Alain Rougier

Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis

Many experimental studies suggest that NFkappaB, a transcription factor involved in acute inflammation, and cytokines participate in neuronal excitability and/or glial scar formation in epilepsy. In this report, we looked for the expression of NFkappaB in hippocampi surgically removed in patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS) who had an history of febrile convulsions. We analyzed 18 hippocampi from epileptic patients with MTLE and HS, and we used as control specimens three hippocampi from non-epileptic patients and four hippocampi from patients with cryptogenic MTLE without HS. We used antibodies raised against the NFkappaB-p65 subunit and we identified glial cells with specific antibodies. Hippocampi from patients with MTLE and HS displayed severe neuronal loss surrounded by gliosis in CA1 area and more or less in CA3/CA4 areas. Double immunolabeling showed that reactive astrocytes of lesioned areas over-expressed NFkappaB-p65 (significantly when compared to control specimens). Moreover, some surviving pyramidal neurons in these areas and numerous dentate granule cells were strongly positive for NFkappaB-p65 in cytoplasm and nucleus, whereas control hippocampi showed a faint basal cytoplasmic staining in neurons. These results suggest that in epileptic hippocampi with typical sclerosis, inflammatory processes are chronically active or transiently re-induced by recurrent seizures. Whether NFkappaB over-expression reflects protective or deleterious mechanisms in the epileptic focus remains to be elucidated.

Short- and Long-Delay Intracranial ERP Repetition Effects Dissociate Memory Systems in the Human Brain

Prior exposure to a stimulus can facilitate the performance to subsequent presentations of that stimulus. ERP studies have shown that this facilitation is associated with the modulation of two components (N400 and P600). Investigation of the time course of both behavioral and ERP repetition effects have led to the assumption that it is subserved by the combination of at least two mechanisms operating at different time-points: a short-delay semantic activation and a long-lasting episodic mechanism. The present experiment recorded intracranial ERPs from various structures during a continuous recognition memory task to investigate the respective contribution of the different brain regions to short-and long-delay ERP repetition effects. The results are in good agreement with both the classical neuropsychological literature and the more recent data obtained with functional imagery techniques. They provide electrophysiological evidence of multiple anatomo-functional memory systems in the human brain: a short-term semantic activation system and a long-term episodic memory system, with interface structures that coordinate the functioning of these two systems.

Delayed kindling epileptogenesis and increased neurogenesis in adult rats housed in an enriched environment.

Environmental risk factors such as stressful experiences have long been recognized to affect seizure susceptibility, but little attention has been paid to the potential effects of improving housing conditions. In this study, we investigated the influence of an enriched environment on epileptogenesis. Epileptic susceptibility was assessed in animals housed in an enriched environment either before and during (group I) or only during (group II) a kindling procedure and in animals placed in isolated conditions (group III). The kindling paradigm provides a reliable assessment of the capacity to develop seizures following repeated daily low-frequency electrical stimulations. As both enriched environment and seizures are known to interfere with hippocampal neurogenesis, the number of newly generated dentate cells was assessed before and after the kindling procedure to investigate in more detail the relationship between epileptogenesis and neurogenesis. We found that susceptibility to developing epilepsy differed in animals housed in complex enriched environments and in those housed in isolated conditions. Kindling epileptogenesis occurred significantly later in animals housed in enriched conditions throughout the procedure (group I) than in animals from groups II and III. We also demonstrated that cells generated during kindling survived for at least 42 days and that these cells were more numerous on both sides of the brain following environmental enrichment than in rats housed in isolated conditions. As similar values were obtained regardless of the duration of the period of enrichment, these cellular changes may not play a major role in delaying kindling development. We suggest that the increase response in neurogenesis following seizures may be an adaptative rather an epileptogenic response.

Distinct striatal targets in treating obsessive-compulsive disorder and major depression.

The ventral striatum, including the head of the caudate nucleus and the nucleus accumbens, is a putative target for deep brain stimulation (DBS) in the treatment of obsessive-compulsive disorder (OCD) and major depression (MD). However, the respective roles of these structures in the pathophysiology of OCD and MD remain to be clarified. To address this issue, DBS of the ventral striatum was tested in 2 patients with severely distressing and intractable forms of OCD and MD. Comparisons of clinical outcomes and anatomical data on electrode positioning showed that caudate nucleus stimulation preferentially alleviated OCD manifestations, whereas nucleus accumbens stimulation improved depressive symptoms. These findings suggest that the caudate nucleus and nucleus accumbens participate differently in the pathogenesis of both of these psychiatric conditions.

Correlations between granule cell dispersion, mossy fiber sprouting, and hippocampal cell loss in temporal lobe epilepsy

Summary: Purpose: Correlations between granule cell dispersion (GCD), collateral mossy fiber (MF) sprouting, and hippocampal cell loss were studied to assess the relation between GCD and synaptic reorganization in the dentate gyrus of patients with epilepsy.

Granule cell dispersion is correlated with early epileptic events in human temporal lobe epilepsy

Granule cell dispersion (GCD) into the dentate gyrus (DG) molecular layer was observed in hippocampal specimens in 10 out of 22 cases of human non-lesional temporal lobe epilepsy (TLE) and was associated with hippocampal sclerosis (HS). The presence of GCD was significantly linked to events of epileptic nature arising during the first 4 years of life but not with the durations of epilepsy, nor the number of seizures. Dispersion could be induced by seizure-linked structural plasticity occurring during a specific early permissive period.

Neuronal Correlates of Obsessions in the Caudate Nucleus

BACKGROUND Metabolic overactivity of corticosubcortical loops including the caudate nucleus (CN) has been reported in obsessive-compulsive disorder (OCD) using functional imaging techniques. However, direct proof of a modification of neuronal activity within the CN of OCD patients is still lacking. We tested the hypothesis that obsessions or compulsions might be associated with particular features of neuronal activity in the CN of OCD patients. METHODS Single unit recordings were performed peroperatively in the CN of three patients with severe forms of obsessive-compulsive disorder (OCD) who were candidates for deep brain stimulation of the CN. Severity of obsessions was assessed preoperatively with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and peroperatively with a subjective obsession score based on a visual analog scale (VAS). RESULTS Frequency of CN discharge and variability of interspike intervals were found to be abnormally high in two patients with a high VAS score during surgery but not in one with a low VAS score. Lateralization and depth of recording influenced neuronal activity variably among patients. CONCLUSIONS Because the three patients had high Y-BOCS scores before surgery, these findings suggest that caudate hyperactivity in OCD is concomitant with the occurrence of the obsession process.

Effect of age of onset of temporal lobe epilepsy on the severity and the nature of preoperative memory deficits.

The nature and severity of pre-operative memory deficits observed in unilateral temporal lobe epilepsy depend upon a number of variables. Among these variables, age of seizure onset seems to be important. The age at which the lesion is sustained could modify the normal functional organization of the brain. Many studies have examined the effect of age of onset on the severity of memory deficits but have seldom focused on the nature of such deficits (verbal/nonverbal) as a function of epileptic focus laterality. This study investigates the effect of age of onset on the nature and severity of memory impairments. Fifty-six epileptics with unilateral temporal lobe epilepsy and 20 normal subjects were administered a neuropsychological evaluation. Four groups of patients were constituted: left or right temporal lobe epilepsy with early (0-5 years) or late (10 years and over) age of seizure onset. The early group showed major verbal and nonverbal memory deficits. The late group presented minor specific deficits: essentially verbal deficits with left temporal lobe seizures and nonverbal deficits with right temporal lobe seizures. These results may be interpreted in the framework of ontogenesis theories of hemispheric specialization.

Improvement of severe trunk spasms by bilateral high-frequency stimulation of the motor thalamus in a patient with chorea-acanthocytosis

We report on a patient with a severe form of chorea‐acanthocytosis, intractable to medical treatment, who benefited from bilateral high‐frequency stimulation (HFS) of the posterior ventral oral nucleus of the thalamus. The frequency of trunk spasms dramatically decreased after surgery and the clinical benefit remained stable 1 year later. However, no clear effect was observed on dysarthria nor on hypotonia, which always impaired gait. We propose that HFS of the motor thalamus is a potential treatment for choreic or truncal dystonic symptoms whenever hypotonia is not the main feature of the syndrome.

Exploration of hemispheric specialization and lexico-semantic processing in unilateral temporal lobe epilepsy with verbal fluency tasks

Verbal production has been shown to rely on both hemispheres differentially. To determine how lateralized brain lesions affect the generation of isolated words, we evaluated three subject groups: normal controls (n=22), and patients with right (n=23), and left (n=22) non-operated temporal lobe epilepsy (TLE) using three verbal fluency tasks (letter, phonetic, semantic). LTLE patients produced fewer words than controls in the phonetic, letter, semantic conditions, whereas RTLE patients were only impaired in the semantic task. Hence, there would be a hemispheric specialization in language where phonetic processing involves mostly the left temporal lobe and semantic aspects of production involve both temporal lobes. And, in order to study disruption of semantic lexicon involved in supermarket fluency (to name things which can be bought in a supermarket), specific indicators Tröster et al., (1998) [Tröster AI, Fields JA, Testa JA, Paul RH, Blanco CR, Hames KA, Salmon DP, Beatty WW. Cortical and subcortical influences on clustering and switching in the performance of verbal fluency Tasks, Neuropsychologia 1998;36:295-304.] were exploited. Our results indicated that TLE groups made fewer category shifts than controls. Also, RTLE patients used labels more frequently and produced fewer exemplars. Results show the specificity of processing according to cue, and suggest that the semantic fluency deficits due to TLE be primarily due to an alteration of the mental lexicon.