsumoto et al., 2000; Ikeda et al., 2009). Detailed patient’s electro-clinical data and methodol- ogy of EEG–fMRI coregistration have been already published for dif- ferent purposes (Vaudano et al., 2013). IED and ictal events were modeled within one model as separate regressors (stick function or variable duration blocks as appropriate). Epileptic discharges (ED) were convolved with canonical hemodynamic response function (HRF), its temporal (TD) and dispersion derivatives (DD). The computed SPM{F} was thresholded at p < 0.05, corrected for multiple comparisons. Interictal ED data analysis showed a cluster of significant BOLD signal increase in the left frontal dorso-lateral cortex and no areas of BOLD decrements (Supplementary Fig. S1). One 30 s-length typical patient’s seizure was recorded character- ized by low voltage fast activity over the left frontal area. During the seizure, the patient was asked via interphone to squeeze the alarm button but he did not perform the task. At the end of the scan sessions, he reported to be alert and conscious, but he was not able to push the alarm button as requested. Ictal BOLD response demon- strated a PBR over the left dorso-lateral frontal cortex (concordant with the one obtained from IED analysis) plus a smaller cluster in the ipsilateral temporal cortex. A strong NBR was detected covering the bilateral central cortex (Fig. 1A). The temporal pattern of the BOLD signal showed that the left frontal ‘‘positive’’ and the two primary sensory motor cortices ‘‘negative’’ clusters peaked simulta- neously (Supplementary Fig. S2). The patient underwent an intracranial EEG study (icEEG) according to the stereo-EEG methodology. Eleven depth electrodes were implanted in the left fronto-temporo-insulo-central region (Supplementary Fig. S3). Each electrode was comprised of 8–18 contacts, spaced 1.5 mm apart (DIXI Ò , Besancon, France). Continuous stereo-EEG was recorded with a 1000 Hz sampling rate by means of a 192 channel-EEG device (Nihon Kohden Ò ). Data were subsequently exported and contacts of interest were selected. A band-pass filter (0.015–500 Hz) was applied to avoid any aliasing effect. Since the ictal semiology was characterized by motor arrest we used a protocol to assess movement, speech and consciousness during seizures. Motor tasks were executed simultaneously with both hands, keeping the arms outstretched, in order to evaluate the occurrence of ictal weakness. In order to compare the electrophysiological data with functional neuroimaging results, the T1-weighted anatomical MRI acquired during the fMRI session and the pre-implantation T1- weighted MRI were co-registered. The same spatial transformation was applied with the post-implantation volumetric brain CT, allowing us to determine which contacts lied within the cortical regions endowed with positive or negative BOLD response. In order to detect a focal activity and avoid a reference bias, the bipolar EEG signal between two adjacent contacts was calculated and http://dx.doi.org/10.1016/j.clinph.2014.07.030 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. ⇑ Corresponding author. Address: University of Modena and Reggio Emilia, Department of Biomedical, Metabolic, and Neural Sciences, Via Giardini 1355, 41126 Modena, Italy. Tel.: +39 0593961676; fax: +39 0593961336. E-mail address: Stefano.meletti@unimore.it (S. Meletti). Clinical Neurophysiology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph Please cite this article in press as: Meletti S et al. Intracranial time–frequency correlates of seizure-related negative BOLD response in the sensory-motor network. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.07.030