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Based on numerous imaging and electrophysiological studies, the presupplementary motor area (pre-SMA) and the rostral cingulate motor area are cortical regions considered to be essential to voluntary movement initiation and behavioral control. However, their respective roles and functional interactions remain a long-standing and still debated question.Here, we trained 2 rhesus monkeys (Macaca mulatta) in a complex cognitive task to compare the neuronal activity of these 2 regions on the medial wall during both perceptual and internally guided decisions.We confirmed the implication of both areas throughout the decision process. Critically, we demonstrate that instead of a stable invariant role, the pre-SMA and rostral cingulate motor area manifested a versatile hierarchical relationship depending on the mode of movement initiation. Whereas pre-SMA neurons were primarily engaged in decisions based on perceptual information, rostral cingulate motor area neurons preempted the decision process in case of an internally doubt-driven checking behavior, withholding pre-SMA recruitment during the time spent inhibiting the habitual action.We identified a versatile hierarchical organization of the mediofrontal area that may substantially affect normal and pathological decision processes because adaptive behaviors, such as doubt-checking and its compulsive counterpart, rely on this subtle equilibrium in controlling action initiation.

When a subject faces conflicting situations, decision-making becomes uncertain. The human dorsal anterior cingulate cortex (dACC) has been repeatedly implicated in the monitoring of such situations, and its neural activity is thought to be involved in behavioral adjustment. However, this hypothesis is mainly based on neuroimaging results and is challenged by animal studies that failed to report any neuronal correlates of conflict monitoring. This discrepancy is thought be due either to methodological or more fundamental cross-species differences. In this study, we eliminated methodological biases and recorded single-neuron activity in monkeys performing a Stroop-like task. We found specific changes in dACC activity during incongruent trials but only in a small subpopulation of cells. Critically, these changes were not related to reaction time and were absent before any incorrect action was taken. A larger fraction of neurons exhibited sustained activity during the whole decision period, whereas another subpopulation of neurons was modulated by reaction time, with a gradual increase in their firing rate that peaked at movement onset. Most of the neurons found in these subpopulations exhibited activity after the delivery of an external negative feedback stimulus that indicated an error had been made. These findings, which are consistent with an executive control role, reconcile various theories of prefrontal cortex function and support the homology between human and monkey cognitive architectures.

International audience; Behavioral adaptation generally follows the contextual changes arising from the consequences (rewards and punishments) of an action. According to the reciprocal determinism model, there is a mutual influence between external context, cognitive processes and behavior. The maladaptive behaviors observed in obsessive-compulsive disorder (OCD) have been hypothesized to result from the disruption of the interactions between these three entities. For this, we assessed the influence of error signals and checking behavior on prefrontal cortical functions during decision-making in 14 OCD patients and 14 matched healthy participants. We used a behavioral task designed to elicit intolerance of uncertainty (IU) followed by the free expression of checking behaviors, which was coupled with functional magnetic resonance imaging. At the behavioral level, IU intensity was correlated to the number of checking behaviors in both checking OCD patients and healthy controls during decision-making. However, external error signals did not influence checking behaviors in OCD patients, whereas they appeared to trigger checking behaviors in healthy subjects. At the neural level, IU intensity was positively correlated with activation in the orbitofrontal cortex (OFC) in both the OCD and control groups. At the region of interest (ROI) level, error signals increased IU-related OFC activations; in contrast, checking behaviors contributed to decreasing these neural activations in the healthy subjects, but no such modulation was observed in the OCD patients. Our results show that IU-related OFC dysfunctions are not under the influence of the context and the behavioral response in OCD, suggesting that alterations of the dynamic features for this neural network may contribute to the expression of OCD symptoms.

When facing doubt, humans can go back over a performed action in order to optimize subsequent performance. The present study aimed to establish and characterize physiological doubt and checking behavior in non-human primates (NHP). We trained two rhesus monkeys (Macaca mulatta) in a newly designed “Check-or-Go” task that allows the animal to repeatedly check and change the availability of a reward before making the final decision towards obtaining that reward. By manipulating the ambiguity of a visual cue in which the reward status is embedded, we successfully modulated animal certainty and created doubt that led the animals to check. This voluntary checking behavior was further characterized by making EEG recordings and measuring correlated changes in salivary cortisol. Our data show that monkeys have the metacognitive ability to express voluntary checking behavior similar to that observed in humans, which depends on uncertainty monitoring, relates to anxiety and involves brain frontal areas.

The pattern of activity of globus pallidus (GP) neurons is tightly regulated by GABAergic inhibition. In addition to extrinsic inputs from the striatum (STR-GP) the other source of GABA to GP neurons arises from intrinsic intranuclear axon collaterals (GP-GP). While the contribution of striatal inputs has been studied, notably its hyperactivity in Parkinson's disease (PD), the properties and function of intranuclear inhibition remain poorly understood. Our objective was therefore to test the impact of chronic dopamine depletion on pallido-pallidal transmission. Using patch-clamp whole-cell recordings in rat brain slices, we combined electrical and optogenetic stimulations with pharmacology to differentiate basic synaptic properties of STR-GP and GP-GP GABAergic synapses. GP-GP synapses were characterized by activity-dependent depression and insensitivity to the D(2) receptor specific agonist quinpirole and STR-GP synapses by frequency-dependent facilitation and quinpirole modulation. Chronic dopamine deprivation obtained in 6-OHDA lesioned animals boosted the amplitude of GP-GP IPSCs but did not modify STR-GP transmission and increased the amplitude of miniature IPSCs. Replacement of calcium by strontium confirmed that the quantal amplitude was increased at GP-GP synapses. Finally, we demonstrated that boosted GP-GP transmission promotes resetting of autonomous activity and rebound-burst firing after dopamine depletion. These results suggest that GP-GP synaptic transmission (but not STR-GP) is augmented by chronic dopamine depletion which could contribute to the aberrant GP neuronal activity observed in PD.

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.

The therapeutic benefit of L-DOPA is commonly attributed to restoration of dopamine (DA) extracellular levels in the striatum of Parkinsonian patients. However, the loss of efficacy of L-DOPA after chronic use is paradoxically associated with a similar or enhanced striatal DA response. Release of L-DOPA-derived DA depends on the widespread serotonergic (5-HT) innervation in the brain. Chronic exposure of 5-HT neurons to L-DOPA could lead to aberrant neurochemical responses beyond the striatum. Using multi-site intracerebral microdialysis in a rat model of Parkinson's disease, we showed that chronic L-DOPA treatment at a therapeutic dose (12 mg/kg/day for 10 days) homogeneously reduced basal 5-HT release and metabolism. These effects were paralleled by a decrease in tissue content of 5-HT and its metabolite. Chronic L-DOPA treatment severely altered the brain pattern of 5-HT and DA release responses to L-DOPA (3-12 mg/kg) with an overall loss of efficacy of L-DOPA to increase DA release. Our data demonstrate for the first time in vivo that the impairment of 5-HT neuronal function induced by chronic L-DOPA alters in a region-dependent manner L-DOPA-induced DA release. Changes in neurochemical pattern of L-DOPA in the brain may favour the occurrence of both motor and non-motor side effects.

SUMMARY Study objectives were to determine the prevalence of sleepy driving accidents and to explore the factors associated with near-miss driving accidents and actual driving accidents in France. An epidemiological survey based on telephone interviews was conducted on a representative sample of French drivers. The questionnaire included sociodemographics, driving and sleep disorder items, and the Epworth sleepiness scale. Of 4774 drivers (response rate: 86%), 28% experienced at least one episode of severe sleepiness at the wheel (i.e. requiring to stop driving) in the previous year; 11% of drivers reported at least one near-miss accident in the previous year (46% sleep-related); 5.8% of drivers reported at least one accident, 5.2% of these being sleep related (an estimate of 90 000 sleep-related accidents per year in France). Sleepy driving accidents occurred more often in the city (53.8%), during short trips (84.6%) and during the day (84.6%). Using logistic regression, the best predictive factor for near-misses was the occurrence of at least one episode of severe sleepiness at the wheel in the past year [odds ratio (OR) 6.50, 95% confidence interval (CI), 5.20–8.12, P < 0.001]. The best predictive factors for accidents were being young (18–30 years; OR 2.13, 95% CI, 1.51– 3.00, P < 0.001) and experiencing at least one episode of severe sleepiness at the wheel (OR 2.03, 95% CI, 1.57–2.64, P < 0.001). Sleepiness at the wheel is a risk factor as important as age for traffic accidents. Near-misses are highly correlated to sleepiness at the wheel and should be considered as strong warning signals for future accidents.

Benefit and motor side effects of l-DOPA in Parkinson's disease have been related to dopamine transmission in the striatum. However, the putative involvement of serotonergic neurons in the dopaminergic effects of l-DOPA suggests that the striatum is not a preferential target of l-DOPA. By using microdialysis in a rat model of Parkinson's disease, we found that l-DOPA (3-100 mg/kg) increased dopamine extracellular levels monitored simultaneously in four brain regions receiving serotonergic innervation: striatum, substantia nigra, hippocampus, prefrontal cortex. The increase was regionally similar at the lowest dose and 2-3 times stronger in the striatum at higher doses. Citalopram, a serotonin reuptake blocker, or the destruction of serotonergic fibers by 5,7-dihydroxytryptamine impaired l-DOPA-induced dopamine release in all regions. These data demonstrate that l-DOPA induces an ectopic release of dopamine due to serotonergic neurons. The new pattern of dopamine transmission created by l-DOPA may contribute to the benefit and side effects of l-DOPA.

The subthalamic nucleus (STN) modulates the activity of globus pallidus (GP), entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr) neurons via its direct glutamatergic projections. To investigate the mechanism by which STN affects activity in these structures and whether STN induced activity is comparable among STN target neurons, we performed patch clamp recordings in a tilted, parasagittal, basal ganglia slice (BGS) that preserves these functional connections. We report that single, brief stimulation of the STN generates a brief monosynaptic AMPA-mediated excitatory postsynaptic current (EPSC) in GP, EP and SNr neurons. A higher intensity, supra-threshold activation evokes a compound EPSC consisting of an early monosynaptic component followed by a slow inward NMDA-mediated current with an overlying barrage of AMPA-mediated EPSCs. These late EPSCs were polysynaptic and gave rise to bursts of spikes that lasted several hundreds of milliseconds. They were eliminated by surgical removal of the STN from the BGS slice, indicating that the STN is required for their generation. Reconstruction of biocytin-filled STN neurons revealed that a third of STN neurons project intra-STN axon collaterals that may underlie polysynaptic activity. We propose that activation of the STN yields comparable long lasting excitations in its target neurons by means of a polysynaptic network.

Recent advances in multiple areas of research have contributed to the identification of several pathophysiological factors underlying obsessive-compulsive disorder (OCD). In particular, the glutamate transporter gene SLC1A1 has been associated with the diagnosis of OCD. Immunological and infectious studies have reported alterations of the immune system and the presence of immune complexes directed against the Borna disease virus in OCD patients. In addition, neuroimaging of OCD patients has demonstrated abnormalities in the anterior cingulate cortex, orbitofrontal cortex, thalamus, and the basal ganglia. Neuropsychological assessments have found several cognitive disruptions that have been identified in OCD, especially impairments in cognitive flexibility. Here, we attempt to bridge the gap between these remarkable findings through several previously unpredicted pathophysiological mechanisms. We propose an integrative hypothesis that indicates how genetic and environmental factors may contribute to the structural and functional alterations of cortico-subcortical circuits, leading to the characteristic cognitive disruptions underlying OCD symptoms.

Many voxel-based morphometry (VBM) studies have found abnormalities in gray matter density (GMD) in obsessive–compulsive disorder (OCD). Here, we performed a quantitative meta-analysis of VBM studies contrasting OCD patients with healthy controls (HC). A literature search identified 10 articles that included 343 OCD patients and 318 HC. Anatomic likelihood estimation meta-analyses were performed to assess GMD changes in OCD patients relative to HC. GMD was smaller in parieto-frontal cortical regions, including the supramarginal gyrus, the dorsolateral prefrontal cortex, and the orbitofrontal cortex, and greater in the basal ganglia (putamen) and the anterior prefrontal cortex in OCD patients relative to HC. No significant differences were found between children and adults. Our findings indicate differences in GMD in parieto-frontal areas and the basal ganglia between OCD patients and HC. We conclude that structural abnormalities within the prefrontal-basal ganglia network are involved in OCD pathophysiology.

To replicate the sleep-wake disorders of Parkinson's disease (PD) and to understand the temporal relationship between these sleep disturbances and the occurrence of parkinsonism, we performed long-term continuous electroencephalographic monitoring of vigilance states in unrestrained rhesus monkeys using an implanted miniaturized telemetry device and tested the effect of MPTP intoxication on their sleep-wake organization. MPTP injection yielded a dramatic disruption of sleep-wake architecture with reduced sleep efficacy that persisted years after MPTP administration. Primary deregulation of REM sleep and increased daytime sleepiness occurring before the emergence of motor symptoms were a striking feature of the MPTP effect. This was concomitant with a breakdown of dopaminergic homeostasis, as evidenced by decreased dopamine turnover measured after a single MPTP injection. In the long term, partial re-emergence of REM sleep paralleled the partial adaptation to parkinsonism, the latter being known to result from compensatory mechanisms within the dopaminergic system. Altogether, these findings highlight the suitability of the MPTP model of PD as a tool to model the sleep/wake disturbances of the human disease. Ultimately, this may help in deciphering the specific role of dopamine depletion in the occurrence of these disorders.

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.

Background Involuntary movements, or dyskinesia, represent a debilitating complication of dopamine replacement therapy for Parkinson disease (PD). The transcription factor ΔFosB accumulates in the denervated striatum and dimerizes primarily with JunD upon repeated L-3,4-dihydroxyphenylalanine (L-DOPA) administration. Previous studies in rodents have shown that striatal ΔFosB levels accurately predict dyskinesia severity and indicate that this transcription factor may play a causal role in the dyskinesia sensitization process. Methods We asked whether the correlation previously established in rodents extends to the best nonhuman primate model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. We used western blotting and quantitative polymerase chain reaction (PCR) to compare ΔFosB protein and messenger RNA (mRNA) levels across two subpopulations of macaques with differential dyskinesia severity. Second, we tested the causal implication of ΔFosB in this primate model. Serotype 2 adeno-associated virus (AAV2) vectors were used to overexpress, within the motor striatum, either ΔFosB or ΔJunD, a truncated variant of JunD lacking a transactivation domain and therefore acting as a dominant negative inhibitor of ΔFosB. Results A linear relationship was observed between endogenous striatal levels of ΔFosB and the severity of dyskinesia in Parkinsonian macaques treated with L-DOPA. Viral overexpression of ΔFosB did not alter dyskinesia severity in animals previously rendered dyskinetic, whereas the overexpression of ΔJunD dramatically dropped the severity of this side effect of L-DOPA without altering the antiparkinsonian activity of the treatment. Conclusions These results establish a mechanism of dyskinesia induction and maintenance by L-DOPA and validate a strategy, with strong translational potential, to deprime the L-DOPA–treated brain.

Several models of dystonia have emerged from clinical studies providing a comprehensive explanation for the pathophysiology of this movement disorder. However, several points remain unclear notably concerning the specific role of brainstem, basal ganglia nuclei and premotor cortex. We review data collected in sub-human primate to see whether they might provide new insights into the pathophysiology of dystonia. As in human patients, lesions of the putamen induce dystonia, as well as pharmacological manipulations of the dopaminergic system. In addition, primate studies revealed that lesions in brain stem areas involved in the control of muscular tone and GABAergic manipulations in various basal ganglia nuclei or thalamus also lead to dystonia. Moreover, there is a dramatic disruption in the processing of proprioceptive information with abnormal large receptive fields in the basal ganglia, thalamus, primary somesthetic cortex and premotor cortex of dystonic monkeys. These data highlight the idea that dystonia is associated with aberrant sensory representations interfering with motor control. Considering that the supplementary motor area (SMAp) is the target of basal ganglia projections within the motor loop, we propose a model of dystonia in which abnormal excitability, associated with alteration in sensory receptive fields within the SMAp, leads to an abnormal synchronization between primary motor cortex columns. Such a phenomenon might account for the co-contractions of antagonist muscles favored by action and the abnormal postures observed in dystonia.

Background Many neuroimaging studies exploring the volumes of brain structures in obsessive-compulsive disorder (OCD) have been published in the past 2 decades. In this study, we attempted to provide a complete overview of structural alterations in OCD by meta-analyzing magnetic resonance imaging (MRI) data. Methods We conducted a systematic search of MRI studies that reported volumetric measurements in both OCD patients and healthy subjects. Data were entered into the meta-analysis through calculation of the standardized mean differences (SMDs) between the volumes of cerebral regions in OCD patients and the corresponding volumes in control subjects. We then performed a meta-regression to explore the influence of clinical covariates on effect sizes. Results Although no volumetric differences were found for the whole brain, intracranial region, gray matter, or prefrontal cortex, OCD patients did show a reduced volume of the left anterior cingulate cortex (ACC) and the left and right orbitofrontal cortex (OFC). No significant volumetric differences within the basal ganglia were observed, although the left and right thalamic volumes were significantly increased in OCD patients. The severity of obsessive or compulsive symptoms correlated significantly with the effect sizes for the left and right thalamus. Conclusions Our findings indicate volumetric differences between OCD patients and control subjects in the cortical and thalamic regions, suggesting that structural alteration of the thalamocortical pathways may contribute to the functional disruptions of frontosubcortical circuits observed in OCD.

Sleepiness at the wheel is a major risk factor for traffic accidents. Because of the potential medical and legal implications, in this study, we evaluated the correlation between subjective and objective measures of sleepiness and driving performances in patients suffering from excessive daytime sleepiness.Thirty-eight untreated sleep apnea patients (mean age +/- standard deviation, 51 +/- 9 years; mean apnea-hypopnea index +/- standard deviation, 41 +/- 25), and 14 healthy control subjects (mean age +/- standard deviation, 46 +/- 9 years) were included in the study. Nocturnal polysomnography, mean sleep latency as measured by four 40-minute Maintenance of Wakefulness Test (MWT) trials, Epworth Sleepiness Scale, Karolinska Sleepiness Scale, and the number of inappropriate line crossings during a 90-minute real-life driving session were analyzed.The number of inappropriate line crossings correlated with MWT scores (Spearman's Rho: r = -0.339; p0.05), Karolinska Sleepiness Scale scores measured at halfway in total driving distance (Rho: r = 0.367; p0.01), and Epworth Sleepiness Scale (Rho: r = 0.389; p0.01). We found a significant difference in the number of inappropriate line crossings among the four groups defined by MWT scores (very sleepy [0-19 minutes], sleepy [20-33 minutes], alert [34-40 minutes], and controls) (Kruskal-Wallis test: H = 11.319; p0.01). Very sleepy and sleepy patients had more inappropriate line crossings than the control drivers (p0.05).In addition to subjective sleepiness scales, the MWT can be used to assess driving ability in untreated sleep apnea patients.

It is well established that parkinsonian syndrome is associated with alterations in the temporal pattern of neuronal activity and local field potentials in the basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in parkinsonian patients and animal models of this disease. However, the mechanisms underlying this phenomenon remain unclear. This study investigates the functional connectivity in the cortex-BG network of a rodent model of Parkinson's disease. Single neurons and local field potentials were simultaneously recorded in the motor cortex, the striatum, and the substantia nigra pars reticulata (SNr) of freely moving rats, and high-voltage spindles (HVSs) were used to compare signal transmission before and after dopaminergic depletion. It is shown that dopaminergic lesion results in a significant enhancement of oscillatory synchronization in the BG: the coherence between pairs of structures increased significantly and the percentage of oscillatory auto- and cross-correlograms. HVS episodes were also more numerous and longer. These changes were associated with a shortening of the latency of SNr response to cortical activation, from 40.5 ± 4.8 to 10.2 ± 1.07 ms. This result suggests that, in normal conditions, SNr neurons are likely to be driven by late inputs from the indirect pathway; however, after the lesion, their shorter latency also indicates an overactivation of the hyperdirect pathway. This study confirms that neuronal signal transmission is altered in the BG after dopamine depletion but also provides qualitative evidence for these changes at the cellular level.

Akinesia (or absence of movement) is a prominent feature of Parkinson's disease. Akinetic symptoms, however, are also observed in depression and schizophrenia, which support the hypothesis that akinesia involves more than only motor behavior. A common feature of these disorders is the disruption of dopamine homeostasis in the CNS. Here we aimed at relating the respective involvement of the nigrostriatal and mesocortical dopaminergic pathways to akinesia. We investigated in the rat the relative effects of selective bilateral partial lesions of substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) which did not affect locomotion, on fine motor, motivational and cognitive behaviors. Motor impairments were measured by the evaluation of fine motor control in the stepping test and in the paw reaching test. Cognitive functions were assessed by various paradigms: spontaneous alternation in the Y maze and object exploration task. Motivational behavior was evaluated by the 100-pellets test. The results suggested that specific behavioral impairments are obtained following selective lesions of either SNc or VTA. SNc-lesioned rats exhibited deficits in fine motor functions as previously described in animal models of Parkinson's disease, whereas VTA-lesioned rats demonstrated traits of perseveration without significant motor impairments.

Dystonia, a movement disorder characterized by abnormal postures, is associated in primary forms of the disease with subtle proprioceptive troubles and aberrant somatotopic representation in the somatosensory cortex (SC). However, it is unclear whether these sensory features are a causal phenomenon or a consequence of dystonia. The supplementary motor area proper (SMAp), a premotor cortical region, receives strong inputs from both the SC and basal ganglia. We hypothesized that disruption in sensory-motor integration within the SMAp may play a part in the pathophysiology of dystonia. Using a model of secondary dystonia obtained by 3-nitropropionic acid intoxication in rhesus monkeys, we first provide evidence that the SMAp was overexcitable in dystonic animals. Second, we show that proprioceptive inputs processed by SMAp neurons were dramatically increased with wider sensory receptive fields and a mismatch between sensory inputs and motor outputs. These findings suggest that abnormal sensory inputs impinging upon SMAp neurons play a critical role in the pathophysiology of dystonia.

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.

The recent announcement that a Lasker award has been attributed to Professor Alim-Louis Benabid for pioneering the application of high frequency stimulation, named deep brain stimulation, of the subthalamic nucleus in patients suffering from Parkinson's disease prompts us to evoke the decisive role played by the non-human primate model in the discovery of this neurosurgical therapy, now regarded as the current therapeutic gold standard of the disease. The era of human functional surgery started in the 1950s by performing ablative procedures aiming to avoid the side effects of the commonly performed frontal lobotomy in the treatment of psychiatric illness (Spiegel et al., 1952). During surgery, intraoperative electrical stimulation was used from the beginning to explore the brain target prior to ablation. During the same period of time, Delgado et al. (1952) were the first to develop a technique of subcortical stimulation using chronically implanted electrodes connected to a subcutaneous receiver implanted in the scalp, a “Stimoceiver,” that could be controlled by radio waves. This technique of “radio communication with the brain” was initially developed for use in psychiatric patients. The chronological order of applications of chronic deep brain stimulation was first for psychiatry and behavior, then for pain and epilepsy. Deep brain stimulation for Parkinson's disease and other movement disorders was the last indication of the older era of chronic subcortical stimulation. Hariz and colleagues reported a detailed history of deep brain stimulation between 1947 and 1987 (Hariz et al., 2010). In the late 1980s, considerable progress was made in the understanding of the role played by the basal ganglia in the pathophysiology of Parkinson's disease (Albin et al., 1989) and the subthalamic nucleus was highlighted as an optimal therapeutic target. This small nucleus, the only excitatory glutamatergic structure of the basal ganglia network (Smith and Parent, 1988) playing a key role in movement control (DeLong, 1990), is considered as a driving force regulating the basal ganglia output nuclei; it was therefore suggested that activation of the subthalamic nucleus should inhibit movement and conversely its inhibition should be related to the release of movement. Back in 1927 it had already been reported that a focal lesion of the subthalamic area could induce hemiballismus, the manifestation of abnormal involuntary movements (Martin, 1927) and this association was reproduced later by lesion of the subthalamic nucleus in the non-human primate (Hammond et al., 1979). Single unit extracellular electrophysiology (Miller and De Long, 1987) and autoradiography of 2-deoxyglucose uptake (Mitchell et al., 1989) likewise showed that systemic injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys resulted in dopamine cell degeneration in the substantia nigra pars compacta and the manifestation of akinesia and rigidity, associated with a hyperactivity of subthalamic nucleus neurons. In the light of these results, Bergman et al. (1990) and Aziz et al. (1991) a year later proposed therapeutic lesion of the subthalamic nucleus and both demonstrated an effective alleviation of parkinsonian motor symptoms in monkeys. Since lesioned animals unfortunately also developed severely abnormal involuntary movements, this irreversible approach could not be proposed to patients. Pursuing a parallel line of research, our team in Bordeaux at the “Centre National de la Recherche Scientifique” (CNRS) was the first, in the period 1991-1992, to carry out rigorous studies of the effects of high frequency stimulation of the subthalamic nucleus in Macaca mulatta monkeys rendered parkinsonian by MPTP, observations which allowed objective quantification of the modifications of the principal movement parameters this treatment induced. The results obtained were spectacular; rigidity disappeared and akinesia was hardly observable (Benazzouz et al., 1993). Impressed by these results, we proposed the transfer of this neurosurgical approach to parkinsonian patients. Only a few months later, in collaboration with our team, Alim-Louis Benabid who was already a recognized expert in the field of functional neurosurgery and who realized the importance of these observations, attempted the first application of high frequency stimulation of the subthalamic nucleus in human patients (Pollak et al., 1993; Limousin et al., 1995) with a success that has never failed since. This example of cooperation provides a perfect illustration of how irreplaceable the phylogenetic proximity between humans and non-human primates can be, not only from the physiological and clinical point of view but also for the design of relevant pathophysiological models and the definition of new therapeutic strategies. In such an exemplary case of ≪ bench to bedside ≫ translation, it is important to cite all the links that have built the chain and engendered such positive results. This is a new era of neuromodulation and it is clear now that the success of this functional neurosurgery involves the modulation of circuitry properties and cortical-subcortical synchronies involving also stations not strictly attributable to the direct/indirect pathway scheme (Stefani et al., 2007). Furthermore, despite possible adverse events, deep brain stimulation in patients contributed in large part to the understanding of the pathophysiology of Parkinson's disease and opened the way to the treatment of a number of chronic and disabling neurologic and psychiatric disorders. In order to ensure continued progress in this field, we need to have a better understanding of the pathophysiology of brain diseases, as well as to develop a next generation of electrodes and stimulation devices with combined electrical and chemical sensing (Rosin et al., 2011; Priori et al., 2013). These technological improvements cannot be done without complimentary works in patients and laboratoty animal models of brain diseases.

STUDY OBJECTIVE: To test the effects of coffee and napping on nocturnal driving in young and middle-aged participants. DESIGN: A cup of coffee (200 mg of caffeine), a placebo (decaffeinated coffee, 15 mg of caffeine), or a 30-minute nap were tested. Participants drove 125 highway miles between 18:00 and 19:30 and between 02:00 and 03:30 after coffee, placebo, or a nap. SETTING: Sleep laboratory and open French highway. PARTICIPANTS: Twelve young (range, 20-25 years) and 12 middle-aged participants (range, 40-50 years). MEASUREMENTS: Inappropriate line crossings, self-perceived fatigue and sleepiness, and polysomnographic recordings were analyzed. RESULTS: Compared to daytime, after placebo the number of inappropriate line crossings was significantly increased (2 versus 73 for young participants, P < 0.01 and 0 versus 76 for the middle-aged participants, P < 0.05). Both coffee and napping reduced the risk of inappropriate line crossings, compared with placebo, in young participants (respectively, by three-quarters, incidence rate ratios [IRR] = 0.26 95% confidence interval [CI], 0.09-0.74, P < 0.05 and by two thirds, IRR = 0.34 95% CI, 0.20-0.58, P < 0.001) and in middle-aged participants (respectively by nine tenths, IRR = 0.11 95% CI, 0.05-0.21, P < 0.001 and by one fifth, IRR = 0.77 95% CI, 0.63-0.95, P < 0.05). A significant interaction between age and condition (IRR = 2.27 95% CI, 1.28-4.16 P < 0.01) showed that napping led to fewer inappropriate line crossings in younger participants than in middle-aged participants. During napping, young participants slept more (P < 0.01) and had more delta sleep (P < 0.05) than middle-aged participants. Self-perceived sleepiness and fatigue did not differ in both age groups, but coffee improved sleepiness (P < 0.05), whereas napping did not. CONCLUSIONS: Coffee significantly improves performance in young and middle-aged participants. Napping is more efficient in younger than in older participants. Countermeasures to sleepiness should be adapted according to the age of drivers. Language: en

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings in parkinsonian patients and animals have shown the emergence of abnormal synchronous oscillatory activity in the cortico-basal ganglia network in the pathological condition. In addition, previous studies pointed out an altered response pattern during movement execution in the pallidum of parkinsonian animals. To investigate the dynamics of these changes during disease progression and to relate them to the onset of the motor symptoms, we recorded spontaneous and movement-related neuronal activity in the internal pallidum of nonhuman primates during a progressive dopamine depletion process. Parkinsonian motor symptoms appeared progressively during the intoxication protocol, at the end of which both animals displayed severe akinesia, rigidity and postural abnormalities. Spontaneous firing rates did not vary significantly after intoxication. During the early phase of the protocol, voluntary movements were significantly slowed down and delayed. At the same time, the neuronal response to movement execution was modified and inhibitory responses disappeared. In contrast, the unitary and collective dynamic properties of spontaneous neuronal activity, as revealed by spectral and correlation analysis, remained unchanged during this period. Spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. The pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and stands as the best candidate to account for this motor symptom.

Performance evaluation is a prerequisite for behavioral adaptation. Although the anterior cingulate cortex (ACC) is thought to play a central role in error detection, little is known about the electrophysiological activity of this structure during the performance-monitoring process. We directly addressed this issue by training monkeys to perform a Stroop-like task and then recorded neuronal activity in the rostral cingulate motor area (CMAr), a relatively unexplored region of the ACC known to be involved in motor processing. We found that most CMAr neurons responded during the evaluation period to both positive and negative feedback, but neuronal changes were more important after an error than after a successful trial. Interestingly, this performance-monitoring activity was not directly modulated by the degree of difficulty of the cognitive situation because changes in discharge frequency were similar whatever the level of attentional control imposed on the monkey. Firing activity during the evaluation period increased more, however, in erroneously completed than in incompleted trials and when the reward was delivered in an active rather than passive context, indicating that performance evaluation was conditioned by the degree of commitment of the animal to the task. It would thus seem that CMAr neurons could constitute a system for the evaluation of behavioral performance contingent on the subject's commitment to the task.

The mechanisms of action of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) remain only partially understood. Hitherto, experimental studies have suggested that STN-HFS reduces the activity of STN neurons. However, some recent reports have challenged this view, showing that STN-HFS might also increase the activity of globus pallidus internalis (GPi) neurons that are under strong excitatory drive of the STN. In addition, most results emanate from studies applying acute STN-HFS, while parkinsonian patients receive chronic stimulation. Thus, the present study was designed to assess the effect of chronic (10 days) STN-HFS in the 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate. For this purpose, 2-deoxyglucose (2-DG) uptake, a measure of global synaptic activity, was assessed in the basal ganglia and the motor thalamus after chronic unilateral STN-HFS. Cytochrome oxidase subunit 1 (COI) mRNA expression, a marker of efferent metabolic activity, was additionally assessed in the globus pallidus. Chronic STN-HFS (i) reversed abnormally decreased 2-DG uptake in the STN of parkinsonian nonhuman primates, (ii) reversed abnormally increased 2-DG accumulation in the GPi while COI mRNA expression was increased, suggesting global activation of GPi neurons, and (iii) reversed abnormally increased 2-DG uptake in the ventrolateral motor thalamus nucleus. The simultaneous decrease in 2-DG uptake and increase in COI mRNA expression are difficult to reconcile with the current model of basal ganglia function and suggest that the mechanisms by which STN-HFS exerts its clinical benefits are more complex than a simple reversal of abnormal activity in the STN and its targets.

Obsessive-compulsive disorder (OCD), that affects 2 to 3 % of the general population, is characterized by recurrent intrusive thoughts and repetitive, time-consuming behaviors. It is a severely incapacitating mental illness that causes profound impairment in psychosocial functioning and quality of life. Although the physiopathology of OCD is still far from resolved, the existence of a biological basis for OCD is now clearly established and should be interpreted from phenomenological considerations, on the one hand, and in the light of our increasing knowledge of the physiology of cortico-subcortical functional loops, on the other. In a phenomenological view, the heart of the obsessional process is the subject’s underlying impression that « something is wrong ». In other words, obsessions may be thought of as the permanent perception of a mistake and/or error in certain behavioral situations. Compulsions occur as behavioral responses aimed at relieving the tensions or anxiety generated by the situation. If obtained, this relief may be felt to be a form of reward. Nevertheless, it is only transient, thereby creating a feeling of considerable anxiety. This contributes to immediately reproducing the behavior in a cyclic manner, on the basis of an internal motivational state through an expectation of the reward. Therefore, it can be assumed that several malfunctioning processes are altered within the OCD : 1) error recognition ; and, 2) emotion and motivation. This suggests that there is a dysfunction of the brain regions mediating these cognitive and emotional functions. Experimental neurophysiology in laboratory animals indicates the central role of the fronto-subcortical circuits originating in the orbitofrontal and anterior cingulate cortices, respectively. The orbitofrontal cortex (OFC) and ventromedial areas are involved in appraisal of the emotional and motivational values of environmental information, and in integrating the subject’s prior experience, which is crucial in decision-making. The OFC also contributes to the selection, comparison and judgment of stimuli and error detection. The anterior cingulate cortex (ACC) is comprised of 1) a ventral or affective region that could keep attention on the internal emotional and motivational status and regulation of autonomic responses, and 2) a dorsal and cognitive region that serves a wide range of functions including attention, working memory, error detection, conflict monitoring, response selection, and anticipation of incoming information. Ventral striatum, that is intimately connected to the OFC and ACC, participates in the preparation, initiation and execution of behavioral responses oriented toward reward delivery following the cognitive and emotional integration of behaviorally relevant information at the cortical level. Functional imaging research in humans has shown an increased functional activity in the OFC, ACC, head of the caudate nucleus and thalamus in OCD patients. These functional abnormalities have been found in basal conditions and during provocation tests. Moreover, the therapeutic efficacy of antidepressants with preponderant serotonin-reuptake inhibiting properties and cognitive-behavioral therapies seems to be associated with a progressive reduction in activity of the OFC, ACC and the caudate nucleus. Therefore, these observations are suggestive of the responsibility of 5HT neurotransmission in the dysfunction of the frontal-subcortical loops that emanate from the OFC and ACC. However, several lines of research suggest that the dopamine system, with which 5HT interacts, may play a major role in the expression of OC symptoms. In conclusion, it seems that in OCD there is a dysfunction of the brain regions that belong to the orbitofrontal and anterior cingulate loops in view of evidence obtained from separate and complementary approaches.

Synchronous oscillations in various frequency ranges have been recorded in several nuclei of the basal ganglia (BG) and are thought to be an information processing mechanism. High-voltage spindles (HVSs) are 5-13 Hz spike-and-wave oscillations, which are commonly recorded in rats and which have been reported in some recent studies where their occurrence in the BG has been investigated. We recorded single neurons and local field potentials (LFPs) simultaneously in the motor cortex, striatum and substantia nigra pars reticulata (SNr) of the freely moving rat. We took advantage of the high level of synchronization observed during HVSs to study signal transmission in the cortex-BG network in the awake animals. The results show that LFPs are synchronized in the motor cortex, striatum and SNr during HVS episodes and that the latter propagate from the cortex to the SNr via the striatum. Moreover, > 50% of single neurons in each of these structures are triggered by the HVS. Following the discharge of cortical cells, SNr neurons are first inhibited after approximately 19 ms and then activated after approximately 45 ms. This response is probably driven by the direct and indirect pathways, respectively, without any involvement of the hyperdirect pathway. Here, it is shown that cortex-BG connectivity can be studied using physiological signals in the freely moving animal as opposed to artificial stimulation under anaesthetized conditions. This opens the door to further studies under various experimental conditions, such as animal models of basal ganglia disorders.

International audience; The striatum is a key neural interface for cognitive and motor information processing in which associations between reward value and visual stimulus can be used to modify motor commands. It can guide action–selection processes that occur farther downstream in the basal ganglia (BG) circuit, by encoding the reward value of an action. Here, we report on the study of simultaneously recorded neurons in the dorsal striatum (input stage of the BG) and the internal pallidum (output stage of the BG) in two monkeys performing a center-out motor task in which the visual targets were associated with different reward probabilities. We show that the tuning curves of motor-related neurons in both structures are modulated by the value of the action before movement initiation and during its execution. The representations of values associated with different actions change dynamically during the task in the internal globus pallidus, with a significant increase in the number of encoding neurons for the chosen target at the onset of movement. This report sheds additional light on the functional differences between the input and output structures of the BG and supports the assertion that the dorsal basal ganglia are involved in movement-related decision-making processes based on incentive values.

To determine the prevalence of excessive daytime sleepiness (EDS) and that of dozing and sudden onset of sleep episodes (SOS) while driving in ambulatory patients with Parkinson's disease (PD) in France, a national sample of private and public neurologists was asked to recruit the first 10 consecutive nondemented PD patients. Each patient completed a questionnaire including the Epworth Sleepiness Scale (ESS) and the likelihood of dozing off and experiencing SOS episodes behind the wheel. Clinical and demographic data were collected. One thousand six hundred and twenty-five patients with PD were included in the survey. Twenty-nine percent of the patients suffered from EDS (ESS score ≥10) but only 0.8% declared a high chance of dozing while driving and 0.5% reported totally unpredictable SOS episodes while driving. Risk factors for EDS were male gender, reduced activity of daily living, and a high daily levodopa equivalent dosage. Risk factors for SOS episodes while driving were an ESS score ≥10, male gender, and low Hoehn and Yahr staging. EDS is common in ambulatory patients with PD and is a major risk factor for dozing and for SOS episodes behind the wheel in patients who drive. © 2007 Movement Disorder Society

Insomnia is common and associated with poor health status and quality of life. We designed a study to evaluate the impact of insomniac complaints with and without comorbidity on health status and absenteeism.This is a cross-sectional study performed within a 1-year follow up study on a prospective cohort of French employees. Insomniac subjects (n=986) were compared to control subjects (n=584). Insomniacs suffering from self-reported depressive feelings and behavioral and organic sleep complaints were excluded.Subjects with insomniac complaints (whether with mood or behavioral and organic sleep complaints or not) reported poorer quality of life and had a higher absenteeism rate than controls (9.6+/-31 versus 5.8+/-19 days, P0.01). A logistic regression model adjusting for depressive and behavioral and organic sleep complaints showed that insomniac complaints were no longer predictive of absenteeism.Insomniac complaints are strongly associated with deterioration in quality of life but not necessarily with higher absenteeism.

Since electrophysiological correlates of l -dopa-induced dyskinesia (LID) are almost unknown, changes of striatal dopamine (DA) transmission and electrophysiological activity of the substantia nigra pars reticulata (SNr) were recorded before and after acute l -dopa administration in sham-operated and 6-hydroxydopamine (6-OHDA)-lesioned rats that were previously treated with vehicle or l -dopa for 10 days. Abnormal involuntary movements occurred only in the l -dopa-primed 6-OHDA-lesioned rats that showed after acute l -dopa administration a decrease in firing rate, the highest local field potential power in the theta/alpha band, a consequent oscillatory activity in the same frequency band at the single neuron level and an excessive increase in striatal DA release associated with the lowest level of DA metabolism. These results suggest that increased synchronised afferent activity may drive SNr oscillations in the same frequency band and is associated with abnormal involuntary movements, further suggesting the potential use of desynchronising drugs for managing LID in Parkinson's disease.

In our 24-h society, nocturnal sleep-related accidents are common. Because all individuals are not equal in their responses to sleep loss, it is very important to identify predictors of vulnerability to sleep deprivation in normal subjects. We investigated the performance of a cognitive test of sustained attention, electroencephalogram theta/alpha power, subjective sleepiness, and two circadian markers (core temperature and melatonin) in 18 healthy men (nine morning types and nine evening types, 21.4 +/- 1.9 years) during a 36-h sleep deprivation in a constant routine protocol. Sleep need (self-reported) and baseline sleep structure were also investigated. Nighttime performance impairment was defined as the difference between the mean nocturnal number of lapses (00:00-07:30 [corrected] hours) and the mean diurnal number of lapses (07:30-20:30 hours) expressed as a percentage. Feeling fully alert in the morning just after awakening and/or sleepy in early afternoon were the only two factors (Multiple R > 0.80, > 60% of explained variance) which better predicted the decrease in performances of nocturnal operational tasks requiring sustained attention.

The aim of this study was principally to assess the impact of sleep deprivation on interference performance in short Stroop tasks (Color-Word, Emotional, and Specific) and on subjective anxiety. Subjective sleepiness and performance on a psychomotor sustained attention task were also investigated to validate our protocol of sleep deprivation. Twelve healthy young subjects were tested at four-hourly intervals through a 36-h period of wakefulness under a constant routine protocol. Analyses of variance for repeated measurements revealed that self-assessment of sleepiness on a visual analogue scale as well as mean reaction time performance on the sustained attention task, both for the first minute and for 10 min of testing, were worsened by sleep deprivation. Analyses revealed an increase in self-reported anxiety scores on the STAI questionnaire but did not reveal any significant effect after sleep deprivation either on indexes of interference or on accuracy in Stroop tasks. However, analyses showed sensitivity to circadian effect on verbal reaction times in the threat-related (Emotional) and sleep-related (Specific) Stroop tasks. We concluded that 36 h of prolonged wakefulness affect self-reported anxiety and Emotional Stroop task resulting in a cognitive slowing. Moreover, total sleep deprivation does not affect interference control in any of the three short Stroop tasks.

To determine whether real-life driving would produce different effects from those obtained in a driving simulator on fatigue, performances and sleepiness.Cross-over study involving real driving (1200 km) or simulated driving after controlled habitual sleep (8 hours) or restricted sleep (2 hours).Sleep laboratory and open French Highway.Twelve healthy men (mean age +/- SD = 21.1 +/- 1.6 years, range 19-24 years, mean yearly driving distance +/- SD = 6563 +/- 1950 miles) free of sleep disorders.Self-rated fatigue and sleepiness, simple reaction time before and after each session, number of inappropriate line crossings from the driving simulator and from video-recordings of real driving.Line crossings were more frequent in the driving simulator than in real driving (P.001) and were increased by sleep deprivation in both conditions. Reaction times (10% slowest) were slower during simulated driving (P = .004) and sleep deprivation (P = .004). Subjects had higher sleepiness scores in the driving simulator (P = .016) and in the sleep restricted condition (P = .001). Fatigue increased over time (P = .011) and with sleep deprivation (P = .000) but was similar in both driving conditions.Fatigue can be equally studied in real and simulated environments but reaction time and self-evaluation of sleepiness are more affected in a simulated environment. Real driving and driving simulators are comparable for measuring line crossings but the effects are of higher amplitude in the simulated condition. Driving simulator may need to be calibrated against real driving in various condition.

Information processing in the brain requires adequate background neuronal activity. As Parkinson's disease progresses, patients typically become akinetic; the death of dopaminergic neurons leads to a dopamine-depleted state, which disrupts information processing related to movement in a brain area called the basal ganglia. Using agonists of dopamine receptors in the D1 and D2 families on rat brain slices, we show that dopamine receptors in these two families govern the firing pattern of neurons in the subthalamic nucleus, a crucial part of the basal ganglia. We propose a conceptual frame, based on specific properties of dopamine receptors, to account for the dominance of different background firing patterns in normal and dopamine-depleted states.

The anatomies of the tongue and uvula in monkeys share many similarities with humans, such that this species has the closest approximation to the human upper airway than any other species. In this study, we investigated the feasibility of using small monkeys as experimental animals for an obstructive sleep apnea model. Monkeys received intradermal injections of liquid collagen in the uvula, tongue, and lateral pharyngeal walls every 2 weeks. Polysomnography was performed bi-monthly in order to control the impact of injections on breathing events, respiratory effort (as measured by esophageal pressure), and sleep. Before injections, the three animals showed normal breathing during sleep with a mean of 4.8 +/- 2.0 events/h. After injections, a mean of 27.9 +/- 19.7 hypopneas/h was recorded (P = 0.023). Total sleep time was significantly reduced, with a decrease of REM sleep and stage II sleep; however, stage I sleep increased. Collagen injections in monkey's upper airways can create sleep-disordered breathing and abnormal sleep, as seen in sleep apneic patients.