fMRI of generalized absence status epilepticus in conscious marmoset monkeys reveals corticothalamic activation

PURPOSE: A nonhuman primate model of generalized absence status epilepticus was developed for use in functional magnetic resonance imaging (fMRI) experiments to elucidate the brain mechanisms underlying this disorder. METHODS: Adult male marmoset monkeys (Callithrix jacchus) were treated with gamma-butyrolactone (GBL) to induce prolonged absence seizures, and the resulting spike-wave discharges (SWDs) were analyzed to determine the similarity to the 3-Hz SWDs that characterize the disorder. In addition, blood-oxygenation-level-dependent (BOLD) fMRI was measured at 4.7 Tesla after absence seizure induction with GBL. RESULTS: Electroencephalographic recordings during imaging showed 3-Hz SWDs typical of human absence seizures. This synchronized EEG pattern started within 15 to 20 min of drug administration and persisted for >60 min. In addition, pretreatment with the antiepileptic drug, ethosuximide (ESM), blocked the behavioral and EEG changes caused by GBL. Changes in BOLD signal intensity in the thalamus and sensorimotor cortex correlated with the onset of 3-Hz SWDs. The change in BOLD signal intensity was bilateral but heterogeneous, affecting some brain areas more than others. No significant negative BOLD changes were seen. CONCLUSIONS: The BOLD fMRI data obtained in this marmoset monkey model of absence status epilepticus shows activation within the thalamus and cortex.     

FMRI of brain activation in a genetic rat model of absence seizures

PURPOSE: EEG-triggered functional magnetic resonance imaging (fMRI) was used to identify areas of brain activation during spontaneous spike-and-wave discharges (SWDs) in an epileptic rat strain under awake conditions. METHODS: Spontaneous absence seizures from 10 WAG/Rij rats were imaged by using T2*-weighted echo planar imaging at 4.7 Tesla. fMRI of the blood-oxygenation-level-dependent (BOLD) signal was triggered based on EEG recordings during imaging. Images obtained during spontaneous SWDs were compared with baseline images. RESULTS: Significant positive BOLD signal changes were apparent in several areas of the cortex and several important nuclei of the thalamus. In addition, no negative BOLD signal was found in any brain area. CONCLUSIONS: We have shown that EEG-triggered BOLD fMRI can be used to detect cortical and thalamic activation related to the spontaneous SWDs that characterize absence seizures in awake WAG/Rij rats. These results draw an anatomic correlation between areas in which increased BOLD signal is found and those in which SWDs have been recorded. In addition, no negative BOLD signal was found to be associated with these spontaneous SWDs. We also demonstrated the technical feasibility of using EEG-triggered fMRI in a genetic rat model of absence seizure.     

Sequential analysis of fMRI images: A new approach to study human epileptic networks

Purpose: The aim of this study was to introduce a new approach for analysis of functional magnetic resonance imaging (fMRI) data in order to illustrate the temporal development of the blood oxygenation level–dependent (BOLD) signal changes induced by epileptic seizures. Method: In order to sequentially analyze the fMRI images acquired during epileptic seizures, a continuous series of echo planar imaging (EPI) scans covering the complete period of a seizure was acquired. Data were segmented into 10‐s blocks. Each block, representing a unique experimental condition, was contrasted with a neutral (no seizure) baseline condition. Visual comparison of the activations from one block to the next highlighted the course of activations and deactivations during the seizure event. This analysis was applied to three independent seizures of one patient with peri‐rolandic epilepsy secondary to chronic encephalitis: one seizure before epilepsy surgery and two after unsuccessful tailored resection. Observations were compared to results from invasive subdural electroencephalography (EEG) monitoring, single‐photon emission computed tomography (SPECT) coregistered to MRI (SISCOM), and independent component analysis (ICA), a model‐free method of BOLD‐signal analysis. Results: The initial increase in BOLD signal occurred 10–40 s before clinical onset in the same location compared to the seizure‐onset zone determined by invasive subdural evaluation and SISCOM. Sequential involvement of cortical and subcortical structures was in agreement with SISCOM, intracranial EEG recordings, and ICA results. Discussion: In selected patients, sequential analysis of changes in BOLD signal induced by epileptic seizures might represent a useful approach for investigating the temporal development of brain activity during epileptic seizures, thereby allowing imaging of those cerebral structures involved in seizure generation and propagation.     

Noninvasive dynamic imaging of seizures in epileptic patients

Epileptic seizures are due to abnormal synchronized neuronal discharges. Techniques measuring electrical changes are commonly used to analyze seizures. Neuronal activity can be also defined by concomitant hemodynamic and metabolic changes. Simultaneous electroencephalogram (EEG)‐functional MRI (fMRI) measures noninvasively with a high‐spatial resolution BOLD changes during seizures in the whole brain. Until now, only a static image representing the whole seizure was provided. We report in 10 focal epilepsy patients a new approach to dynamic imaging of seizures including the BOLD time course of seizures and the identification of brain structures involved in seizure onset and discharge propagation. The first activation was observed in agreement with the expected location of the focus based on clinical and EEG data (three intracranial recordings), thus providing validity to this approach. The BOLD signal preceded ictal EEG changes in two cases. EEG‐fMRI may detect changes in smaller and deeper structures than scalp EEG, which can only record activity form superficial cortical areas. This method allowed us to demonstrate that seizure onset zone was limited to one structure, thus supporting the concept of epileptic focus, but that a complex neuronal network was involved during propagation. Deactivations were also found during seizures, usually appearing after the first activation in areas close or distant to the activated regions. Deactivations may correspond to actively inhibited regions or to functional disconnection from normally active regions. This new noninvasive approach should open the study of seizure generation and propagation mechanisms in the whole brain to groups of patients with focal epilepsies. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Linking generalized spike-and-wave discharges and resting state brain activity by using EEG/fMRI in a patient with absence seizures

PURPOSE: To illustrate a functional interpretation of blood oxygen level-dependent (BOLD) signal changes associated with generalized spike-and-wave discharges in patients with absence seizures and to demonstrate the reproducibility of these findings in one case. METHODS: In a 47 year-old patient with frequent absence seizures, BOLD signal changes during generalized spike-and-wave discharges (GSWD) were mapped by using simultaneous and continuous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) at 1.5 T and 6 months later at 3 T. GSWDs were modeled as individual events and as blocks. RESULTS: The patient studied exhibited frequent generalized spike-wave activity with temporal properties ideal for study with EEG/fMRI. Highly reproducible GSWD-associated fMRI signal decreases (deactivations) were seen in bilateral frontal and temporoparietal cortices and the precuneus, in addition to activations in occipital cortex and, at 3 T, the posterior thalamus. CONCLUSIONS: The GSWD-associated changes seen here involve cortical regions that have been shown to be more active at conscious rest compared with sleep and with various types of extroverted perception and action. These regions have been proposed to constitute the core of a functional "default mode" system. We propose that the findings of deactivation of this distributed brain system during GSWDs mirrors the clinical manifestation of GSWDs (i.e., absence seizures). Furthermore, we suggest that these deactivations may reflect the functional consequences of GSWDs on physiologic brain activity at rest rather than direct hemodynamic correlates of epileptic discharges.     

Simultaneous BOLD fMRI and local field potential measurements during kainic acid-induced seizures

Purpose: To investigate how kainic acid–induced epileptiform activity is related to hemodynamic changes probed by blood oxygenation level–dependent functional magnetic resonance imaging (BOLD fMRI). Methods: Epileptiform activity was induced with kainic acid (KA) (10 mg/kg, i.p.), and simultaneous fMRI at 7 Tesla, and deep electrode local field potential (LFP) recordings were performed from the right hippocampus in awake and medetomidine‐sedated adult Wistar rats. Key Findings: Recurrent seizure activity induced by KA was detected in LFP both in medetomidine‐sedated and awake rats, even though medetomidine sedation reduced the mean duration of individual seizures as compared to awake rats (33 ± 24 and 46 ± 34 s, respectively, mean ± SD p < 0.01). KA administration also triggered robust positive BOLD responses bilaterally in the hippocampus both in awake and medetomidine‐sedated rats; however, in both animal groups some of the seizures detected in LFP recording did not cause detectable BOLD signal change. Significance: Our data suggest that medetomidine sedation can be used for simultaneous fMRI and electrophysiologic studies of normal and epileptic brain function, even though seizure duration after medetomidine administration was shorter than that in awake animals. The results also indicate that neuronal activity and BOLD response can become decoupled during recurrent kainic acid–induced seizures, which may have implications to interpretation of fMRI data obtained during prolonged epileptiform activity.     

Imaging the neural substrates involved in the genesis of pentylenetetrazol-induced seizures

PURPOSE: Functional imaging of animal models makes it possible to map the functional neuroanatomy contributing to the genesis of seizures. Pentylenetetrazol (PTZ)-induced seizure in rats, a relevant model of human absence and of generalized tonic-clonic epilepsy, was used to stimulate seizure activity within 30 s of administration while collecting continuous, high-resolution, multislice images at subsecond intervals. METHODS: Pilot studies were conducted to establish a quick and effective PTZ model for the imaging experiments. PTZ was then used to stimulate seizure activity in rats while collecting multislice functional MRI (fMRI) images from the entire forebrain at 4.7 Tesla. Ethosuximide (ESM) also was used to block seizure activity. RESULTS: Within 2-4 s of PTZ administration, a rapid increase in blood oxygen level-dependent (BOLD) signal intensity was noted in the thalamus, especially the anterior thalamic nuclei. Activity in the anterior thalamus peaked approximately 15 s before seizure onset and was more than twofold greater than that in all other thalamic areas. The retrosplenial cortex showed a twofold greater increase in activity as compared with other cortical areas, also peaking at approximately 15 s. The dentate gyrus was twice as active as other hippocampal areas but peaked just before seizure onset. Treatment with ESM blocked seizures, decreasing PTZ-induced activation in most forebrain areas. The anterior thalamus and retrosplenial cortex were essentially blocked by pretreatment with ESM. CONCLUSIONS: The anterior thalamus, retrosplenial cortex, and dentate gyrus show the greatest increases in BOLD signal activity before seizure onset. Neurons in these areas may contribute to the neural network controlling the initiation of generalized tonic-clonic seizure.     

Increased cortical BOLD signal anticipates generalized spike and wave discharges in adolescents and adults with idiopathic generalized epilepsies

Purpose: Electroencephalography–functional magnetic resonance imaging (EEG‐fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so‐called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level–dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset. Methods: Twenty‐one patients with IGE underwent EEG‐fMRI coregistration. EEG‐related analyses were run both at the single‐subject and at group level (random effect). The time‐course analysis was conducted for 3 s time windows before, during, and after GSWDs, and they were included until no further BOLD signal changes were observed. Key Findings: Fifteen patients (nine female, mean age 28 years) had GSWDs during EEG‐fMRI coregistration (262 total events, mean duration 4 s). Time‐course group analysis showed BOLD increments starting approximately 10 s before GSWD onset located in frontal and parietal cortical areas, and especially in the precuneus‐posterior cingulate region. At GSWD onset, BOLD increments were located in thalamus, cerebellum, and anterior cingulate gyrus, whereas BOLD decrements were observed in the DMN regions persisting until 9 s after onset. Significance: Hemodynamic changes (BOLD increments) occurred in specific cortical areas, namely the precuneus/posterior cingulate, lateral parietal, and frontal cortices, several seconds before EEG onset of GSWD. A dysfunction of these brain regions, some of which belongs to the DMN, may be crucial in generating GSWDs in patients with IGE.     

A sheep model for the study of focal epilepsy with concurrent intracranial EEG and functional MRI

PURPOSE: We describe a sheep model of penicillin-induced seizure activity using electroencephalography (EEG) and functional MRI (fMRI). METHODS: Ten adult sheep were used. Spikes and seizures were generated by instillation of 8,000-10,000 IU of penicillin into the right prefrontal cortex via a specially designed port. Bilateral intracranial EEG was acquired by using carbon fiber electrodes. Animals had behavioral characterization of their seizures and were then anesthetized for fMRI studies. Functional MRI was performed at 1.5 and 3 Tesla by measuring blood oxygen level-dependent (BOLD) weighted signal intensity at different times during the evolution of seizures. RESULTS: Behavioral seizures were associated with electrographic seizures. Intracranial EEG obtained in the MR scanner was of high quality. Focal spiking and seizures were seen in all animals and developed 11.3 +/- 11.2 s and 17.3 +/- 12.1 min after penicillin administration, respectively. An average of 13 +/- 4.8 seizures were seen per animal, each lasting 27.3 +/- 12.3 s. Functional MR images with little parenchymal artefact were obtained. Regional BOLD signal-intensity changes were observed during seizures at the seizure focus and ipsilateral amygdala. CONCLUSIONS: We have developed an animal model of partial epilepsy in which seizures can be reliably elicited with concurrent fMRI and intracranial EEG. During unilateral electrographic seizures, focal BOLD signal changes occurred at the seizure focus and ipsilateral amygdala, suggesting the presence of a cortico-subcortical loop. This observation illustrates the potential of the model for understanding seizure generation, spread, and possibly the consequences of repeated seizures on the brain.     

Distinct Neurophysiological Correlates of the fMRI BOLD Signal in the Hippocampus and Neocortex

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood oxygenation level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modeling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70–150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30–70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex.SIGNIFICANCE STATEMENT The BOLD signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in the frontal and parietal cortices. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.     

Simultaneous EEG-fMRI in drug-naive children with newly diagnosed absence epilepsy

Purpose: In patients with idiopathic generalized epilepsy (IGE), blood oxygen level dependent (BOLD) EEG during functional MRI (EEG‐fMRI) has been successfully used to link changes in regional neuronal activity to the occurrence of generalized spike‐and‐wave (GSW) discharges. Most EEG‐fMRI studies have been performed on adult patients with long‐standing epilepsy who were on antiepileptic medication. Here, we applied EEG‐fMRI to investigate BOLD signal changes during absence seizures in children with newly diagnosed childhood absence epilepsy (CAE). Methods: Ten drug‐naive children with newly diagnosed CAE underwent simultaneous EEG‐fMRI. BOLD signal changes associated with ictal EEG activity (i.e., periods of three per second GSW) were analyzed in predefined regions‐of‐interests (ROIs), including the thalamus, the precuneus, and caudate nucleus. Results: In 6 out of 10 children, EEG recordings showed periods of three per second GSW during fMRI. Three per second GSW were associated with regional BOLD signal decreases in parietal areas, precuneus, and caudate nucleus along with a bilateral increase in the BOLD signal in the medial thalamus. Taking into account the normal delay in the hemodynamic response, temporal analysis showed that the onset of BOLD signal changes coincided with the onset of GSW. Discussion: In drug‐naive individuals with CAE, ictal three per second GSW are associated with BOLD signal changes in the same striato‐thalamo‐cortical network that changes its regional activity during primary and secondary generalized paroxysms in treated adults. No BOLD signal changes in the striato‐thalamo‐cortical network preceded the onset of three per second GSW in unmediated children with CAE.     

Pathophysiology of encephalopathy related to continuous spike and waves during sleep: the contribution of neuroimaging

In the last three decades, studies on functional neuroimaging have helped us to understand pathophysiological mechanisms responsible for electro‐clinical patterns associated with epileptic encephalopathies with continuous spikes and waves during slow sleep (ECSWS). MEG and EEG source reconstruction have revealed sources of pathological brain activity associated with epileptiform discharges in the perisylvian region pointing to the significance of this brain area for ECSWS. PET studies have revealed areas of focal hypermetabolism in perisylvian, superior temporal and inferior parietal regions as well as central cortices which were related to epileptic activity. The widespread hypometabolism in regions that belong to the default network (prefrontal and posterior cingulate cortices, parahippocampal gyrus and precuneus) was interpreted as remote inhibition following epileptic activity, which could contribute to cognitive deficits in affected individuals. Note that the described metabolic changes were functional and disappeared after successful treatment and recovery of ECSWS and were found in both sleep and wakefulness which may account for cognitive deficits in patients during the day. EEG‐fMRI studies have revealed a functional fingerprint of epileptic encephalopathy: significant positive BOLD signal changes were identified in the perisylvian regions, prefrontal cortex and anterior cingulate as well as thalamus and negative BOLD signal changes in the regions of the default mode network. The pattern of activation represents a propagation of epileptic activity specific to encephalopathy, which is independent of etiology and type of seizure associated with ECSWS. In summary, methods of neuroimaging have shed light on pathogenic mechanisms of ECSWS which may account for a number of clinical phenomena associated with this condition.     

Functional deactivations: multiple ipsilateral brain areas engaged in the processing of somatosensory information

Somatosensory signals modulate activity throughout a widespread network in both of the brain hemispheres: the contralateral as well as the ipsilateral side of the brain relative to the stimulated limb. To analyze the ipsilateral somatosensory brain areas that are engaged during limb stimulation, we performed functional magnetic resonance imaging (fMRI) in 12 healthy subjects during electrical median nerve stimulation using both a block- and an event-related fMRI design. Data were analyzed through the use of model-dependent (SPM) and model-independent (ICA) approaches. Beyond the well-known positive blood oxygenation level-dependent (BOLD) responses, negative deflections of the BOLD response were found consistently in several ipsilateral brain areas, including the primary somatosensory cortex, the supplementary motor area, the insula, the dorsal part of the posterior cingulate cortex, and the contralateral cerebellum. Compared to their positive counterparts, the negative hemodynamic responses showed a different time course, with an onset time delay of 2.4 s and a peak delay of 0.7 s. This characteristic delay was observed in all investigated areas and verified by a second (purely tactile) event-related paradigm, suggesting a systematic difference for brain areas involved in the processing of somatosensory information. These findings may indicate that the physiological basis of these deactivations differs from that of the positive BOLD responses. Therefore, an altered model for the negative BOLD response may be beneficial to further model-dependent fMRI analyses.     

Simultaneous EEG,fMRI, and behavior in typical childhood absence seizures

Purpose: Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3–4‐Hz spike–wave discharges (SWDs) on electroencephalography (EEG). Prior EEG–functional magnetic resonance imaging (fMRI) studies of SWDs 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 (CAE). 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 SWDs 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 SWDs 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 SWDs, whereas 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 cortical–subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in CAE, and may help guide development of new therapies for this disorder.     

Origin of negative blood oxygenation level-dependent fMRI signals.

Functional magnetic resonance imaging (fMRI) techniques are based on the assumption that changes in spike activity are accompanied by modulation in the blood oxygenation level-dependent (BOLD) signal. In addition to conventional increases in BOLD signals, sustained negative BOLD signal changes are occasionally observed and are thought to reflect a decrease in neural activity. In this study, the source of the negative BOLD signal was investigated using T2*-weighted BOLD and cerebral blood volume (CBV) techniques in isoflurane-anesthetized cats. A positive BOLD signal change was observed in the primary visual cortex (area 18) during visual stimulation, while a prolonged negative BOLD change was detected in the adjacent suprasylvian gyrus containing higher-order visual areas. However, in both regions neurons are known to increase spike activity during visual stimulation. The positive and negative BOLD amplitudes obtained at six spatial-frequency stimuli were highly correlated, and negative BOLD percent changes were approximately one third of the positive changes. Area 18 with positive BOLD signals experienced an increase in CBV, while regions exhibiting the prolonged negative BOLD signal underwent a decrease in CBV. The CBV changes in area 18 were faster than the BOLD signals from the same corresponding region and the CBV changes in the suprasylvian gyrus. The results support the notion that reallocation of cortical blood resources could overcome a local demand for increased cerebral blood flow induced by increased neural activity. The findings of this study imply that caution should be taken when interpreting the negative BOLD signals as a decrease in neuronal activity.     

fMRI correlates of interictal epileptic activity in patients with idiopathic benign focal epilepsy of childhood. A simultaneous EEG-functional MRI study

EEG-correlated fMRI (EEG/fMRI) can identify alterations of brain function associated with interictal epileptiform discharges (IED). fMRI activation can localize the irritative zone and indicate functional disturbance distant from the spike focus. This might be of particular interest in paediatric epilepsy syndromes with frequent IED. Using simultaneous EEG/fMRI in a 3T MR scanner we studied blood oxygen level-dependent (BOLD) signal changes related to spontaneous IED in 10 children with typical and atypical benign focal epilepsy of childhood (BFE) or benign epileptic activity of childhood (BEAC). EEG artefacts were subtracted offline and IED were used as regressors for event-related fMRI analysis in SPM2. In four of the seven children with IED during EEG/fMRI we found IED related positive and negative signal changes (p<0.001, uncorrected). In three children we found only significant negative signal changes. At a more liberal threshold (p<0.05, uncorrected) these three children had positive signal changes congruent with the four children with significant positive signal changes. In summary, we found positive or negative signal changes in perisylvian, central, premotor and prefrontal regions. One child showed additional bilateral occipital fMRI activation. In addition to former reports our results indicated that frontal brain areas are functionally disturbed during IED corresponding to general neuropsychological findings in BFE and BEAC. We conclude that using EEG/fMRI it might be possible to localize generators of IED and functionally disturbed brain regions in children with BFE. Further studies are required to differentiate between BFE subtypes and to identify fMRI signatures of specific syndromes or corresponding neuropsychological deficits.     

BOLD fMRI activation induced by vagus nerve stimulation in seizure patients

OBJECTIVE: To identify the cerebral activated regions associated with the vagus nerve stimulation in epilepsy patients. DESIGN: Blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) was employed to detect areas of the brain activated by vagus nerve stimulation in five patients with documented complex partial seizures. METHODS: Functional MRI was done on a GE 1.5T Echospeed horizon scanner. Before each patient entered the scanner, the vagal nerve stimulator was set to a specific ON-OFF paradigm so that the data could be analysed using a box-car type of design. The brains were scanned both anatomically and functionally. The functional images were corrected for head motion and co-registered to the anatomical images. Maps of the activated areas were generated and analysed using the brain mapping software, SPM99. The threshold for activation was chosen as p < 0.001. RESULTS: All patients showed activation in the frontal and occipital lobes. However, activation in the thalamus was seen only in the two patients with improved seizure control. CONCLUSIONS: BOLD fMRI can detect activation associated with vagus nerve stimulation. There may be a relation between thalamic activation and a favourable clinical outcome.     

Spatiotemporal Reconfiguration of Large-Scale Brain Functional Networks during Propofol-Induced Loss of Consciousness

Applying graph theoretical analysis of spontaneous BOLD fluctuations in functional magnetic resonance imaging (fMRI), we investigated whole-brain functional connectivity of 11 healthy volunteers during wakefulness and propofol-induced loss of consciousness (PI-LOC). After extraction of regional fMRI time series from 110 cortical and subcortical regions, we applied a maximum overlap discrete wavelet transformation and investigated changes in the brain's intrinsic spatiotemporal organization. During PI-LOC, we observed a breakdown of subcortico-cortical and corticocortical connectivity. Decrease of connectivity was pronounced in thalamocortical connections, whereas no changes were found for connectivity within primary sensory cortices. Graph theoretical analyses revealed significant changes in the degree distribution and local organization metrics of brain functional networks during PI-LOC: compared with a random network, normalized clustering was significantly increased, as was small-worldness. Furthermore we observed a profound decline in long-range connections and a reduction in whole-brain spatiotemporal integration, supporting a topological reconfiguration during PI-LOC. Our findings shed light on the functional significance of intrinsic brain activity as measured by spontaneous BOLD signal fluctuations and help to understand propofol-induced loss of consciousness.     

Absence seizures: Individual patterns revealed by EEG‐fMRI

Purpose: Absences are characterized by an abrupt onset and end of generalized 3–4 Hz spike and wave discharges (GSWs), accompanied by unresponsiveness. Although previous electroencephalography–functional magnetic resonance imaging (EEG–fMRI) studies showed that thalamus, default mode areas, and caudate nuclei are involved in absence seizures, the contribution of these regions throughout the ictal evolution of absences remains unclear. Furthermore, animal models provide evidence that absences are initiated by a cortical focus with a secondary involvement of the thalamus. The aim of this study was to investigate dynamic changes during absences. Methods: Seventeen absences from nine patients with absence epilepsy and classical pattern of 3–4 Hz GSWs during EEG‐fMRI recording were included in the study. The absences were studied in a sliding window analysis, providing a temporal sequence of blood oxygen–level dependent (BOLD) response maps. Results: Thalamic activation was found in 16 absences (94%), deactivation in default mode areas in 15 (88%), deactivation of the caudate nuclei in 10 (59%), and cortical activation in patient‐specific areas in 10 (59%) of the absences. Cortical activations and deactivations in default mode areas and caudate nucleus occurred significantly earlier than thalamic responses. Discussion: Like a fingerprint, patient‐specific BOLD signal changes were remarkably consistent in space and time across different absences of one patient but were quite different from patient to patient, despite having similar EEG pattern and clinical semiology. Early frontal activations could support the cortical focus theory, but with an addition: This early activation is patient specific.     

BOLD signal changes preceding negative responses in EEG‐fMRI in patients with focal epilepsy

Purpose: In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), increased neuronal activity from epileptiform spikes commonly elicits positive blood oxygenation level–dependent (BOLD) responses. Negative responses are also occasionally seen and have not been explained. Recent studies describe BOLD signal changes before focal EEG spikes. We aimed to systematically study if the undershoot of a preceding positive response might explain the negative BOLD seen in the focus. Methods: Eighty‐two patients with focal epilepsy who underwent EEG‐fMRI at 3T were retrospectively studied. Studies with a focal negative BOLD response in the region of the spike field were reanalyzed using models with hemodynamic response functions (HRFs) peaking from ?9 to +9 s around the spike. Results: Eight patients met the inclusion criteria, showing negative BOLD responses in the spike field on standard analysis. None had positive BOLD responses immediately adjacent to the areas of deactivation. Regions of deactivation were found to have congruent preceding positive responses in two cases. These early activations were seen at the combined maps of ?5 to ?9 s. Discussion: This study indicates that in a small proportion of patients with focal epilepsy in whom the standard analysis reveals focal negative responses, an earlier positive BOLD response is probably the cause. The origin of negative BOLD signal changes in the focus as a result of an epileptic event remains, however, unexplained in most of the patients in whom it occurs.