Thomas Boraud

Reversal of Rigidity and Improvement in Motor Performance by Subthalamic High‐frequency Stimulation in MPTP‐treated Monkeys

In Parkinsons disease the loss of dopaminergic neurons in the substantia nigra is associated with global disorganization of basal ganglia activity and, in particular, with increased activity of the excitatory glutamatergic neurons of the subthalamic nucleus. Recent experimental studies have shown that parkinsonian symptoms can be alleviated by selective lesioning of the subthalamic nucleus in monkeys treated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). We measured the effect of high‐frequency stimulation of the subthalamic nucleus in two unilaterally MPTP‐treated monkeys in order to determine whether it was possible to obtain reversible, gradual and controllable functional impairment of this structure. Clinical, mechanographic and electromyographic results demonstrate that this technique can alleviate parkinsonian rigidity and bradykinesia without causing dyskinesia or hemiballismus. This study supports the hypothesis that the subthalamic nucleus and its excitatory projections have an important role in the mechanisms sustaining the expression of parkinsonian motor changes, and suggests that high‐frequency stimulation of the subthalamic nucleus could be included in treatment for parkinsonism.

Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function.

In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor–selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.

Competition between Feedback Loops Underlies Normal and Pathological Dynamics in the Basal Ganglia

Experiments performed in normal animals suggest that the basal ganglia (BG) are crucial in motor program selection. BG are also involved in movement disorders. In particular, BG neuronal activity in parkinsonian animals and patients is more oscillatory and more synchronous than in normal individuals. We propose a new model for the function and dysfunction of the motor part of BG. We hypothesize that the striatum, the subthalamic nucleus, the internal pallidum (GPi), the thalamus, and the cortex are involved in closed feedback loops. The direct (cortex–striatum–GPi–thalamus–cortex) and the hyperdirect loops (cortex–subthalamic nucleus–GPi–thalamus–cortex), which have different polarities, play a key role in the model. We show that the competition between these two loops provides the BG–cortex system with the ability to perform motor program selection. Under the assumption that dopamine potentiates corticostriatal synaptic transmission, we demonstrate that, in our model, moderate dopamine depletion leads to a complete loss of action selection ability. High depletion can lead to synchronous oscillations. These modifications of the network dynamical state stem from an imbalance between the feedback in the direct and hyperdirect loops when dopamine is depleted. Our model predicts that the loss of selection ability occurs before the appearance of oscillations, suggesting that Parkinsons disease motor impairments are not directly related to abnormal oscillatory activity. Another major prediction of our model is that synchronous oscillations driven by the hyperdirect loop appear in BG after inactivation of the striatum.

Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata

HIGH‐FREQUENCY STIMULATION (HFS) of the subthalamic nucleus (STN) has been shown to produce a dramatic alleviation of motor symptoms in patients with advanced Parkinsons disease. Its functional mechanism, however, remains obscure. We used extracellular recording and in situ cytochrome oxidase (CoI) mRNA hybridization to investigate the effects of HFS of the STN on neuronal activity of the STN and the substantia nigra reticulata (SNr) in normal rats and rats with 6‐hydroxydopamine (6‐OHDA) lesion of the substantia nigra compacta (SNc). To allow detection of spikes and analysis of firing activity, artifacts recorded during stimulation were scaled down using a template subtraction method. In both normal and lesioned rats, the activity of a majority of STN neurons was inhibited during stimulation. In the SNr, HFS also induced an inhibition of the activity of a majority of neurons in normal and lesioned rats. In situ hybridization histochemistry confirmed these results in that it showed a significant decrease in levels of CoI mRNA expression in the STN and SNr in both normal and lesioned rats during stimulation. These data afford an interesting insight into the functional mechanism of deep brain stimulation and support the hypothesis that HFS exerts an inhibitory influence on STN neuronal firing.—Tai, C.‐H., Boraud, T., Bezard, E., Bioulac, B., Gross, C., Benazzouz, A. Electrophysiological and metabolic evidence that high‐frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J. 17, 1820–1830 (2003)

Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings.

Neuronal oscillations underlie a number of physiological processes, such as respiration, diurnal rhythms of the sleep-wake cycle, and gait. Oscillatory activity can be observed in many different brain regions and can be synchronized across these different regions or nuclei. Oscillatory activity has

High frequency stimulation of the internal Globus Pallidus (GPi) simultaneously improves parkinsonian symptoms and reduces the firing frequency of GPi neurons in the MPTP-treated monkey

The firing pattern of the neurons of the internal Globus Pallidus (GPi) is greatly disturbed in Parkinsons disease. Surgical lesion or high frequency stimulation (HFS) of the GPi reduces parkinsonian rigidity and akinesia. We evaluated in this study the effects of HFS of the GPi on the firing pattern of its neurons. Extracellular recordings were carried out under three types of experimental conditions in rhesus monkeys, normal state, after MPTP treatment and during HFS of the GPi. After intracarotidian MPTP injection, the firing rate of GPi cells increased significantly. During HFS, MPTP-induced parkinsonian motor symptoms clearly improved correlatively with a significant decrease in the firing rate of GPi cells in the stimulated area. HFS restored a firing frequency similar to that in normal animals and, unexpectedly, did not completely block neuronal activity.

Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study

Previous studies have shown that riluzole (2-amino-6-trifluoromethoxy-benzothiazole), a drug which interferes with glutamate neurotransmission, has a neuroprotective action in rodent models of global and focal cerebral ischemia. In this pilot study, the protective and palliative effects of riluzole have been examined using an animal model of Parkinsons disease. Two monkeys were rendered hemiparkinsonian by one intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and motor signs were evaluated using clinical examination and electromyographic recordings. When riluzole (4 mg/kg) was administered before the injection of MPTP, parkinsonian motor symptoms, in particular bradykinesia and rigidity, were absent. When injected daily in one monkey which presented stable motor symptoms, bradykinesia and rigidity were significantly reduce d. Riluzole pretreatment induced a persistent increase in dopamine turnover when compared to MPTP alone. Thus, a possible neuroprotection and a facilitation of dopamine release may explain the behavioural effects reported with riluzole treatment. These preliminary results suggest that riluzole could possess neuroprotective and palliative effects in a primate model of Parkinsons disease.

Preparatory activity in motor cortex reflects learning of local visuomotor skills

In humans, learning to produce correct visually guided movements to adapt to new sensorimotor conditions requires the formation of an internal model that represents the new transformation between visual input and the required motor command. When the new environment requires adaptation to directional errors, learning generalizes poorly to untrained locations and directions, indicating that such learning is local. Here we replicated these behavioral findings in rhesus monkeys using a visuomotor rotation task and simultaneously recorded neuronal activity. Specific changes in activity were observed only in a subpopulation of cells in the motor cortex with directional properties corresponding to the locally learned rotation. These changes adhered to the dynamics of behavior during learning and persisted between learning and relearning of the same rotation. These findings suggest a neural mechanism for the locality of newly acquired sensorimotor tasks and provide electrophysiological evidence for their retention in working memory.

Spike Synchronization in the Cortex-Basal Ganglia Networks of Parkinsonian Primates Reflects Global Dynamics of the Local Field Potentials

Cortical local field potentials (LFPs) reflect synaptic potentials and accordingly correlate with neuronal discharge. Because LFPs are coherent across substantial cortical areas, we hypothesized that cortical spike correlations could be predicted from them. Because LFPs recorded in the basal ganglia (BG) are also correlated with neuronal discharge and are clinically accessible in Parkinsons disease patients, we were interested in testing this hypothesis in the BG, as well. We recorded LFPs and unit discharge from multiple electrodes, which were placed in primary motor cortex or in the basal ganglia (striatum and pallidum) of two monkeys before and after rendering them parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We used the method of partial spectra to construct LFP predictors of the spike cross-correlation functions (CCFs). The predicted CCF is an estimate of the correlation between two neurons under the assumption that their association is explained solely by the association of each with the LFP recorded on a third electrode. In the normal condition, the predictors account for cortical rate covariations but not for the association among the tonically active neurons of the striatum. In the parkinsonian condition, with the appearance of 10 Hz oscillations throughout the cortex-basal ganglia networks, the LFP predictors account remarkably better for the CCFs in both the cortex and the basal ganglia. We propose that, in the parkinsonian condition, the cortex-basal ganglia networks are more tightly related to global modes of brain dynamics that are echoed in the LFP.

Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms

The purpose of the present study was to investigate whether the subthalamic nucleus (STN) was implicated in the glutamatergic compensatory mechanisms which have been shown to mask the parkinsonian motor abnormalities at the end of the presymptomatic period in experimental parkinsonism. Using multiunit electrophysiological recordings, we follow changes of activity occurring in the STN and in both the pars externalis and the pars internalis of the globus pallidus of monkeys chronically intoxicated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), according to a protocol designed to mimic the gradual evolution of dopaminergic neuronal death. STN activity augmented significantly in the course of treatment, even before the first appearance of clinical signs (P < 0.01). This result would indicate that the STN, which increases its level of activity even before the end of the presymptomatic period, is principally responsible for the instigation of glutamatergic compensatory mechanisms which allow the maintenance of the striatal dopaminergic homeostasis.