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BACKGROUND AND PURPOSE Recent studies suggest that a nonnegligible proportion of drug-resistant epilepsy surgery candidates have an epileptogenic zone that involves the insula. We aimed to examine the value of proton magnetic resonance spectroscopy (1 H-MRS) in identifying patients with insular cortex epilepsy. METHODS Patients with possible nonlesional drug-refractory insular epilepsy underwent a voxel-based 1 H-MRS study prior to an intracranial electroencephalographic (EEG) study. Patients were then divided into two groups based on invasive EEG findings: the insular group with evidence of insular seizures and the noninsular group with no evidence of insular seizures. Sixteen age-matched healthy controls were also scanned for normative data. RESULTS Twenty-two epileptic patients were recruited, 12 with insular seizures and 10 with extra-insular seizures. Ipsilateral and contralateral insular N-acetyl-aspartate concentrations ([NAA]) and NAA/Cr ratios were found to be similar in both patient groups. No significant differences in [NAA] or NAA/Cr ratios were found between the insular group, noninsular group, and healthy controls. [NAA] and NAA/Cr asymmetry indices correctly lateralized the seizure focus in only 16.7% and 0% of patients, respectively. CONCLUSIONS Our preliminary findings suggest that 1 H-MRS fares poorly in identifying patients with nonlesional insular epilepsy.

Our comprehension of the neural mechanisms underlying emotional information processing has largely benefited from noninvasive electrophysiological and functional neuroimaging techniques in recent years. However, the spatiotemporal dynamics of the neural events occurring during emotional processing remain imprecise due to the limited combination of spatial and temporal resolution provided by these techniques. This study examines the modulations of high-frequency activity of intracranial electroencephalography recordings associated with affective picture valence, in epileptic patients awaiting neurosurgery. Recordings were obtained from subdural grids and depth electrodes in eight patients while they viewed a series of unpleasant, pleasant and neutral pictures from the International Affective Picture System. Broadband high-gamma (70-150 Hz) power was computed for separate 100-ms time windows and compared according to ratings of emotional valence. Compared to emotionally neutral or pleasant pictures, unpleasant stimuli were associated with an early and long-lasting (≈200-1,000 ms) bilateral increase in high-gamma activity in visual areas of the occipital and temporal lobes, together with a late and transient (≈500-800 ms) decrease found bilaterally in the lateral prefrontal cortex (PFC). Pleasant pictures were associated with increased gamma activity in the occipital cortex, compared to the emotionally neutral stimuli. Consistent with previous studies, our results provide direct evidence of emotion-related modulations in the visual ventral pathway during picture processing. Results in the lateral PFC also shed light on the neural mechanisms underlying its role in negative emotions processing. This study demonstrates the utility of intracranial high-gamma modulations to study emotional process with a high spatiotemporal precision.

Summary Purpose To study the utility of magnetoencephalography (MEG) in patients with refractory insular epilepsy. Covered by highly functional temporal, frontal, and parietal opercula, insular-onset seizures can manifest a variety of ictal symptoms falsely leading to a diagnosis of temporal, frontal, or parietal lobe seizures. Lack of recognition of insular seizures may be responsible for some epilepsy surgery failures. Methods We retrospectively reviewed and analyzed MEG data in 14 patients with refractory insular seizures defined through intracranial electroencephalography (EEG) or by the presence of an epileptogenic lesion in the insula with compatible seizure semiology. MEG was performed as part of the noninvasive presurgical evaluation, using a 275-channel whole head MEG system. MEG data were analyzed using a single equivalent current dipole model. MEG localization was compared to interictal positron emission tomography (PET) and ictal single photon emission computed tomography (SPECT) results and to the resection margin. Key Findings Three patterns of MEG spike sources were observed. Seven patients showed an anterior operculoinsular clusters and two patients had a posterior operculoinsular cluster. No spikes were detected in one patient, and the remaining four patients showed a diffuse perisylvian distribution. Spike sources showed uniform orientation perpendicular to the sylvian fissure. Nine patients proceeded to insular epilepsy surgery with favorable surgical outcome. Among patients with anterior operculoinsular cluster who proceeded to have surgery, MEG provided superior information to ictal SPECT in four of six patients and to interictal PET in five of six patients. Significance MEG is useful in identifying patients who are likely to benefit from epilepsy surgery targeting the insula, particularly if a tight dipole cluster is identified even if other noninvasive modalities fail to produce localizing results.

Summary Purpose: We present two methods of implantation for the investigation of suspected insular and perisylvian epilepsy that combine depth and subdural electrodes to capitalize on the advantages of each technique. Methods: Retrospective study of all intracranial EEG studies that included insular electrodes from 2004–2010. Patients were divided according to the implantation scheme. The first method (type 1) consisted of a craniotomy, insertion of insular electrodes after microdissection of the sylvian fissure, orthogonal implantation of mesiotemporal structures with neuronavigation, and coverage of the adjacent lobes with subdural electrodes. The second method (type 2) consisted of magnetic resonance imaging (MRI)–stereotactic frame-guided depth electrode implantation into insula and hippocampus using sagittal axes, and insertion of subdural electrodes through burr holes to cover the adjacent lobes. The combined implantations were developed and performed by one neurosurgeon (AB). Key Findings: Nineteen patients had an intracranial study that sampled the insula, among other regions. Sixteen patients were implanted using the first method, which allowed a mean of 4, 5, 20, 15, and 42 contacts per patient to be positioned into/over the insular, mesial temporal, neocortical temporal, parietal, and frontal areas, respectively. The second method (three patients) allowed a mean of 8, 7, 16, 6, and 9 contacts per patient to sample the same areas, respectively. The four patients in whom transient neurologic deficits occurred were investigated with use of type 1 implantation. Significance: Combined depth and subdural electrodes can be used safely to investigate complex insular/perisylvian refractory epilepsy. Choice of implantation scheme should be individualized according to presurgical data and the need for functional localization.

Objective Dysregulation of the blood–brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS. Methods We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs). Results We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [14C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC50) of 9.5 × 10−8 and 1.0 × 10−7M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome–derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-γ–inducible protein-10/CXCL10 by BBB-ECs. Interpretation Our data parallel the previously reported magnetic resonance imaging–based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB. Ann Neurol 2006

Protein l-isoaspartyl methyltransferase (PIMT) repairs the damaged proteins which have accumulated abnormal aspartyl residues during cell aging. Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures. Here we investigated the role of PIMT in human mesial temporal lobe epilepsy. Using surgical specimens of hippocampus and neocortex from controls and epileptic patients, we showed that PIMT activity and expression were 50% lower in epileptic hippocampus than in controls but were unchanged in neocortex. Although the protein was down-regulated, PIMT mRNA expression was unchanged in epileptic hippocampus, suggesting post-translational regulation of the PIMT level. Moreover, several proteins with abnormal aspartyl residues accumulate in epileptic hippocampus. Microtubules component β-tubulin, one of the major PIMT substrates, had an increased amount (two-fold) of l-isoaspartyl residues in the epileptic hippocampus. These results demonstrate that the down-regulation of PIMT in epileptic hippocampus leads to a significant accumulation of damaged tubulin that could contribute to neuron dysfunction in human mesial temporal lobe epilepsy.

Summary: Purpose: Intensive long-term monitoring (LTM) for patients with refractory seizures is common and expensive. Methods to decrease the length of stay would improve patient experience and reduce cost. Therefore, we prospectively analyzed seizure occurrence in 36 patients who had LTM. Methods: Antiepileptic drug (AED) levels and reduction were monitored and seizures were related to these changes. Patients were divided into temporal and extratemporal groups. Results: Twenty patients had partial seizures of temporal lobe origin. The temporal lobe partial seizures occurred between LTM days 1 and 16. All but 4 of the patients required reduction or discontinuation of a least one AED and had subtherapeutic levels of the tapered medications. In 16 patients with extratemporal partial seizures, seizures occurred between LTM days 1 and 8. Six of these patients required reduction of at least one AED, and 5 of the 6 had subtherapeutic levels of that medication. These differences between length of monitoring monitoring and AED reduction in temporal and extratemporal patients were statistically significant. The groups did not differ significantly with respect to number or identity of tapered or nontapered medications or levels of nontapered medications. Reported seizure frequency at home was significantly related to number of seizures recorded in the temporal group only. The only significant predictor of secondarily generalized seizure activity during monitoring was a history of such activity occurring at home. Conclusions: We conclude that patients with extratemporal partial seizures need little reduction of AED for seizures to be captured in a minimal time period. Patients with temporal lobe seizures, however, required drastic reduction of AEDs to allow capture of seizures in a long time period.

Purpose How the brain recognizes visual stimuli has been extensively studied using scalp surface electrodes and magnetic resonance imaging. Complex visual stimuli such as objects and faces have been shown to strongly activate the ventral visual stream in humans. The link between this pathway of activation (bottom-up processes) and the memory (top-down processes) still has to be described. Methods In the present experiment, intracranial electroencephalography was carried out in epileptic patients implanted with subdural electrodes to localize the epileptic focus so as to directly assess brain activations evoked by visual stimuli. Fragmented pictures of objects with eight levels of coherence were used whereby at level 1 the stimulus was unrecognizable and at level 8, it constituted the complete picture. We measured the evoked potentials at four levels of recognition: threshold (T-0), two levels before threshold (T-1 and T-2) and one post threshold (T+1). Results Activations were found in V1, V2, LOC, orbito-frontal cortex (OF) and hippocampus. In V1 and V2, the early visual response suggested a higher level of treatment when trying to integrate the information to recognize the stimulus. The higher order structures, such as LOC and OF, gave their largest responses mainly at longer latencies. Conclusion This intracranial study permits precise localization coupled with high temporal resolution, which allows for a better understanding of the different mechanisms involved in a fast and accurate visual recognition of objects.