Alim L. Benabid

Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease†

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinsons disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinsons Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group.

High-frequency stimulation of the sub-thalamic nucleus suppresses absence seizures in the rat: comparison with neurotoxic lesions

High-frequency electrical stimulation of deep brain structures has recently been developed for the surgical approach of neurologic disorders. Applied to the thalamus in tremors or to the subthalamic nucleus in Parkinsons disease, high-frequency stimulation has been demonstrated to exert a local inhibiting influence, leading to symptoms alleviation. In the present study, bilateral high-frequency stimulations (130 Hz) of the subthalamic nuclei suppressed ongoing spontaneous absence seizures in rats. This effect was dissociated from motor side-effects and appears specific to the subthalamic nucleus. Bilateral excitotoxic lesions of the subthalamic nuclei only partially suppressed absence-seizures. These results confirm the involvement of the basal ganglia system in the control of generalized seizures and suggest that high-frequency stimulations could be used in the treatment of some forms of seizures.

Future prospects of brain stimlation

Abstract Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim has replaced thalamotomy as a treatment of tremor of various origins and was extended to two other targets (Subthalamic nucleus (STN) and the medial pallidus (CPO), since 1993 based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then suppresses also levodopa induced dyskinesias. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of network functions could be induced, by jamming ofa retroactive loop for tremor, or by shutdown ofneurotransmitter release in STN. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. The effects remain stable over more than five years chronic HFS of STN, as the method of choice when a surgical procedure is indicated for the treatment of Parkinson!s disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsies. It is therefore possible that OAS in STN as well as in other targets could become a potent therapeutic tool in the future for neurological disorders. The future of brain stimulation will depend on new technologies (new circuits, electrodes, web based programmers), waveforms (alternatives to square waves, random distribution), targets (hypothalamic nuclei, locus coeruleus) and indications (dystonia, epilepsy, eating disorders). [Neural Res 2000; 22: 237-246]

Evidence for dopamine D2 receptor mRNA expression by striatal astrocytes in culture: in situ hybridization and polymerase chain reaction studies

The expression of dopamine D2 receptor mRNA in cultured rat striatal and cerebellar astrocytes was examined by in situ hybridization (ISH) and polymerase chain reaction (PCR). Cells double-labelled for glial fibrillary acidic protein (GFAP) immuno-histochemistry and dopamine D2 receptor mRNA (ISH) provide evidence that striatal but not cerebellar astrocytes express the dopamine D2 gene in vitro. These results were confirmed by polymerase chain reaction studies. As judged by GFAP immunostaining and morphology of the cells, this gene is almost exclusively expressed by astrocytes type 1. The expression of dopamine D2 receptor mRNA by striatal astrocytes in vitro, as found in this study, brings thus evidences for the existence of dopamine D2 receptors in such glial cells. This had been previously suggested from ligand binding studies but the typical dopaminergic nature of the binding to striatal astrocytes was left questionable. Our results with molecular biological techniques thus suggest that striatal dopamine might modulate the functions of striatal astrocytes.

Immunocytochemical investigation on dysplastic human tissue from epileptic patients

In this report we describe three patients with developmental cortical abnormalities (generally referred as cortical dysplasia), revealed by MRI and operated on for intractable epilepsy. Tissue, removed for strictly therapeutic reasons, was defined as the epileptogenic area by electroclinical data and stereo EEG (SEEG) recordings. Tissue samples were processed initially for histology, and selected sections were further processed for immunocytochemical investigation in order to determine whether the region of cortical dysplasia was co-extensive with the epileptogenic area. In two patients with nodular heterotopia, disorganized aggregates of neurons (as revealed by neuronal cytoskeletal markers) were found within the nodules. Both pyramidal and local circuit neurons were present in the nodules, but no reactive gliosis was present. When nodules reached the cortex, the cortical layers were disrupted. In the patient with localized cortical dysplasia, a complete disorganization of the cortical lamination was found, and numerous neurons were also present in the white matter. Disoriented pyramidal neurons weakly labelled with cytoskeletal neuronal markers were also present but no cytomegalic cells were found. One of the patients with nodular heterotopia underwent only partial resection of both the epileptogenic area and of the lesion; this patient still presents with seizures. The other patient with nodular heterotopia is seizure-free after a complete lesionectomy and excision of the epileptogenic area. The third patient, with focal cortical dysplasia, had two surgeries; she became seizure-free only after the excision of the epileptogenic area detected by SEEG recording. The present data suggest that the dysplastic areas identified by MRI should not be considered as the only place of origin of the ictal discharges. From the neuropathological point of view, the focal cortical dysplasia can be considered as a pure form of migrational disorder. However, the presence of large aggregates of neurons interspersed within the white matter, in the subcortical nodular heterotopia, suggests that a defect of neuronal migration could be associated with an exuberant production of neuroblasts and/or a disruption of mechanisms for naturally occurring cell death.

Intracerebral Low Frequency Electrical Stimulation: a New Tool for the Definition of the “Epileptogenic Area”?

Low Frequency (1 Hz) Electrical Stimulation (LFES) has been systematically utilized, during stereo-EEG investigations, in 24 consecutive young adult patients considered for surgical treatment of severe drug-resistant partial epilepsy. Ninety seizures (1-14/patient) identical to the spontaneous ones previously recorded were thus obtained in 19 patients (79%). LFES is less effective for induction of seizures than high frequency (50 Hz) stimulation (5.9% vs 22.9%), and it also provokes less false positive responses (1% vs 17%). The main sensitive structures to LFES are the hippocampus, the amygdala, and the hippocampal gyrus. However, seizures were also induced by stimulating the temporal lobe white matter, the temporal pole, and the temporal neocortex, as well as the orbito-frontal cortex (in the only patient with fronto-temporal epilepsy). The more frequently observed electrical pattern is a gradual increase of spikes and spikes and waves frequency, with or without occurrence of low voltage fast activity. The high percentage of early subjective manifestations similar to the spontaneous ones, the lack of major electrical artifact, and the good visualization of the spatial evolution of the induced-discharge, strongly suggest that LFES is of great help for defining the epileptogenic area.

Met-enkephalin receptors in human gliomas.

Endogenous opioid systems (opioid peptides and receptors) are involved in many functions including the regulation of cell growth. We investigated the presence of Met-enkephalin binding sites in gliomas by displacement assays. Results demonstrated that few gliomas exhibit Met-enkephalin binding sites and that the percentage of tumours which express these binding sites strongly decreases with increasing malignancy. Moreover, we observed a shift from mu Met-enkephalin binding sites in low grade gliomas to delta Met-enkephalin binding sites in high grade gliomas. These results suggest an inactivation of the Met-enkephalinergic system in gliomas which could lead to loss of the inhibitory effect exerted by Met-enkephalin on normal astrocyte growth and thus favour progression of malignancy.

Lip and tongue force control in patients with Parkinson’s disease

The objective of the present study was to characterize the motor control of idiopathic Parkinson’s disease patients and normal subjects during orofacial nonverbal tasks. The fine force control associated with speechlike force magnitudes in three articulatory organs: Upper lip, lower lip, and tongue were examined by means of force transducers. Using visual feedback, subjects produced ramp‐and‐hold compression forces as rapidly and accurately as possible to end‐point target levels ranging from 0.25 to 2 N. The relationship among several parameters of the ramp‐and‐hold force contraction and target force level was quantified in 14 Parkinsonian patients (7 males and 7 females) and 14 age‐ and sex‐matched control subjects. All patients were successively evaluated in two conditions, that is, without and with levodopa therapy. The results demonstrated an abnormal isometric control force of the articulatory organs in patients with Parkinson’s disease. Moreover, differences were observed between lip and tongue moto...

Orofacial and finger force control in normal subjects

The relationship among several parameters of the ramp‐and‐hold force contraction and target force level was quantified for the upper lip, lower lip, and tongue on the one hand, and right and left index on the other hand, in 12 normal subjects (6 males and 6 females). Using visual feedback, subjects produced ramp‐and‐hold compression lip, tongue, and index forces as rapidly and accurately as possible to end‐point target levels ranging from 0.25 to 2 newtons, these fine force occurring within physiologic levels presumably involved in speech production. Given the special anatomic and physiologic characteristics of the orofacial system, the purpose of this study was to compare lip, tongue, and finger force control in order to determine whether the motor control is uniform in both systems, that of the speech production and that of the limb, and within subsystems of speech production. Consequently, can be pathophysiology of a movement disorder in its stereotypic form be considered across limb and speech systems...

Identification and characterization of an anti-tyrosine kinase factor in cystic gliomas

In view of the frequent activation of the epidermal growth factor receptor (EGF‐R) in gliomas and autocrine hypothesis, we searched for ‘EGF‐like’ factor(s) in cystic fluids (CFs) associated with gliomas. Membranes of A431 cells, which overexpress EGF‐R, were used to explore such activity in 20 CFs. In all cases CFs induced inhibition of EGF‐R phosphorylation. Biochemical analysis revealed an anti‐tyrosine kinase activity which was identified as a 18 kDa proteic factor. Effectiveness at high dilution and anti‐proliferative effect on living cells in culture suggest that this factor may be involved in the negative regulation of glial oncogenesis.