Stéphane Clemenceau

Perturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy

Changes in chloride (Cl−) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl− homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABAA receptor-mediated postsynaptic events, indicating a perturbed Cl− homeostasis. We assessed possible contributions of changes in expression of the potassium–chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from ∼30% of CaMKIIα (calcium/calmodulin-dependent protein kinase IIα)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium–sodium–chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABAA reversal potentials and suppressed interictal activity. Changes in Cl− transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

Converging Intracranial Markers of Conscious Access

We compared conscious and nonconscious processing of briefly flashed words using a visual masking procedure while recording intracranial electroencephalogram (iEEG) in ten patients. Nonconscious processing of masked words was observed in multiple cortical areas, mostly within an early time window (<300 ms), accompanied by induced gamma-band activity, but without coherent long-distance neural activity, suggesting a quickly dissipating feedforward wave. In contrast, conscious processing of unmasked words was characterized by the convergence of four distinct neurophysiological markers: sustained voltage changes, particularly in prefrontal cortex, large increases in spectral power in the gamma band, increases in long-distance phase synchrony in the beta range, and increases in long-range Granger causality. We argue that all of those measures provide distinct windows into the same distributed state of conscious processing. These results have a direct impact on current theoretical discussions concerning the neural correlates of conscious access.

Mapping interictal oscillations greater than 200 Hz recorded with intracranial macroelectrodes in human epilepsy

Interictal high-frequency oscillations over 200 Hz have been recorded with microelectrodes in the seizure onset zone of epileptic patients suffering from mesial temporal lobe epilepsy. Recent work suggests that similar high-frequency oscillations can be detected in the seizure onset zone using standard diagnostic macroelectrodes. However, only a few channels were examined in these studies, so little information is available on the spatial extent of high-frequency oscillations. Here, we present data on high-frequency oscillations recorded from a larger number of intracerebral contacts spatial (mean 38) in 16 patients. Data were obtained from 1 h of interictal recording sampled at 1024 Hz and was analysed using a new semi-automatic detection procedure based on a wavelet decomposition. A detailed frequency analysis permitted a rapid and reliable discrimination of high-frequency oscillations from other high-frequency events. A total of 1932 high-frequency oscillations were detected with an average frequency of 261 +/- 53 Hz, amplitude of 11.9 +/- 6.7 microV and duration of 22.7 +/- 11.6 ms. Records from a patient often showed several different high-frequency oscillation patterns. We classified 24 patterns from 11 patients. Usually (20/24 patterns) high-frequency oscillations were nested in an epileptic paroxysm, such as a spike or a sharp wave, and typically high-frequency oscillations (19/24) were recorded from just one recording contact. Unexpectedly in other cases, high-frequency oscillations (5/24) were detected simultaneously on two or three contacts, sometimes separated by large distances. This large spatial extent suggests that high-frequency oscillations may sometimes result from a neuronal synchrony manifest on a scale of centimetres. High-frequency oscillations were almost always recorded in seizure-generating structures of patients suffering from mesial (9/9) or polar (1/3) temporal lobe epilepsy. They were never found in the epileptic or healthy basal, lateral temporal or extra temporal neocortex nor in the healthy amygdalo-hippocampal complex. These findings confirm that the generation of oscillations at frequencies higher that 200 Hz is, at this scale, a specific, intrinsic property of seizure-generating networks in medial and polar temporal lobes, which have a common archaic phylogenetic origin. We show that this activity can be detected and its spatial extent determined with conventional intracranial electroencephalography electrodes in records from patients with temporal lobe epilepsy. It is a reliable marker of the seizure onset zone that should be considered in decisions on surgical treatment.

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

The mechanisms involved in the transition to an epileptic seizure remain unclear. To examine them, we used tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability along with alkalinization or low Mg2+. During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of subjects with epilepsy revealed that similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster and had larger amplitudes than interictal discharges and had a distinct initiation site. These events depended on glutamatergic mechanisms and were preceded by pyramidal cell firing, whereas interneuron firing preceded interictal events that depended on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggered seizures. Thus, the subiculum supports seizure generation, and the transition to seizure involves an emergent glutamatergic population activity.

Three-dimensional Computed Tomographic Angiography in Detection of Cerebral Aneurysms in Acute Subarachnoid Hemorrhage

OBJECTIVE Three-dimensional computed tomographic angiography (CTA) is a recently developed imaging modality. We demonstrate the value of this noninvasive method in replacing digital subtraction angiography (DSA) in the detection of aneurysms of the circle of Willis in patients with subarachnoid hemorrhage admitted to our institution. METHODS A helical acquisition was performed for computed tomographic scans obtained for 120 patients with a 1 mm per second table speed and a 1-mm collimation, 1:1 pitch. Axial source images were transferred on a console Advantage Windows workstation (General Electric, Milwaukee, WI) and CTA was obtained using maximum intensity projection reconstruction. All patients had undergone DSA of the circle of Willis (80 patients preoperatively and 40 postoperatively). RESULTS A total of 129 aneurysms were detected in 107 patients. Three-dimensional CTA disclosed nothing abnormal in 13 patients. Ninety-two patients sustained one aneurysm, 10 patients sustained two, 3 patients sustained three, and 2 patients sustained four. All results were confirmed by DSA. In two cases, aneurysms of the middle cerebral artery were defected by CTA but not by DSA. When using angiographic views, the aneurysm was always masked by a branch of the middle cerebral artery. CONCLUSION The sensitivity of three-dimensional CTA is comparable with that of DSA, and its specificity is 100%. Because CTA is simple, quick, noninvasive, and reliable, we think that it can eventually replace DSA.

Role of the supplementary motor area in motor deficit following medial frontal lobe surgery.

Objective: Patients undergoing surgical resection of medial frontal lesions may present a transient postoperative deficit that remains largely unpredictable. The authors studied the role of the supplementary motor area (SMA) in the occurrence of this deficit using fMRI. Methods: Twenty-three patients underwent a preoperative fMRI before resection of medial frontal lesions. Tasks included self-paced flexion/extension of the left and right hand, successively. Preoperative fMRI data were compared with postoperative MRI data and with neurologic outcome. Results: Following surgery, 11 patients had a motor deficit from which all patients recovered within a few weeks or months. The deficit was similar across patients, consisting of a global reduction in spontaneous movements contralateral to the operated side with variable severity. SMA activation was observed in all patients. The deficit was observed when the area activated in the posterior part of the SMA (SMA proper) was resected. Conclusions: fMRI is able to identify the area at risk in the SMA proper whose resection is highly related to the occurrence of the motor deficit. The clinical characteristics of this deficit support the role of the SMA proper in the initiation and execution of the movement.

Spatial memory deficits in patients with lesions affecting the medial temporal neocortex.

Lesion studies in monkeys suggest that neocortical subregions of the medial temporal lobe (MTL) carry memory functions independent of the hippocampal formation. The present study investigates possible differential contributions of MTL subregions to spatial memory in humans. Eye movements toward remembered spatial cues (memory‐guided saccades) with unpredictably varied memorization delays of up to 30 seconds were recorded in patients with postsurgical lesions of the right MTL, either restricted to the hippocampal formation (n = 3) or including the adjacent neocortex (n = 5) and in 10 controls. Although saccadic targeting errors of patients with selective hippocampal lesions did not differ from controls, saccadic targeting errors of patients with additional neocortical involvement showed a significant and contralaterally pronounced increase at memorization delays above 20 seconds. We conclude that the human medial temporal neocortex carries spatial memory functions independent of the hippocampal formation and distinct from spatial short‐term memory. Ann Neurol 1999;45:312–319

A Candidate Mechanism Underlying the Variance of Interictal Spike Propagation

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocorticographic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IISs). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA receptor blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spreads through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.

Is Amygdalohippocampectomy Really Selective in Medial Temporal Lobe Epilepsy? A Study Using Positron Emission Tomography with 18Fluorodeoxyglucose

Summary:  Purpose: Selective amygdalohippocampectomy (SAH) is a surgical technique effective for the treatment of medial temporal lobe epilepsy, which selectively removes the epileptogenic hippocampus and amygdala but spares the temporal neocortex. However, the benefit of SAH in terms of functional outcome is debated. In this study, we aimed to assess the metabolic consequences of SAH.

Different mechanisms of ripple-like oscillations in the human epileptic subiculum.

Transient high‐frequency oscillations (HFOs; 150–600Hz) in local field potentials generated by human hippocampal and parahippocampal areas have been related to both physiological and pathological processes. The cellular basis and effects of normal and abnormal forms of HFOs have been controversial. This lack of agreement is clinically significant, because HFOs may be good markers of epileptogenic areas. Better defining the neuronal correlate of specific HFO frequency bands could improve electroencephalographic analyses made before epilepsy surgery.