Michel F. Levesque

Synaptic reorganization by mossy fibers in human epileptic fascia dentata.

This study was designed to identify whether synaptic reorganizations occur in epileptic human hippocampus which might contribute to feedback excitation. In epileptic hippocampi, (n = 21) reactive synaptogenesis of mossy fibers into the inner molecular layer of the granule cell dendrites was demonstrated at the light microscopic and electron microscopic levels. There was no inner molecular layer staining for mossy fibers in autopsy controls (n = 4) or in controls with neocortex epilepsy having no hippocampal sclerosis (n = 2). Comparing epileptics to controls, there were statistically significant correlations between Timm stain density and hilar cell loss. Since hilar neurons are the origin of ipsilateral projections to the inner molecular layer, this suggests that hilar deafferentation of this dendritic zone precedes mossy fiber reafferentation. Quantitative Timm-stained electron microscopy revealed large, zinc-labelled vesicles in terminals with asymmetric synapses on dendrites in the inner molecular and granule cell layers. Terminals in the middle and outer molecular layers did not contain zinc, were smaller and had smaller vesicles. These histochemical and ultrastructural data suggest that in damaged human epileptic hippocampus, mossy fiber reactive synaptogenesis may result in monosynaptic recurrent excitation of granule cells that could contribute to focal seizure onsets.

Presurgical evaluation for partial epilepsy : relative contributions of chronic depth-electrode recordings versus FDG-PET and scalp-sphenoidal ictal EEG

One hundred fifty-three patients with medically refractory partial epilepsy underwent chronic stereotactic depth-electrode EEG (SEEG) evaluations after being studied by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and scalp-sphenoidal EEG telemetry. We carried out retrospective standardized reviews of local cerebral metabolism and scalp-sphenoidal ictal onsets to determine when SEEG recordings revealed additional useful information. FDG-PET localization was misleading in only 3 patients with temporal lobe SEEG ictal onsets for whom extratemporal or contralateral hypometabolism could be attributed to obvious nonepileptic structural defects. Two patients with predominantly temporal hypometabolism may have had frontal epileptogenic regions, but ultimate localization remains uncertain. Scalp-sphenoidal ictal onsets were misleading in 5 patients. For 37 patients with congruent focal scalp-sphenoidal ictal onsets and temporal hypo-metabolic zones, SEEG recordings never demonstrated extratemporal or contralateral epileptogenic regions; however, 3 of these patients had nondiagnostic SEEG evaluations. The results of subsequent subdural grid recordings indicated that at least 1 of these patients may have been denied beneficial surgery as a result of an equivocal SEEG evaluation. Weighing risks and benefits, it is concluded that anterior temporal lobectomy is justified without chronic intracranial recording when specific criteria for focal scalp-sphenoidal ictal EEG onsets are met, localized hypometabolism predominantly involves the same temporal lobe, and no other conflicting information has been obtained from additional tests of focal functional deficit, structural imaging, or seizure semiology.

The magnetic and electric fields agree with intracranial localizations of somatosensory cortex

We measured the magnetoencephalogram (MEG), electroencephalogram (EEG), and electrocorticogram (ECoG) after stimulation of contralateral median nerve in four patients with partial epilepsy evaluated for surgery. Quantitative localization estimates from equivalent source modeling were compared with locations of central fissure in hand sensorimotor area determined by cortical stimulations, intraoperative photographs, and examination after excision in frontal lobe. We also measured MEG and EEG in nine control subjects. MEG and EEG localizations were within 2.5 cm of the estimated location of central fissure in all 13 subjects. In the three patients who had complete mapping of all three fields, the average distance of localizations from central fissure was approximately 4 mm in both MEG and EEG, 3 mm in ECoG, and 3 mm in combined MEG and EEG. MEG was simpler than EEG, which was simpler than ECoG. MEG resolved ambiguities in both EEG and ECoG. The combination of the three fields added information about the spatiotemporal activity of somatosensory cortex. Localization of central fissure was essential to surgical treatment.

Comparisons of MEG, EEG, and ECoG source localization in neocortical partial epilepsy in humans

In order to delineate the characteristics of epileptic spikes, 1946 different spikes were studied in 6 patients with complex partial epilepsy. Non-invasive MEG and EEG source analysis of interictal spikes were contrasted to ECoG localization, surgical outcome and presence of lesions on MRI. Results indicated that: (1) using the most frequent occurring spike topography patterns from a large sample of spikes improved goodness-of-fit values for both MEG and EEG localization, (2) when spike patterns could be appropriately matched on several successive MEG measurements to provide an adequate matrix (3 of 6 subjects), there was excellent agreement between MEG dipole sources and ECoG sources as well as surgical outcome and presence of MRI lesions, (3) EEG source analyses also gave good results but not as consistently as MEG.

Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices

To investigate physiological properties of epileptogenic neurons in relation to epileptic pathology, intracellular recording and intracellular dye injection after the recording were obtained in dentate granule cells in slices prepared from excised human epileptic hippocampus in which selective cell degeneration has been documented. Markedly prolonged excitatory postsynaptic potentials (EPSPs) were recorded in 67% of the total neurons sampled during perforant path stimulation. Such EPSPs were voltage dependent and sensitive to the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid. Neurons that generated the increased N-methyl-D-aspartate (NMDA) responses were accompanied by abnormal dendritic morphology, i.e. loss of dendritic spines and development of beaded shafts. These findings suggest that an NMDA receptor-mediated toxic process that impinges specifically on dendritic components might take place in intractable epilepsy.

Interictal cerebral metabolism in partial epilepsies of neocortical origin

We performed interictal [18F]fluorodeoxyglucose positron emission tomography (FDG PET) in 24 patients with partial epilepsy of neocortical origin. Two-thirds of patients had regions of hypometabolism. The zone of intracranially recorded electrographic ictal onset was always located in a region of hypometabolism, in those with hypometabolism. Hypometabolic regions in partial epilepsies of neocortical origin were usually associated with structural imaging abnormalities. Regional hypometabolism occasionally occurred without localizing ictal scalp EEG and cerebral magnetic resonance imaging findings, however. FDG PET may be useful in directing placement of intracranial electrodes for presurgical evaluation of refractory neocortical seizures.

The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy.

In temporal lobe epilepsy (TLE) lesion patients the pathology, location of intracranial ictal EEG onsets, and hippocampal neuron losses were compared. Patients (n = 63) were classified into: (1) Tumors (n = 26, e.g. astrocytomas, gangliogliomas); (2) vascular (n = 9, e.g. cavernous and venous angiomas); (3) developmental (n = 17, e.g. cortical dysplasia, heterotopias); or (4) atrophic (n = 11, e.g. cortical or white matter encephalomalacia). Other variables were; (1) the location of the temporal lesion in the mesial to lateral, and anterior to posterior plane, (2) a clinical history of an initial precipitating injury (IPI) prior to the onset of TLE (e.g. prolonged first seizure, head trauma), (3) hippocampal neuron densities, (4) focal or regional location by intracranial depth EEG of ictal onsets, and (5) seizure outcomes. Results showed that severe hippocampal neuron losses were associated with two statistically significant findings. First, patients with mesial lesions in or adjacent to the body of the hippocampus had greater neuron losses compared to mesial lesions anterior or posterior to the hippocampus (P = 0.04). Second, lesion patients with an IPI history had greater Ammons horn (AH) neuron losses compared to those without IPI histories (P = 0.0005), and the profile of loss was similar to hippocampal sclerosis (HS). Granule cell losses correlated in a complex manner in that; 1) by regression analysis densities decreased with longer intervals of TLE (P = 0.006), (2) tumor patients with IPIs had less granule cell loss compared to those without IPIs intervals of TLE (P = 0.006), (2) tumor patients with IPIs had less granule cell loss compared to those without IPIs (P = 0.05), and (3) developmental patients with IPIs had greater granule cell loss than patients without IPIs (P = 0.009). Mesial-temporal depth EEG electrodes were the first areas of ictal activity in 15 of 16 patients (94%), and greater hippocampal neuron losses were not associated with focal mesial-temporal EEG onsets. Seizure outcomes were worse in tumor patients compared to HS patients (P = 0.01), and patients with post-resection seizures had incomplete resections of their lesions and/or hippocampi. These results indicate that in TLE lesion patients the amount and pattern of hippocampal neuron loss depends on the location of the lesion, the pathologic classification, and a history of an IPI. Further, despite variable neuron losses, in temporal lesion patients the hippocampus was nearly always involved in the genesis or propagation of the chronic seizures.

Cortical sensory representation of the human hand Size of finger regions and nonoverlapping digit somatotopy

Findings differ on cortical representation of fingers between human and animal studies, and on digit somatotopy among human studies. To resolve these differences, we mapped cortical sensory representation of each of the five digits and of median and ulnar nerves in three patients, using focal peripheral electrical shock stimuli. We compared locations and sizes of cortical regions among digits and nerves, using the model of a current dipole in a sphere applied to electrocorticography from subdural grids. Cortical representation was larger for the index finger than for the little finger and for the middle finger than for the ring finger, which are similar to findings in the monkey but different from Penfields classic sensory homunculus. The thumb was larger than the middle finger, as in the homunculus. There was nonoverlapping somatotopy of all digits in each patient. These findings demonstrate a previously unrecognized similarity of cortical sensory organization of the fingers between humans and other primates.

Physiologic properties of human dentate granule cells in slices prepared from epileptic patients

The neurophysiological properties of human dentate granule cells were studied in hippocampal slices prepared from patients undergoing surgical treatment for medically intractable temporal lobe epilepsy. In 24 neurons which were morphologically identified as dentate granule cells by intracellular staining with biocytin, there were 2 types of synaptic responses to perforant path stimulation: one showed an EPSP-IPSP sequence (n = 10) and the other showed prolonged EPSPs without accompanying hyperpolarizing IPSPs (n = 14). The prolonged EPSPs were markedly retarded by the application of an NMDA receptor antagonist, APV. Membrane properties of neurons showing the different classes of synaptic responses were similar in resting membrane potential (pooled average: -56.2 mV +/- 0.94 SEM) and spike amplitude (pooled average: 65.2 mV +/- 1.69 SEM). However, membrane resistance tended to be lower in neurons with prolonged EPSPs (31.8 M omega +/- 2.63 SEM) than in neurons that showed EPSP-IPSP responses (40.2 +/- 4.33) (P less than 0.05, Fisher). No spontaneous and/or evoked burst firing was observed. These data provide fuller information on the neurophysiological properties of human dentate granule cells in surgically resected epileptogenic hippocampus, implicating a role of NMDA receptor activation in human temporal lobe epilepsy.

Functional anatomy of human hand sensorimotor cortex from spatiotemporal analysis of electrocorticography

We measured chronic electrocorticography (ECoG) of sensorimotor cortex during contralateral median nerve stimulation in 6 patients with partial seizures evaluated for surgery. We analyzed the spatiotemporal structure of the somatosensory evoked response (SER) using multiple source modeling to investigate functional anatomy of its neuronal sources. Two dipole sources in postcentral gyrus explained the large majority of the first 60 msec of the SER, indicating a subregion of hand somatosensory cortex generating this activity. The source locations agreed with normal functional anatomy from cortical stimulations, intraoperative photographs, and postoperative neurological examinations after focal excisions. The time patterns of both sources were biphasic like the previously described N20-P30 and P25-N35 peaks. The spatiotemporal patterns of both sources overlapped. Spatiotemporal analysis with multiple dipole sources appears useful to determine the number, locations, and spatiotemporal field patterns of cortical regions active during peripheral somatosensory stimulation and reveals simplicity in the macroscopic functional anatomy of dynamic human sensorimotor cortex.