The adaptive value of probability distortion and risk-seeking in macaques' decision-making.

In humans, the attitude toward risk is not neutral and is dissimilar between bets involving gains and bets involving losses. The existence and prevalence of these decision features in non-human primates are unclear. In addition, only a few studies have tried to simulate the evolution of agents based on their attitude toward risk. Therefore, we still ignore to what extent Prospect theory's claims are evolutionarily rooted. To shed light on this issue, we collected data from nine macaques that performed bets involving gains or losses. We confirmed that their overall behaviour is coherent with Prospect theory's claims. In parallel, we used a genetic algorithm to simulate the evolution of a population of agents across several generations. We showed that the algorithm selects progressively agents that exhibit risk-seeking, and has an inverted S-shape distorted perception of probability. We compared these two results and found that monkeys' attitude toward risk is only congruent with the simulation when they are facing losses. This result is consistent with the idea that gambling in the loss domain is analogous to deciding in a context of life-threatening challenges where a certain level of risk-seeking behaviour and probability distortion may be adaptive. This article is part of the theme issue 'Existence and prevalence of economic behaviours among non-human primates'.

Opiate dependence induces network state shifts in the limbic system.

Among current theories of addiction, hedonic homeostasis dysregulation predicts that the brain reward systems, particularly the mesolimbic dopamine system, switch from a physiological state to a new "set point." In opiate addiction, evidence show that the dopamine system principal targets, prefrontal cortex (PFC), nucleus accumbens (NAC) and basolateral amygdala complex (BLA) also adapt to repeated drug stimulation. Here we investigated the impact of chronic morphine on the dynamics of the network of these three interconnected structures. For that purpose we performed simultaneous electrophysiological recordings in freely-moving rats subcutaneously implanted with continuous-release morphine pellets. Chronic morphine produced a shift in the network state underpinned by changes in Delta and Gamma oscillations in the LFP of PFC, NAC and BLA, in correlation to behavioral changes. However despite continuous stimulation by the drug, an apparent normalization of the network activity and state occurred after 2 days indicating large scale adaptations. Blockade of µ opioid receptors was nonetheless sufficient to disrupt this acquired new stability in morphine-dependent animals. In line with the homeostatic dysregulation theory of addiction, our study provides original direct evidence that the PFC-NAC-BLA network of the dependent brain is characterized by a de novo balance for which the drug of abuse becomes the main contributor.

Interaction between cognitive and motor cortico-basal ganglia loops during decision making: a computational study.

In a previous modeling study, Leblois et al. (2006) demonstrated an action selection mechanism in cortico-basal ganglia loops based on competition between the positive feedback, direct pathway through the striatum and the negative feedback, hyperdirect pathway through the subthalamic nucleus. The present study investigates how multiple level action selection could be performed by the basal ganglia. To do this, the model is extended in a manner consistent with known anatomy and electrophysiology in three main areas. First, two-level decision making has been incorporated, with a cognitive level selecting based on cue shape and a motor level selecting based on cue position. We show that the decision made at the cognitive level can be used to bias the decision at the motor level. We then demonstrate that, for accurate transmission of information between decision-making levels, low excitability of striatal projection neurons is necessary, a generally observed electrophysiological finding. Second, instead of providing a biasing signal between cue choices as an external input to the network, we show that the action selection process can be driven by reasonable levels of noise. Finally, we incorporate dopamine modulated learning at corticostriatal synapses. As learning progresses, the action selection becomes based on learned visual cue values and is not interfered with by the noise that was necessary before learning.

Oscillatory entrainment of subthalamic nucleus neurons and behavioural consequences in rodents and primates.

We investigated the functional role of oscillatory activity in the local field potential (LFP) of the subthalamic nucleus (STN) in the pathophysiology of Parkinson's disease (PD). It has been postulated that beta (15-30 Hz) oscillatory activity in the basal ganglia induces PD motor symptoms. To assess this hypothesis, an LFP showing significant power in the beta frequency range (23 Hz) was used as a stimulus both in vitro and in vivo. We first demonstrated in rat brain slices that STN neuronal activity was driven by the LFP stimulation. We then applied beta stimulation to the STN of 16 rats and two monkeys while quantifying motor behaviour. Although stimulation-induced behavioural effects were observed, stimulation of the STN at 23 Hz induced no significant decrease in motor performance in either rodents or primates. This study is the first to show LFP-induced behaviour in both rats and primates, and highlights the complex relationship between beta power and parkinsonian symptoms.

Pallidal border cells: an anatomical and electrophysiological study in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey.

A dopamine transporter-radioligand binding study demonstrated a dopaminergic innervation around the pallidal complex in the normal monkey (n=5), i.e. where a subpopulation of pallidal neurons known as "border cells" is classically identified. Surprisingly, this peripallidal binding persists in monkeys rendered parkinsonian (n=5) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The border cell electrophysiological activity was then analysed in normal and parkinsonian monkeys (n=2), either in the untreated state or following administration of levodopa. Pallidal border cell firing frequency was significantly decreased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (8.9+/-0.7 vs 31.4+/-1.6Hz, P<0.05). This decrease was partly corrected by levodopa administration (19.2+/-1.0Hz, P<0.05 vs both normal and parkinsonian situations). The peripallidal dopaminergic innervation suggests that pallidal border cells are under a direct dopaminergic control, arising from the ventral tegmental area and/or the basal forebrain magnocellular complex, the role of which remains unknown. Moreover, the relative sparing of these dopaminergic fibers in parkinsonian monkeys suggests that they would exhibit specific adaptive properties totally different from those described in the nigrostriatal pathway.

Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey.

Despite the importance and frequency of levodopa-induced dyskinesias, little is known about their causal mechanisms. In this study, electrophysiological single-unit recordings of the neuronal activity of the globus pallidus internalis (GPi), the main basal ganglia output structure, and the globus pallidus externalis (GPe) were recorded continuously in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated subhuman primates before and after the administration of three dopamine agonists--apomorphine (a dopaminergic mixed agonist), SKF-38393 (a D1 partial agonist) and piribedil (a D2/D3 agonist)--at doses known to induce dyskinesias in the parkinsonian monkey. Changes in both the firing frequency and the firing pattern were analysed in relation to behavioural modifications. In both the normal and the parkinsonian monkey, the three agonists induced a decrease in the mean firing frequency of GPi neurones, although dyskinesias were induced only in the parkinsonian animals. In this situation, the improvement of parkinsonian motor abnormalities was correlated with the decrease in GPi firing frequency, whereas firing pattern changes were concomitant with the onset of dyskinesias. Moreover, firing frequency seemed to be decreased excessively during dyskinesias. The results indicate that the electrophysiological mechanism of dyskinesia involves an excessive decrease in GPi firing frequency and a modification of the firing pattern. However, the similarity between the induced decrease in firing frequency in normal and parkinsonian animals underlines the need for dopamine depletion in the induction of dyskinesias.

Spontaneous long-term compensatory dopaminergic sprouting in MPTP-treated mice.

The present study sought to determine whether severe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication elicits spontaneous long-term compensatory sprouting in mice. Animals, once treated, were kept without further treatment for 0.5, 1, 5, or 7 months. The stability of the nigral degeneration was checked by evaluation of the number of tyrosine hydroxylase immunoreactive (TH-IR) neurons, whereas sprouting was assessed using both [(3)H]-dopamine (DA) uptake by striatal synaptosomes and optical density of TH-immunolabeled fibers in the striatum as markers. At 0.5 month after MPTP intoxication (80 mg/kg, i.p.), we observed comparable decreases of 83% in DA uptake, 83.3% in TH fiber density, and 74% in the number of TH-IR neurons compared to age-matched saline-treated animals. From 5 months onwards, both DA uptake and striatal TH fiber density increased significantly (50% and 34.9% at 5 months, 65% and 67.4% at 7 months, respectively) in comparison with age-matched saline-treated animals, although the number of TH-IR neurons remained stable (73% of degeneration at 7 months). These results indicate clearly that spontaneous long-term compensatory dopaminergic sprouting is a phenomenon that is not restricted to situations of partial nigral degeneration but can, on the contrary, constitute a response even to severe stable MPTP-induced nigral degeneration.

Bicuculline injections into the rostral and caudal motor thalamus of the monkey induce different types of dystonia.

The pathophysiology of dystonia remains unclear in comparison with other movement disorders. Recent data suggest that there may exist in dystonia an increased thalamic drive to the mesial premotor cortex. To test this hypothesis, we induced overactivity of the motor thalamus by injecting a GABA-A (gamma-aminobutyric acid) antagonist (bicuculline) into the rostral (pallidal) and caudal (cerebellar) ventrolateral nuclei of the thalamus in both hemispheres of one monkey. Dystonic postures were observed in the contralateral limbs and axis. Electromyographic recordings revealed bursts of muscular activation with co-contractions during spontaneous dystonic movements and alterations in muscular patterns during sequential visually guided arm movements. The type of dystonia depended on the site of injections. Rostral thalamic injections induced more severe dystonic postures, whereas myoclonic jerks predominated following caudal injections. We conclude that these two distinct clinical patterns, which are frequently associated in humans, are probably due to a dysfunctioning of segregated thalamic projections to the supplementary motor area (from the rostral part) and to the primary motor cortex (from the caudal part).

Ratio of inhibited-to-activated pallidal neurons decreases dramatically during passive limb movement in the MPTP-treated monkey.

Mink advanced the hypothesis in 1996 that the role of the basal ganglia (BG) is primarily one of focused selection; the encouragement of motor mechanisms inducing a desired movement and the inhibition of competing mechanisms. This would imply, in normal subjects, a ratio of inhibited-to-activated (I/A) movement-related globus pallidus pars internalis (GPi) neurons <1 and a drastic decrease of this ratio in the parkinsonian state. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication should therefore decrease the specificity of the response of this neuronal population. To test this working hypothesis we studied the activity of GPi neurons in response to passive limb movement in the normal and the parkinsonian monkey. Extracellular unit recordings monitored any correlation between passive limb movements and eventual modifications of the neuronal activity of the GPi in two calm, awake, and drug naive monkeys (Macaca fascicularis) before and after MPTP intoxication. In the normal animal, arm- and leg-related neurons were located in clusters in the medial part of the GPi. The I/A ratio was 0.22. Most GPi cells were linked to a single joint. In the MPTP-treated monkey, the number of movement-related neurons increased, the I/A ratio dropped significantly to 0.03, and most responding cells were linked to several joints. These data, which cannot be explained by the classic "box" model, endorse Mink's hypothesis.

Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the Macaque monkey.

The most valuable model of Parkinson's disease available at present is the primate model treated with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), frequently used to study response to new drugs or surgical treatments. The evaluation of such therapies requires clinical rating scales which measure precisely motor behaviour in both normal and parkinsonian monkeys. It is obvious that such evaluation can only be valid if parallel studies are carried out under similar experimental conditions with well-defined objective criteria. Hence the need to compare and assess the different rating scales in use if we want to be able to compare the results of clinical studies. In order to give rise to some fresh thinking on the necessity of a certain uniformity of assessment, this study compares eight clinical rating scales and considers their capacity to express in quantitative terms both the severity of MPTP intoxication in five cynomolgus monkeys and the alleviation afforded by levodopa. None of the eight scales reaches all the criteria despite the Kurlan scale would appear as an interesting working basis for a further consensual definition of a worldwide used parkinsonian monkey clinical rating scale

Effects of riluzole on the electrophysiological activity of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey.

The effect of riluzole administration, an antiglutamatergic compound, on the electrophysiological activity of the pallidal complex of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys is compared with those induced by two dosages of levodopa (L-DOPA), the first affording the best clinical alleviation, the second sufficient to induce dyskinesias. Both dosages of L-DOPA reduced sharply the firing frequency of globus pallidus pars internalis (GPi) neurons (respectively, 43.8+/-23.0 and 27.4+/-20.2 vs. 111. 2+/-31.4 Hz), decreased the percentage of bursting cells (respectively, 60.7 and 50.0 vs. 80.3%) and augmented the number of regular cells (respectively, 6.5 and 33.0 vs. 4.8%). Riluzole restored the firing frequency (75.0+/-26.9 Hz) and the firing pattern of the GPi (39.7% bursting, 9.5% regular and 50.8% irregular). These results suggest that the emergence of dyskinesia may well be due to a modification of the neuronal messages transmitted from the GPi to the motor nuclei of the thalamus. Riluzole would represent an interesting alternative to dopamine therapy in Parkinson's disease since it regularizes firing but does not cause dyskinesia.

From experimentation to the surgical treatment of Parkinson's disease: prelude or suite in basal ganglia research?

Parkinson's disease remains one of the greatest challenges facing those who work in the field of neurological research. Although the development of levodopa treatment revolutionised management of this debilitating diseases, no effective long-term therapy has yet been found. With recent advances in the understanding of basal ganglia physiopathology and the experimental demonstration of the efficacy of certain surgical procedures, there is a renewed interest in the surgical approach. This paper provides a chronological overview of the history of parkinsonian surgery and discusses the principal surgical options at our disposal today. These take three main forms: ablation (thalamotomy, pallidotomy and subthalamotomy); cell graft and gene therapy (mainly in the striatum); and deep brain stimulation (of the thalamus, globus pallidus pars internalis and the subthalamic nucleus). Our knowledge of basal ganglia function and our conception of how motor information is processed by this network have evolved parallel to the development of surgical techniques. Recent results from both clinical and experimental studies underline the complexity of the physiopathological mechanisms which generate parkinsonian symptomatology and lead us to question our assumption that each class of clinical signs (tremor, akinesia, rigidity, levodopa-induced dyskinesias...) is produced by a specific and separate mechanism. In the same way, comparison of the electrophysiological and biochemical effects of the different techniques induced in brain function vary considerably. This complex world of interaction and interconnection is a labyrinth that we are still far from comprehending in its entirety. All the more reason, in consequence, for extending experimental investigation into the impact of any new therapy before proposing its clinical application.

Trichloroethylene and parkinsonism: a human and experimental observation.

This report describes the case of a 47-year-old woman who developed Parkinson's disease after seven years of professional exposure to trichloroethylene. In the light of this clinical report, mice were intoxicated with trichloroethylene and tyrosine hydroxylase immunoreactivity was used to measure neuronal death in the substantia nigra pars compacta. Treated mice presented significant dopaminergic neuronal death in comparison with control mice (50%). The environmental trichlorethylene pollution, as well as other unspecific neurotoxic solvents, could potentially contribute to the genesis of some cases of Parkinson's disease.

Cortical stimulation and epileptic seizure: a study of the potential risk in primates.

OBJECTIVE: The recent successful development of chronic stimulation of the motor cortex as a treatment for neuropathic and central pain does not exclude the possibility of eventual side effects, such as epileptic seizure or a lowering of the epileptic threshold. This study evaluates the behavioral and electroencephalographic impact of this treatment in three normal monkeys. RESULTS: None of the monkeys presented epileptic behavior or abnormal electroencephalographic activity at parameters of stimulation currently used in clinical series, i.e., frequency and pulse duration of approximately 40 Hz and 90 microseconds, respectively, and an intensity just under the threshold for inducing muscle twitch in painful areas. Higher intensities did, however, induce reversible epileptic seizure. There was, nonetheless, no modification of the epileptic threshold, because even after these seizures, intermittent light stimulation elicited no abnormal electroencephalographic activity. CONCLUSION: It thus seems that motor cortex stimulation does not induce epileptic complications when the classic clinical criteria of stimulation are respected. Nevertheless, it would be wise to subject candidates for implantation to intermittent light stimulation before and after a period of stimulation to ascertain the innocuousness of the cortical stimulation.

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.

Riluzole delayed appearance of parkinsonian motor abnormalities in a chronic MPTP monkey model.

Preliminary studies have shown that riluzole, a Na+ channel blocker with antiglutamatergic activity, has neuroprotective efficacy in several models of acute dopaminergic neurodegeneration. A chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model which comes closer to the slow evolution of Parkinson's disease has recently been developed in order to allow dynamic studies. The present results show that riluzole delayed the appearance of parkinsonian motor abnormalities in this dynamic model, using from 10.2 +/- 1.6 daily injections for the MPTP-treated monkeys (n = 4) to 16.5 +/- 2.0 daily injections for the MPTP + riluzole-treated monkeys (n = 4). These results strongly suggest that riluzole may be beneficial to slow down the rate of progression of Parkinson's disease.

Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey.

We studied the effects of L-DOPA on the firing patterns of pallidal neurons in experimental parkinsonism. After a unilateral injection of MPTP, we observed a decrease in the firing rate of GPe neurons, and a slight increase in their bursting activity. In the GPi, there was a considerable augmentation of both neuronal firing frequency and the number of bursting cells. During l-DOPA treatment (10 mg/kg), GPe neurons.pattern is almost unmodified. The firing frequency of GPi neurons, on the contrary, decreased even lower than the control level. A slight reduction was observed in bursting activity. These unexpected results would show that the normalizing effect of L-DOPA on GPi output is limited.

High-frequency stimulation of the globus pallidus internalis in Parkinson's disease: a study of seven cases.

The effectiveness of ventroposterolateral pallidotomy in the treatment of akinesia and rigidity is not a new discovery and agrees with recent investigations into the pathogenesis of Parkinson's disease, which highlight the role played by the unbridled activity of the subthalamic nucleus (STN) and the consequent overactivity of the globus pallidus internalis (GPi). Because high-frequency stimulation can reversibly incapacitate a nerve structure, we applied stimulation to the same target. Seven patients suffering from severe Parkinson's disease (Stages III-V on the Hoehn and Yahr scale) and, particularly, bradykinesia, rigidity, and levodopa-induced dyskinesias underwent unilateral electrode implantation in the posteroventral GPi. Follow-up evaluation using the regular Unified Parkinson's Disease Rating Scale has been conducted for 1 year in all seven patients, 2 years in five of them, and 3 years in one. In all cases high-frequency stimulation has alleviated akinesia and rigidity and has generally improved gait and speech disturbances. In some cases tremor was attenuated. In a similar manner, the authors observed a marked diminution in levodopa-induced dyskinesias. This could be an excellent primary therapy for younger patients exhibiting severe bradykinesia, rigidity, and levodopa-induced dyskinesias, which would allow therapists to keep ventroposterolateral pallidotomy in reserve as a second weapon.

Compensatory effects of glutamatergic inputs to the substantia nigra pars compacta in experimental parkinsonism.

The effect of transitory blockage of substantia nigra pars compacta glutamatergic inputs by intracranial injections of kynurenic acid were evaluated in two monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The MPTP protocol was designed to mimic the gradual evolution of human Parkinson's disease. No effects were observed before MPTP treatment or in the first stage of treatment. Once clinical signs appeared, however, motor abnormalities were significantly aggravated by blockage of these inputs (P < 0.001). Conversely, after full Parkinsonism was established, blockage no longer had any behavioural effect. These results confirm the postulated compensatory role of the glutamatergic pathways feeding the substantia nigra pars compacta. This added insight into the physiopathology of the basal ganglia, when compared with previous data on the presymptomatic revelation of experimental Parkinsonism, should help elucidation of the time pattern of evolution of Parkinson's disease.

Presymptomatic revelation of experimental parkinsonism.

Parkinson's disease results from a progressive loss of dopaminergic neurones of the substantia nigra (SNc). Clinical symptoms only appear, however, when neuronal death exceeds 50-60%: their late appearance is due to compensatory mechanisms. The possibility exists that glutamatergic inputs to the SNc may be implicated in this 'masking' of the disease. To test this hypothesis, we evaluated the effects of reversible pharmacological blockage of these inputs in asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The result was the appearance of motor disturbances. This finding supports the idea that SNc glutamatergic inputs are largely involved in compensatory mechanisms during presymptomatic period. Blockade of these inputs could lead to presymptomatic diagnosis of Parkinson's disease.