Our objective was to evaluate the brain regions showing increased and decreased metabolism in patients at the time of generalized bursts of epileptic discharges in order to understand their mechanism of generation and effect on brain function. By recording the electroencephalogram during the functional MRI, changes in the blood oxygenation level-dependent signal were obtained in response to epileptic discharges observed in the electroencephalogram of 15 patients with idiopathic generalized epilepsy. A group analysis was performed to determine the regions of positive (activation) and negative (deactivation) blood oxygenation leveldependent responses that were common to the patients. Activations were found bilaterally and symmetrically in the thalamus, mesial midfrontal region, insulae, and midline and bilateral cerebellum and on the borders of the lateral ventricles. Deactivations were bilateral and symmetrical in the anterior frontal and parietal regions and in the posterior cingulate gyri and were seen in the left posterior temporal region. Activations in thalamus and midfrontal regions confirm known involvement of these regions in the generation or spread of generalized epileptic discharges. Involvement of the insulae in generalized discharges had not previously been described. Cerebellar activation is not believed to reflect the generation of discharges. Deactivations in frontal and parietal regions remarkably followed the pattern of the default state of brain function. Thalamocortical activation and suspension of the default state may combine to cause the actual state of reduced responsiveness observed in patients during spike-and-wave discharges. This brief lapse of responsiveness may therefore not result only from the epileptic discharge but also from its effect on normal brain function.absence ͉ epilepsy ͉ thalamus T he electroencephalogram (EEG) of patients with epilepsy presents paroxysmal discharges that depend on the type of epilepsy. In epilepsy that has been termed ''idiopathic generalized'' according to the Commission on Classification and Terminology of the International League Against Epilepsy (1), the most common type of discharge is the 2-to 3-Hz spike-and-wave burst, which occurs simultaneously over wide cortical regions, most often with an anterior predominance. The origin of this discharge and of the absence seizures that often accompany spike-and-wave bursts when they last several seconds has been a subject of investigation and controversy for many years (see ref.2 for a review), particularly with respect to the involvement of subcortical structures. The recently developed method of combined EEG and functional magnetic resonance imaging (fMRI) (EEG͞fMRI) allows the investigation of the brain regions, cortical and subcortical, that are involved in metabolic changes as a result of epileptic discharges seen in the scalp EEG. In our recent publication (3), we described for each individual the patterns of increases and decreases in blood oxygenation leveldependent (BOLD) signal resulting from bu...

The objectives of this study were to evaluate the haemodynamic response of the cerebral cortex and thalamus during generalized spike and wave or polyspike and wave (GSW) bursts in patients with idiopathic generalized epilepsy (IGE). The haemodynamic response is measured by fMRI [blood oxygenation level-dependent (BOLD) effect]. We used combined EEG-functional MRI, a method that allows the unambiguous measurement of the BOLD effect during bursts, compared with measurements during the inter-burst interval. Fifteen patients with IGE had GSW bursts during scanning and technically acceptable studies. fMRI cortical changes as a result of GSW activity were present in 14 patients (93%). Changes in the form of activation (increased BOLD) or deactivation (decreased BOLD) occurred symmetrically in the cortex of both hemispheres, involved anterior as much as posterior head regions, but were variable across patients. Bilateral thalamic changes were also found in 12 patients (80%). Activation predominated over deactivation in the thalamus, whereas the opposite was seen in the cerebral cortex. These results bring a new light to the pathophysiolocal mechanisms generating GSW. The spatial distribution of BOLD responses to GSW was unexpected: it involved as many posterior as anterior head regions, contrary to the usual fronto-central predominance seen in EEG. The presence of a thalamic BOLD response in most patients provided, for the first time in a group of human patients, confirmation of the evidence of thalamic involvement seen in animal models. The possible mechanisms underlying these phenomena are discussed.

Combined EEG-fMRI has recently been used to explore the BOLD responses to interictal epileptiform discharges. This study examines whether misspecification of the form of the haemodynamic response function (HRF) results in significant fMRI responses being missed in the statistical analysis. EEG-fMRI data from 31 patients with focal epilepsy were analysed with four HRFs peaking from 3 to 9 sec after each interictal event, in addition to a standard HRF that peaked after 5.4 sec. In four patients, fMRI responses were correlated with gadolinium-enhanced MR angiograms and with EEG data from intracranial electrodes. In an attempt to understand the absence of BOLD responses in a significant group of patients, the degree of signal loss occurring as a result of magnetic field inhomogeneities was compared with the detected fMRI responses in ten patients with temporal lobe spikes. Using multiple HRFs resulted in an increased percentage of data sets with significant fMRI activations, from 45% when using the standard HRF alone, to 62.5%. The standard HRF was good at detecting positive BOLD responses, but less appropriate for negative BOLD responses, the majority of which were more accurately modelled by an HRF that peaked later than the standard. Co-registration of statistical maps with gadolinium-enhanced MRIs suggested that the detected fMRI responses were not in general related to large veins. Signal loss in the temporal lobes seemed to be an important factor in 7 of 12 patients who did not show fMRI activations with any of the HRFs.

SUMMARYPurpose: To investigate the effect of sleep stage on the properties of high-frequency oscillations (HFOs) recorded from depth macroelectrodes in patients with focal epilepsy. Methods: Ten-minute epochs of wakefulness (W), stage 1-2 non-REM (N1-N2), stage 3 non-REM (N3) and REM sleep (R) were identified from stereo-electroencephalography (SEEG) data recor ded at 2 kHz in nine patients. Rates of spikes, ripples (>80 Hz), and fast ripples (>250 Hz) were calculated, as were HFO durations, degree of spike-HFO overlap, HFO rates inside and outside of spikes, and inside and outside of the seizureonset zone (SOZ). Results: Ripples were observed in nine patients and fast ripples in eight. Spike rate was highest in N1-N2 in 5 of 9 patients, and in N3 in 4 of 9 patients, whereas ripple rate was highest in N1-N2 in 4 of 9 patients, in N3 in 4 of 9 patients, and in W in 1 of 9 patients. Fast ripple rate was highest in N1-N2 in 4 of 8 patients, and in N3 in 4 of 8 patients. HFO properties changed significantly with sleep stage, although the absolute effects were small. The difference in HFO rates inside and outside of the SOZ was highly significant (p < 0.000001) in all stages except for R and, for fast ripples, only marginally significant (p = 0.018) in W. Conclusions: Rates of HFOs recorded from depth macroelectrodes are highest in non-REM sleep. HFO properties were similar in stages N1-N2 and N3, suggesting that accurate sleep staging is not necessary. The spatial specificity of HFO, particularly fast ripples, was affected by sleep stage, suggesting that recordings excluding REM sleep and wakefulness provide a more reliable indicator of the SOZ.

Patients with epilepsy often present in their electroencephalogram (EEG) short electrical potentials (spikes or spikewave bursts) that are not accompanied by clinical manifestations but are of important diagnostic significance. They result from a population of abnormally hyperactive and hypersynchronous neurons. It is not easy to determine the location of the cerebral generators and the other brain regions that may be involved as a result of this abnormal activity. The possibility to combine EEG recording with functional MRI (fMRI) scanning opens the opportunity to uncover the regions of the brain showing changes in the fMRI signal in response to epileptic spikes seen in the EEG. These regions are presumably involved in the abnormal neuronal activity at the origin of epileptic discharges. This paper reviews the methodology involved in performing such studies, particularly the challenge of recording a good quality EEG inside the MR scanner while scanning is taking place, and the methods required for the statistical analysis of the combined EEG and fMRI time series. We review the results obtained in patients with different types of epileptic disorders and discuss the difficult theoretical problems raised by the interpretation of an increase (activation) and decrease (deactivation) in blood oxygen level dependent (BOLD) signal, both frequently seen in response to spikes.

Simultaneous electroencephalogram/functional magnetic resonance imaging (EEG-fMRI) during interictal epileptiform discharges can result in positive (activation) and negative (deactivation) changes in the blood oxygenation level-dependent (BOLD) signal. Activation probably reflects increased neuronal activity and energy demand, but deactivation is more difficult to explain. Our objective was to evaluate the occurrence and significance of deactivations related to epileptiform discharges in epilepsy. We reviewed all EEG-fMRI studies from our database, identified those with robust responses (P = 0.01, with > or =5 contiguous voxels with a |t| > 3.1, including > or =1 voxel at |t| > 5.0), and divided them into three groups: activation (A = 8), deactivation (D = 9), and both responses (AD = 43). We correlated responses with discharge type and location and evaluated their spatial relationship with regions involved in the "default" brain state (Raichle et al. [2001]: Proc Natl Acad Sci 98:676-682]. Deactivations were seen in 52/60 studies (AD + D): 26 related to focal discharges, 12 bilateral, and 14 generalized. Deactivations were usually distant from anatomical areas related to the discharges and more frequently related to polyspike- and spike-and-slow waves than to spikes. The "default" pattern occurred in 10/43 AD studies, often associated with bursts of generalized discharges. In conclusion, deactivations are frequent, mostly with concomitant activation, for focal and generalized discharges. Discharges followed by a slow wave are more likely to result in deactivation, suggesting neuronal inhibition as the underlying phenomenon. Involvement of the "default" areas, related to bursts of generalized discharges, provides evidence of a subclinical effect of the discharges, temporarily suspending normal brain function in the resting state.

Summary:Purpose: Simultaneous EEG and functional MRI (f MRI) allows measuring metabolic changes related to interictal spikes. Our objective was to investigate blood oxygenation leveldependent (BOLD) responses to temporal lobe (TL) spikes by using EEG-f MRI recording.Methods: We studied 35 patients who had a diagnosis of temporal lobe epilepsy (TLE) and active TL spiking on routine scalp EEG recording. Two-hour sessions of continuous EEG-f MRI were recorded, and spikes were identified after offline artifact removal and used as events in the f MRI analysis. Each type of spike was analyzed separately, as one EEG-f MRI study. We determined significant (p < 0.05) positive (activation) and negative (deactivation) BOLD responses for each study.Results: Twenty-seven patients had spikes during scanning (19 unilateral and eight bilateral). From a total of 35 f MRI studies, 29 (83%) showed BOLD responses: 14 had both activations and deactivations; 12, activations only; and three, deactivations only.Six (17%) showed no responses. Nineteen studies had mainly neocortical TL activation: Sixteen (84%) of 19 concordant with spikes, 12 of 16 with concomitant activation of the contralateral TL, and 16 of 19 with additional extratemporal activation; few showed exclusively mesial TL activation. Seventeen studies showed deactivation, either extratemporal plus temporal (n = 8) or exclusively extratemporal (n = 9).Conclusions: BOLD responses to TL spikes occurred in 83% of studies, predominated in the spiking temporal lobe, and manifested as activation or deactivation. Responses often involved the contralateral homologous cortex at the time of unilateral spikes and were frequently observed in extratemporal regions, suggesting that TL epileptic spikes can affect neuronal activity at a distance through synaptic connections. Key Words: EEG-f MRI-TLE-Interictal temporal lobe spikes-BOLD response.Temporal lobe epilepsy (TLE) is the prototype of localization-related epilepsy. Nevertheless, evidence for more diffuse changes in this disorder, involving cortical and subcortical structures outside the epileptogenic temporal lobe (TL), is provided from a multiplicity of sources. Surgical results in TLE are good but far from perfect, particularly in long-term follow-up studies (1,2). Electrophysiological studies point to regions outside the epileptogenic TL in some individuals, particularly the insula (3) and perisylvian cortex (4). Volumetric magnetic resonance (MR) measurements suggest involvement of contralateral TL, thalami, and striatum (5,6). Positron emission tomography (7-12) and MR spectroscopy (13,14) also point to widespread abnormalities. These functional neuroimaging studies can provide a broad view of the metabolic dysfunction throughout the brain, but they do not have the Accepted August 23, 2005. Address correspondence and reprint requests to Dr. E. Kobayashi at Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, 3801 University Street, Montreal Que., Canada, H3A 2B4. E-mail: e...

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n=0.91±0.04, M=10.45%) than in the contralateral S1/M1 (n=0.65±0.03, M=10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8-13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR.