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High-frequency deep brain stimulation (HF-DBS) has become a widely used therapeutic method in the field of movement disorders for the treatment of Parkinson's disease, essential tremor or dystonia. New targets and indications are under evaluation in several other conditions such as cluster headache, obesity, epilepsy or psychiatric diseases (depression, OCD). However, the mechanisms of action of HF-DBS remain poorly understood. Herein we present a review of the literature and our current view of the question. The first part deals with the effects of stimulation itself on the different parts of the neuron and tries to answer the question of what is actually stimulated by DBS (cell bodies, dendrites or axons). The second part is devoted to the ortho- and antidromic effects of the stimulation. The third part more specifically focuses on the case of subthalamic nucleus stimulation. The target axons in the subthalamic area are discussed in the light of recent optogenetic studies. In conclusion, HF-DBS leads to a kind of functional deafferentation of the stimulated structure and to the modulation of cortical activity (both ortho and antidromically). Which effects are relevant to the therapeutic effects of DBS is still unclear. Further investigations are required especially regarding the corticosubthalamic pathways.

Focal motor seizures are characterized by transient motor behaviour that occurs simultaneously with paroxystic activity in the controlateral motor cortex. The implication of the basal ganglia has already been shown for generalized seizure but the propagation pathways from the motor cortex towards the basal ganglia during focal motor seizures are largely unknown. With a better knowledge of those pathways, a therapeutic modulation for reducing drug resistant motor epilepsy could be considered. Here, we recorded single-unit activities and local field potentials in the basal ganglia of two Macaca fascicularis in which acute focal motor seizures were induced by the injection of penicillin over the arm motor cortex territory. Each neuron was characterized using its mean firing rate and its type of firing pattern during interictal periods and seizures. Time-frequency analyses of local field potentials and electroencephalographic signals were used to assess dynamic changes occurring during seizure at a larger spatial level. The firing rate of neurons of input stages of basal ganglia (subthalamic nucleus and putamen) and those from the external part of the globus pallidus were significantly higher during seizures as compared to interictal periods. During seizures, the proportion of oscillatory neurons in subthalamic nucleus (71%), external globus pallidus (45%) and putamen (53%) significantly increased in comparison to interictal periods. Rhythmic activity was synchronized with ictal cortical spikes in external globus pallidus and subthalamic nucleus, but not in the putamen which oscillated faster than motor cortex. In contrast, no significant modification of the firing rate of the output stages of basal ganglia (internal part of the globus pallidus, substantia nigra pars reticulata) could be found during seizures. The local field potentials of subthalamic nucleus and external globus pallidus changed abruptly at the onset of the seizure, showing synchronization with the cortical activity throughout the seizure. In putamen, the synchronization appeared only by the end of seizures and for the two output structures, despite some increase of the oscillatory activity, the synchronization with the cortex was not significant. Our results suggest that the subthalamo-(external)-pallidal pathway is the main subcortical route involved during ictal motor seizures. Surprisingly, ictal activity did not propagate to the output structure of basal ganglia in that model. This finding may be important for clinical decisions of targeting when considering anti-epileptic neuromodulation in human beings suffering from disabling, drug resistant motor epilepsy. * Abbreviations : STN : subthalamic nucleus

The original version of this article, published on 12 July 2017, unfortunately contained mistakes. The following corrections have therefore been made in the original.

Object The aim of this study was to study the effects of MR imaging on the electrical settings of deep brain stimulation (DBS) systems and their clinical consequences. Methods The authors studied the effects of 1.5-T MR imaging on the electrical settings of implanted DBS systems, including 1 or more monopolar or quadripolar leads, extension leads, and single- or dual-channel implantable pulse generators (IPGs). The IPG was switched off during the procedure and the voltage was set to 0. The impedances were checked before and after MR imaging. Results Five hundred seventy patients were treated with DBS for movement disorders and underwent brain MR imaging after lead implantation and before IPG implantation. None of the patients experienced any adverse events. Thirty-one of these patients underwent 61 additional MR imaging sessions after the entire DBS system had been implanted. The authors report neither local cutaneous nor neurological disorders during or after the MR imaging session. No change in the IPG settings occurred when the magnet reed switch function remained disabled during the procedure. Conclusions This study demonstrates that 1.5-T MR imaging can be performed safely with continuous monitoring in patients with a DBS system. The ability to disable the magnet reed switch function of the IPG prevents any change in the electrical settings and thus any side effects. The increasing number of DBS indications and the widespread use of MR imaging indicates the need for defining safety guidelines for the use of MR imaging in patients with implanted neurostimulators.

International audience; Neurostimulation represents an interesting alternative therapy for patients resistant to drug treatment or who cannot benefit from resective surgery. Theoretically, neurostimulation allows the control of seizures to be tailored to the individual patient and specific form of epilepsy. Here, we review both experimental and clinical studies that have reported the possible control of epileptic seizures by means of different approaches using electrical stimulation (vagus nerve stimulation, deep brain stimulation and repetitive transcranial magnetic stimulation). The rationale for targeting specific areas that have thus far been considered (i.e., vagus nerve, cerebellum, anterior or centromedial thalamus, basal ganglia, cortex and temporal lobe) is addressed in the light of experimental data and clinical effectiveness in different models and forms of epilepsy. The type of seizures that can be considered for neurostimulation, as well as the optimal parameters such as stimulation frequency and modes of stimulation (chronic, continuous or adaptative), are discussed to determine the best candidates for such a therapeutic strategy. This review points out the need for improved knowledge of neural circuits that generate seizures and/or allow their propagation, as well as a better understanding of the mechanisms of action of neurostimulation.

A model is a simplified preparation that reproduces only the most critical features of a disease. To be considered as a validated animal model, such an experimental preparation must fulfill three criteria: isomorphism or similarities of the symptoms; predictivity or identical pharmacological reactivity; homology or etiological similarity. In epilepsy, the use of animal models helps our understanding of physiological and pathological networks involved in the genesis, maintenance, and propagation of seizures. The animal models of epilepsy are also useful in designing and testing new surgical therapeutical strategies, in particular using deconnection or neuromodulation in drug-resistant focal epilepsies. Here we describe three animal models of focal epilepsy, adapted to addressing experimental surgery issues. Kindling consists in the regular liminar stimulation of a given brain structure in the rodent to develop a focal discharge that is secondarily generalized. The local application of epileptogenic agents such as cobalt, iron, or penicillin leads to focal discharges that do not generalize in the rodent or the primate. It is a model of focal neocortical epilepsy without secondary generalization. The focal application of kainate, an excitotoxic glutamate agonist, in the dorsal hippocampus of the adult mouse results, after a latent period, in spontaneous and recurrent focal discharges, behavioral interictal troubles, drug resistance, and histological anomalies reminiscent of hippocampal sclerosis. This constitutes a model of mesial-temporal epilepsy. Better knowledge, in these models, of the neural networks generating, propagating, and/or controlling the seizures should make it possible to design innovative surgical approaches for the treatment of drug-resistant epilepsies.

In the stereo-electro-encephalography (SEEG) methodology developed by Talairach and Bancaud in Sainte-Anne Hospital in Paris, France, the objective of placing depth electrode recordings in presurgical evaluation is to study the spatial and temporal organization of a seizure. This defines for each patient the cortical onset zone, the propagation pattern of the seizure, and the possible involvement of eloquent areas of the cortex. This methodology requires a meticulous stereotactic surgical technique. We report here the SEEG methodology, surgical technique, and morbidity.

The surgical treatment of intractable epilepsies involving eloquent areas of the cortex is still challenging. Deep-brain stimulation could be an alternative to resective surgery because it can modulate the remote control systems of epilepsy, such as the thalamus and basal ganglia. The surgical experience acquired in the field of movement disorder surgery and the low morbidity of this technic could allow one to apply DBS to intractable epilepsies, such as generalized, motor and bitemporal epilepsies. Here we discuss the main experimental and clinical data reported so far in the literature and taken from our own experience.

Temporal lobe epilepsy (TLE) is the most common form of intractable partial epilepsy in adults. Surgery (lobectomy or amygdalohippocampectomy) is effective in most patients. However, some complications can occur and brain shift, hematoma into the post operative cavity and occulomotor nerve palsy have been reported due to the surgical technic. We report the technique, safety and efficacy of temporal disconnection in nonlesional TLE. Forty-seven patients (18 males, 29 females; handedness: 12 left, 33 right; aged 35 years+/-10; mean duration of epilepsy: 24+/-10 years) underwent temporal disconnection (20 left, 27 right) guided by neuronavigation. Sixteen patients (35 %) underwent additional presurgical evaluation with SEEG. The outcome was assessed using Engel's classification. At the two-year follow-up, 85 % of the patients were seizure-free (Engel I), 26 (58 %) of whom were Ia. Postoperative persistent morbidity included mild hemiparesis (n=1), mild facial paresis (n=1), quadranopsia (n=23) and hemianopia (n=1). Verbal memory worsened in 13 % of cases when the disconnection was performed in the dominant lobe. MRI follow-up showed two cases of nonsymptomatic thalamic or pallidal limited ischemias, two cases of temporal horn-cystic dilatation, one requiring surgical reintervention without sequelae. There was one case of postoperative phlebitis. In the seizure-free patient group, postoperative EEG showed interictal temporal spikes at three months, one year and two years located in the anterior temporal region. Temporal disconnection is effective, prevents the occurrence of subdural cyst and hematomas in the temporal cavity, prevents the occurrence of oculomotor palsy, and limits the occurrence of quadranopsia. However, comparative studies are required to evaluate temporal disconnection as an alternative to lobectomy in nonlesional TLE.

We report here the results of the first survey on epilepsy surgery activity in France. Data from a questionnaire sent to 17 centers practicing epilepsy surgery were analyzed. All centers responded; however, all items were not completely documented. Over 50 years, more than 5000 patients have been operated on for drug-resistant epilepsy and more than 3000 patients underwent some invasive monitoring, most often SEEG. Currently, nearly 400 patients (including more than 100 children) are operated on yearly for epilepsy in France. Over a study period varying among centers (from two to 20 years; mean, 9.5 years), results from more than 2000 patients including one-third children were analyzed. Important differences between adults and children, respectively, were observed in terms of location (temporal: 72% versus 4.3%; frontal: 12% versus 28%; central: 2% versus 11%), etiology (hippocampal sclerosis: 41% versus 2%; tumors 20% versus 61%); and procedures (cortectomy: 50% versus 23%; lesionectomy: 8% versus 59%), although overall results were identical (seizure-free rates following temporal lobe surgery: 80.6% versus 79%; following extratemporal surgery: 65.9% versus 65%). In adults, the best results were observed following temporomesial (TM) resection associated with hippocampal sclerosis or other lesions (class I: 83% and 79%, respectively), temporal neocortical (TNC) lesional (82%), while resections for cryptogenic temporal resections were followed by 69% (TM) and 63% (TNC) class I outcome. Extratemporal lesional resections were associated with 71% class I outcome and cryptogenic 43%. In children, the best results were obtained in tumor-associated epilepsy regardless of location (class I: 80%). A surgical complication occurred in 8% after resective surgery - with only 2.5% permanent morbidity - and 4.3% after invasive monitoring (mostly hemorrhagic). Overall results obtained by epilepsy surgery centers were in the higher range of those reported in the literature, along with a low rate of major surgical complications. Growing interest for epilepsy surgery is clearly demonstrated in this survey and supports further development to better satisfy the population's needs, particularly children. Activity should be further evaluated, while existing epilepsy surgery centers as well as healthcare networks should be expanded.

Obsessive-compulsive disorder (OCD) may be conceptualized as a disorder of self-control and behavioral inhibition.1 Recent studies2,3 suggested interest in deep brain stimulation (DBS) of different subcortical brain targets such as the nucleus accumbens, anterior internal capsule/ventral striatum, and subthalamic nucleus (STN) in severe, resistant OCD. STN is a critical node of the indirect and hyperdirect basal ganglia–thalamocortical circuit. STN-DBS may release its function as a brake on behavioral programs, disinhibiting habitual responses and enabling more flexible goal-directed behavior control in OCD.4,5 Little is known about long-term outcome of STN-DBS in OCD. Based on experience in Parkinson disease, STN-DBS can induce a change from apathetic to disinhibited behavior.6 This target has also a potential impact on addictions.4,6

The mesencephalic reticular formation (MRF) is formed by the pedunculopontine and cuneiform nuclei, two neuronal structures thought to be key elements in the supraspinal control of locomotion, muscle tone, waking, and REM sleep. The role of MRF has also been advocated in modulation of state of arousal leading to transition from wakefulness to sleep and it is further considered to be a main player in the pathophysiology of gait disorders seen in Parkinson's disease. However, the existence of a mesencephalic locomotor region and of an arousal center has not yet been demonstrated in primates. Here, we provide the first extensive electrophysiological mapping of the MRF using extracellular recordings at rest and during locomotion in a nonhuman primate (NHP) (Macaca fascicularis) model of bipedal locomotion. We found different neuronal populations that discharged according to a phasic or a tonic mode in response to locomotion, supporting the existence of a locomotor neuronal circuit within these MRF in behaving primates. Altogether, these data constitute the first electrophysiological characterization of a locomotor neuronal system present within the MRF in behaving NHPs under normal conditions, in accordance with several studies done in different experimental animal models.SIGNIFICANCE STATEMENTWe provide the first extensive electrophysiological mapping of the two major components of the mesencephalic reticular formation (MRF), namely the pedunculopontine and cuneiform nuclei. We exploited a nonhuman primate (NHP) model of bipedal locomotion with extracellular recordings in behaving NHPs at rest and during locomotion. Different MRF neuronal groups were found to respond to locomotion, with phasic or tonic patterns of response. These data constitute the first electrophysiological evidences of a locomotor neuronal system within the MRF in behaving NHPs.

Neuropsychiatric symptoms are common non-motor symptoms in Parkinson's disease (PD). Apathy and impulse control disorders (ICD) are two opposite motivational expressions of a continuous behavioural spectrum involving hypo- and hyperdopaminergia. Both syndromes share pathological (decreased vs increased) dopamine receptor stimulation states. Apathy belongs to the spectrum of hypodopaminergic symptoms together with anhedonia, anxiety and depression. Apathy is a key symptom of PD which worsens with disease progression. Animal models, imaging and pharmacological studies concur in pointing out dopaminergic denervation in the aetiology of parkinsonian apathy with a cardinal role of decreased tonic D2/D3 receptor stimulation. ICDs are part of the hyperdopaminergic behavioural spectrum, which also includes punding, and dopamine dysregulation syndrome (DDS), which are all related to non-physiological dopaminergic stimulation induced by antiparkinsonian drugs. According to clinical data tonic D2/D3 receptor stimulation can be sufficient to induce ICDs. Clinical observations in drug addiction and PD as well as data from studies in dopamine depleted rodents provide hints allowing to argue that both pulsatile D1 and D2 receptor stimulation and the severity of dopaminergic denervation are risk factors to develop punding behavior and DDS. Imaging studies have shown that the brain structures involved in drug addiction are also involved in hyperdopaminergic behaviours with increase of bottom-up appetitive drive and decrease in prefrontal top down behavioural control.

Item does not contain fulltext OBJECTIVE: To compare the influence of low-frequency (10-25 Hz) versus higher (60-80 Hz) frequency stimulation of the pedunculopontine nucleus area (PPNa) on akinaesia, freezing of gait and daytime sleepiness. METHOD: We included nine patients with Parkinson's disease (PD) and severe gait disorders. In this double-blind randomised cross-over study, patients were assessed after 24 h of PPNa stimulation. Assessments included the motor part of the Unified Parkinson's Disease Rating Scale, the Epworth Sleepiness Scale and a behavioural gait assessment. RESULTS: Compared with 60-80 Hz, 10-25 Hz PPNa stimulation led to decreased akinaesia, gait difficulties and daytime sleepiness in 7/9 patients. In one patient, these symptoms were aggravated under 10-25 Hz stimulation compared with 60-80 Hz. CONCLUSION: These results are in keeping with the benefits of chronic PPNa stimulation for gait and postural difficulties in patients with PD, and with regard to the influence of patients' clinical characteristics, differential neuronal loss in the PPNa and electrode location. We conclude that in patients with PPNa stimulation, low frequency provides a better outcome than high-frequency stimulation.

Improvement of surgical accuracy during DBS-lead implantation has been described recently, leading to “frameless” or “MRI-verified“ techniques. However, combining a high-quality definition of the STN using intraoperative 1.5 MRI with the possibility to reduce errors due to co-registration and to monitor lead progression during surgical insertion while checking the absence of surgical complication is an appealing method. We report here surgical methodology, safety, application accuracy, and clinical benefit of STN-lead implantation under MRI guidance. Two patients with a severe PD state were treated by bilateral STN–DBS. Leads were implanted under general anesthesia using intraoperative MRI guidance (ClearPoint system). Lead implantation accuracy was measured on T1 axial images at the level of the target. Clinical improvement was measured on the pre- and post-UPDRS 3 scale at 1-year follow-up. Surgery was safe and uneventful in both cases. Radial error was 0.36 (right) and 0.86 mm (left) in case 1, and 0.41 (right) and 0.14 mm (left) in case 2. No edema or hemorrhage were noticed. Intraoperative MRI guidance allows DBS lead implantation with high accuracy and with great clinical efficacy. A larger cohort of patients is needed to confirm these initial results.

Background Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson9s disease, leading to improvement in health-related quality of life (HRQoL). However, an excessive decrease in dopaminergic medication can lead to a withdrawal syndrome with apathy as the predominant feature. The present study aims to assess the impact of postoperative apathy on HRQoL. Methods A cohort of 88 patients who underwent STN-DBS was divided into two groups, those who were apathetic at 1 year and those who were not, as measured by the Starkstein scale. HRQoL was assessed using the Parkinson9s disease questionnaire 39 (PDQ-39) and was compared between the two groups. We also compared activities of daily living, motor improvement and motor complications (Unified Parkinson9s Disease Rating Scale, UPDRS), depression and anxiety, as well as cognition and drug dosages. Baseline characteristics and postoperative complications were recorded. Results One year after surgery, 27.1% of patients suffered from apathy. While motor improvement was significant and equivalent in both the apathy (−40.4% of UPDRS motor score) and non-apathy groups (−48.6%), the PDQ-39 score did not improve in the apathy group (−5.5%; p=0.464), whereas it improved significantly (−36.7%; p≤0.001) in the non-apathy group. Change in apathy scores correlated significantly with change in HRQoL scores (r=0.278, p=0.009). Depression and anxiety scores remained unchanged from baseline in the apathy group (p=0.409, p=0.075), while they improved significantly in patients without apathy (p=0.006, p≤0.001). A significant correlation was found between changes in apathy and depression (r=0.594, p≤0.001). Conclusions The development of apathy after STN-DBS can cancel out the benefits of motor improvement in terms of HRQoL. Systematic evaluation and management of apathy occurring after subthalamic stimulation appears mandatory.

International audience; The present study demonstrates the application of the Unsupervised Spike Sorting algorithm (USS) to separation of multi-unit recordings and investigation of neuronal activity patterns in the subthalamic nucleus (STN). This nucleus is the main target for deep brain stimulation (DBS) in Parkinsonian patients. The USS comprises a fast unsupervised learning procedure and allows sorting of multiple single units, if any, out of a bioelectric signal. The algorithm was tested on a simulated signal with different levels of noise and with application of Time and Spatial Adaptation (TSA) algorithm for denoising. The results of the test showed a good quality of spike separation and allow its application to investigation of neuronal activity patterns in a medical application. One hundred twenty-four single channel multi-unit records from STN of 6 Parkinsonian patients were separated with USS into 492 single unit trains. Auto- and crosscorrellograms for each unit were analyzed in order to reveal oscillatory, bursting and synchronized activity patterns. We analyzed separately two brain hemispheres. For each hemisphere the percentage of units of each activity pattern were calculated. The results were compared for the first and the second operated hemispheres of each patient and in total.

Resume Le traitement neurochirurgical de la maladie de Parkinson (MP) par stimulation cerebrale profonde (SCP) a ete introduit pour la premiere fois en 1987. Il a depuis lors connu un developpement considerable lie non seulement aux limites du traitement medicamenteux mais egalement a l’amelioration des techniques d’imagerie cerebrale et aux progres realises dans la connaissance du fonctionnement des ganglions de la base. Le tremblement resistant au traitement medicamenteux et les complications motrices liees a la levodopa constituent les principales indications de SCP dans la MP. Le noyau ventral intermediaire du thalamus (Vim) fut la premiere cible utilisee pour le traitement des tremblements severes. L’inconstance des effets observes sur la rigidite et l’akinesie parkinsoniennes ainsi que sur les dyskinesies liees a la levodopa limite les indications de la stimulation du Vim au traitement du tremblement essentiel invalidant. Le pallidum interne et le noyau subthalamique sont les deux autres cibles indiquees dans le traitement des formes severes de MP. La stimulation du pallidum interne est indiquee chez des patients presentant des dyskinesies invalidantes. Elle a l’avantage de pouvoir etre realisee de facon bilaterale, sans complication arthrique, posturale ou neuropsychologique majeure par rapport aux pallidotomies. La taille et la complexite de fonctionnement de la structure pallidale sont vraisemblablement a l’origine de la variabilite des effets observes et des resultats obtenus par differentes equipes. Le noyau subthalamique constitue la cible de reference pour le traitement neurochirurgical de la MP. Sa stimulation chronique permet de controler l’ensemble des symptomes de la triade parkinsonienne. L’amelioration de l’etat moteur permet de reduire considerablement le traitement medicamenteux et, par ce mecanisme, les dyskinesies liees a la levodopa. Des complications severes peuvent survenir dans 2 a 4 p. 100 des cas. Il s’agit d’infections sur materiel implante et de contusions hemorragiques. Ces techniques neurochirurgicales ne peuvent etre mises en œuvre que par des equipes pluridisciplinaires regroupant des neurochirurgiens experts en stereotaxie fonctionnelle, des neurologues specialises dans les troubles du mouvement, des neuroradiologues, des neuropsychologues et des kinesitherapeutes. Ce sont des techniques sophistiquees dont l’indication doit etre posee avec discernement.

background Although the short-term benefits of bilateral stimulation of the subthalamic nucleus in patients with advanced Parkinson’s disease have been well documented, the long-term outcomes of the procedure are unknown. methods We conducted a five-year prospective study of the first 49 consecutive patients whom we treated with bilateral stimulation of the subthalamic nucleus. Patients were assessed at one, three, and five years with levodopa (on medication) and without levodopa (off medication), with use of the Unified Parkinson’s Disease Rating Scale. Seven patients did not complete the study: three died, and four were lost to follow-up. results As compared with base line, the patients’ scores at five years for motor function while off medication improved by 54 percent (P

Deep brain stimulation (DBS) is a neurosurgical treatment of Parkinson's disease that is applied to three targets: the ventral intermediate nucleus of the thalamus (Vim), the globus pallidus internas (GPi) and the subthalamic nucleus (STN). Vim DBS mainly improves contralateral tremor and, therefore, is being supplanted by DBS of the two other targets, even in patients with tremor dominant disease. STN and GPi DBS improve off-motor phases and dyskinesias. There is little comparative data between these procedures. The magnitude of the motor improvement seems more constant with STN than GPi DBS. STN DBS allows a decrease in antiparkinsonian drug doses and consumes moderate current. These advantages of STN over GPi DBS are offset by the need for more intensive postoperative management. The DBS procedure has the unique advantage of reversibility and adjustability over time. Patients with young-onset Parkinson's disease suffering from levodopa-induced motor complications but still responding well to levodopa and who exhibit no behavioral, mood, or cognitive impairment benefit the most from STN DBS. Adverse effects more specific of the DBS procedure are infection, cutaneous erosion, and lead breaking or disconnection. Intracranial electrode implantation can induce a hematoma or contusion. Most authors agree that the benefit to risk ratio of DBS is favorable.

Studying the clinical effects induced by electrical stimulation of the subthalamic nucleus (STN) area in a parkinsonian patient under local anesthesia is a mandatory step to determine the precise location of the final chronic electrode. Using multiple microelectrodes, preferably in a concentric parallel array allows a precise mapping of the STN region. The most reliable features to determine the suitable target are stimulation-induced dyskinesias and rigidity decrease at a low intensity without adverse effects or only at far higher intensities. New skills are needed to assess all stimulation-induced effects and interpret them in anatomo-functional terms.

International audience; Advances in the field of closed-loop neuromodulation call for analysis and modeling approaches capable of confronting challenges related to the complex neuronal response to stimulation and the presence of strong internal and measurement noise in neural recordings. Here we elaborate on the algorithmic aspects of a noise-resistant closed-loop subthalamic nucleus deep brain stimulation system for advanced Parkinson’s disease and treatment-refractory obsessive-compulsive disorder, ensuring remarkable performance in terms of both efficiency and selectivity of stimulation, as well as in terms of computational speed. First, we propose an efficient method drawn from dynamical systems theory, for the reliable assessment of significant nonlinear coupling between beta and high-frequency subthalamic neuronal activity, as a biomarker for feedback control. Further, we present a model-based strategy through which optimal parameters of stimulation for minimum energy desynchronizing control of neuronal activity are being identified. The strategy integrates stochastic modeling and derivative-free optimization of neural dynamics based on quadratic modeling. On the basis of numerical simulations, we demonstrate the potential of the presented modeling approach to identify, at a relatively low computational cost, stimulation settings potentially associated with a significantly higher degree of efficiency and selectivity compared with stimulation settings determined post-operatively. Our data reinforce the hypothesis that model-based control strategies are crucial for the design of novel stimulation protocols at the backstage of clinical applications.

International audience; High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711.

Background Drug-resistant motor epilepsies are particularly incapacitating for the patients. In a primate model of focal motor seizures induced by intracortical injection of penicillin, we recently showed that seizures propagated from the motor cortex towards the basal ganglia. Objective Using the same animal model here, we hypothesized that disruption of subthalamic nucleus (STN) activity by chronic high frequency stimulation (HFS) could modify pathological excessive cortical synchronisation occurring during focal motor seizures, and therefore could reduce seizure activity. Methods Two monkeys were chronically implanted with one electrode positioned into the STN. In each experiment, seizures were induced during 6 hours by injecting penicillin into the motor cortex. During stimulation sessions, HFS-STN was applied at the beginning of penicillin injection. Results Our results indicate that HFS-STN improved focal motor seizures by delaying the occurrence of the first seizure, by decreasing the number of seizures by 47% and therefore the total time spent seizing by 53% compared to control. These results argue for a therapeutic use of HFS-STN in motor seizures because they were obtained in a very severe primate model of motor status similar to that seen in human. Furthermore, HFS-STN was much more efficient than direct cortical HFS of the epileptic focus, which we already tested in the same primate model. Conclusions The present study suggests that HFS-STN could be used as an experimental therapy when other therapeutic strategies are not possible or have failed in humans suffering from motor epilepsy but the present study still warrants controlled studies in humans.

Summary Startle seizures belong to reflex epilepsy syndromes. They usually occur in patients with mental deficiency and showing widely extended cortical lesions, often involving the sensorimotor area. Here we report three cases who did not fulfill these criteria, and in whom stereotactic electroencephalography (SEEG) recordings demonstrated the prominent involvement of the supplementary motor area (SMA). Visual analysis was complemented by time-frequency analysis of SEEG signals using a neuroimaging approach (Epileptogenicity Maps), which showed at seizure onset a significant increase of high frequency oscillations (HFOs, 60–100 Hz) over the premotor and prefrontal areas. Critically, in all cases, the SMA showed ictal HFOs at seizure onset and was included in the surgical resection. All patients became seizure-free after surgery, and histopathological examinations showed no specific lesion. These cases suggest the prominent but not exclusive role of SMA in startle seizures, and highlight the fact that surgery can be considered even in the absence of any magnetic resonance imaging (MRI) lesion.

Background: Parkinson’s disease (PD) is characterized by reduced flexibility, conceptualization, and visuo-spatial abilities. Although these are essential to creativity, case studies show emergence of creativity during PD. Knowledge about the role of dopamine in creativity so far only stems from a few case reports. We aim at demonstrating that creativity can be induced by dopaminergic treatments in PD, and tends to disappear after withdrawal of dopamine agonists. Methods: Eleven consecutive creative PD patients were selected from candidates for subthalamic nucleus deep brain stimulation (STN DBS) surgery, and compared to 22 non-creative control PD patients. Motor disability (UPDRS III), cognition (Frontal score, Mattis scale), and behavior (Ardouin scale) were assessed before surgery and 1 year after. Results: Before surgery, whereas cognitive and motor assessments were similar between groups, dopamine agonist (but not levodopa) dosages were higher in creative patients (p = 0.01). The Ardouin scale revealed also a specific psycho-behavioral profile of creative patients which had higher scores for mania (p

Despite its widespread use, the underlying mechanism of deep brain stimulation (DBS) remains unknown. Once thought to impart a "functional inactivation", there is now increasing evidence showing that DBS actually can both inhibit neurons and activate axons, generating a wide range of effects. This implies that the mechanisms that underlie DBS work not only locally but also at the network level. Therefore, not only may DBS induce membrane or synaptic plastic changes in neurons over a wide network, but it may also trigger cellular and molecular changes in other cells, especially astrocytes, where, together, the glial-neuronal interactions may explain effects that are not clearly rationalized by simple activation/inhibition theories alone. Recent studies suggest that (1) high-frequency stimulation (HFS) activates astrocytes and leads to the release of gliotransmitters that can regulate surrounding neurons at the synapse; (2) activated astrocytes modulate synaptic activity and increase axonal activation; (3) activated astrocytes can signal further astrocytes across large networks, contributing to observed network effects induced by DBS; (4) activated astrocytes can help explain the disparate effects of activation and inhibition induced by HFS at different sites; (5) astrocytes contribute to synaptic plasticity through long-term potentiation (LTP) and depression (LTD), possibly helping to mediate the long-term effects of DBS; and (6) DBS may increase delta-opioid receptor activity in astrcoytes to confer neuroprotection. Together, the plastic changes in these glial-neuronal interactions network-wide likely underlie the range of effects seen, from the variable temporal latencies to observed effect to global activation patterns. This article reviews recent research progress in the literature on how astrocytes play a key role in DBS efficacy.

Objective: To assess the efficacy of epidural motor cortex stimulation (MCS) on dystonia, spasticity, pain, and quality of life in patients with dystonia secondary to a focal basal ganglia (BG) lesion. Methods: In this double-blind, crossover, multicenter study, 5 patients with dystonia secondary to a focal BG lesion were included. Two quadripolar leads were implanted epidurally over the primary motor (M1) and premotor cortices, contralateral to the most dystonic side. The leads were placed parallel to the central sulcus. Only the posterior lead over M1 was activated in this study. The most lateral or medial contact of the lead (depending on whether the dystonia predominated in the upper or lower limb) was selected as the anode, and the other 3 as cathodes. One month postoperatively, patients were randomly assigned to on- or off-stimulation for 3 months each, with a 1-month washout between the 2 conditions. Voltage, frequency, and pulse width were fixed at 3.8 V, 40 Hz, and 60 μs, respectively. Evaluations of dystonia (Burke-Fahn-Marsden Scale), spasticity (Ashworth score), pain intensity (visual analog scale), and quality of life (36-Item Short Form Health Survey) were performed before surgery and after each period of stimulation. Results: Burke-Fahn-Marsden Scale, Ashworth score, pain intensity, and quality of life were not statistically significantly modified by MCS. Conclusions: Bipolar epidural MCS failed to improve any clinical feature in dystonia secondary to a focal BG lesion. Classification of evidence: This study provides Class I evidence that bipolar epidural MCS with the anode placed over the motor representation of the most affected limb failed to improve any clinical feature in dystonia secondary to a focal BG lesion.

Improvement of gait disorders following pedunculopontine nucleus area stimulation in patients with Parkinson’s disease has previously been reported and led us to propose this surgical treatment to patients who progressively developed severe gait disorders and freezing despite optimal dopaminergic drug treatment and subthalamic nucleus stimulation. The outcome of our prospective study on the first six patients was somewhat mitigated, as freezing of gait and falls related to freezing were improved by low frequency electrical stimulation of the pedunculopontine nucleus area in some, but not all, patients. Here, we report the speech data prospectively collected in these patients with Parkinson’s disease. Indeed, because subthalamic nucleus surgery may lead to speech impairment and a worsening of dysarthria in some patients with Parkinson’s disease, we felt it was important to precisely examine any possible modulations of speech for a novel target for deep brain stimulation. Our results suggested a trend towards speech degradation related to the pedunculopontine nucleus area surgery (off stimulation) for aero-phonatory control (maximum phonation time), phono-articulatory coordination (oral diadochokinesis) and speech intelligibility. Possibly, the observed speech degradation may also be linked to the clinical characteristics of the group of patients. The influence of pedunculopontine nucleus area stimulation per se was more complex, depending on the nature of the task: it had a deleterious effect on maximum phonation time and oral diadochokinesis, and mixed effects on speech intelligibility. Whereas levodopa intake and subthalamic nucleus stimulation alone had no and positive effects on speech dimensions, respectively, a negative interaction between the two treatments was observed both before and after pedunculopontine nucleus area surgery. This combination effect did not seem to be modulated by pedunculopontine nucleus area stimulation. Although limited in our group of patients, speech impairment following pedunculopontine nucleus area stimulation is a possible outcome that should be considered before undertaking such surgery. Deleterious effects could be dependent on electrode insertion in this brainstem structure, more than on current spread to nearby structures involved in speech control. The effect of deep brain stimulation on speech in patients with Parkinson’s disease remains a challenging and exploratory research area. * Abbreviations : DBS : deep brain stimulation l-DOPA : levodopa MPT : maximum phonation time PAG : periaqueductal grey matter PPNa : pedunculopontine nucleus area STN : subthalamic nucleus

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has positive and negative effects on mood and cognition, as shown in patients suffering from Parkinson's disease (PD) and severe obsessive-compulsive disorders (OCD). Such behavioural and clinical effects suggest that the STN has an important function in limbic circuitry, which still needs to be clarified from electrophysiological recordings. Here we report two exceptional cases of OCD patients in whom local field potentials (LFP) of the anterior STN were directly recorded during acute obsessive-compulsive symptoms. We found significant symptom-related changes in different frequency bands, with no clear preferential oscillatory pattern. The overall modified STN activity during OCD symptoms suggests a mixture of both pathological and compensatory mechanisms that would reflect the maintenance of an over stable motor/cognitive/emotional set. Whether this activity propagates throughout the entire cognitive-limbic loops that are impaired in OCD is an interesting question for future research in larger series of patients.

Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim, first used in our group in 1987 as a treatment of tremor of various origins, has been used over the last ten years in 137 patients. Since 1993, this method has been extended to two other targets (subthalamic nucleus (STN): 137 patients and the medial pallidum (GPi): 12 patients), based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then also suppresses levodopa induced dyskinesias. The stereotactic technique is based on the determination of the target using ventriculography, MRI and electrophysiology, with both microrecording of single neuron activity and microstimulation inducing therapeutic symptom suppression and side effects. Chronic electrodes are then placed bilaterally at the best physiologically defined location and then connected to implantable stimulators (either 2 Itrel II or the new double channel Kinetra), operated at 130–185 Hz, 60 ms pulse width, 2.5 to 3.5 volts. There was no operative mortality and permanent morbidity was observed in 3 patients. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of neural network functions could be induced, by jamming of a retroactive loop for tremor, or by shutdown of neurotransmitter release in STN. Mechanisms within an individual target are also probably different for tremor or for other symptom alleviation. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. This strong improvement allows the decrease of the drug dosage to approximately 30 % of the preoperative level, which suppresses the levodopa-induced dyskinesias. The off period dystonias are also suppressed as well as freezings and falls. The effects remain stable over more than 5 years and in the same period, the off stimulation-off medication UPDRS remains stable and does not increase at the usual rate The low rate of permanent complications, the minor side effects and their immediate reversibility, the possibility of bilateral implantation in one session and the long-term persistence of symptom relief are strong arguments which support chronic HFS of STN as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsy. It is therefore possible that DBS in STN as well as in other targets could become a potent therapeutic tool in the near future for neurological disorders.

In reflex epilepsies, alteration of gamma oscillations may mediate transition between interictal and ictal states. Here we explored a patient having seizures triggered by syrup intake. From intracranial electroencephalography combined with functional magnetic resonance imaging, the overlap of the gustatory cortex and of the preictal and ictal onset zones, as defined by early gamma changes, motivated the successful resective surgery of the middle short gyrus of the right insula. This case provides a rare demonstration from human gamma activity that the route to seizure may be supported by the interplay between physiological and epileptogenic networks.

Deep brain stimulation by high frequency (HFS) has been developed starting in the thalamic target (Vim) from pragmatic observations and subsequently followed by other targets, such as the subthalamic nucleus (STN) and pallidum as an application of current knowledge from basic preclinical research in neuroscience. The mechanism involved by this neurosurgical approach is not completely solved. For Vim we have formed the hypothesis that HFS induces a jamming of sensory-motor loops but for the STN, from our experimental research in rats we have shown that HFS induces functional inhibition of cell activity in the target nuclei. In our patients the implantation of the stimulation electrodes was carried out stereotactically, under local anesthesia, using ventriculography, MRI, microrecordings and clinical evaluation of the effects of stimulation on rigidity. When the stimulation is turned ON in the STN area a significant decrease in rigidity was determined by the neurologists. Stimulation or even penetration of the electrode may be responsible for transient dyskinesias. The average location of the clinically efficient contact of the chronic stimulating electrodes is statistically located at 5.02 +/- 0.71 1/12 degrees of AC-PC in the AP direction, at -1.5 +/- 0.66 1/8 degrees of the height of the thalamus in the ventricle direction, with laterality at 11.98 +/- 1.12 mm in the lateral direction. The beneficial effects of STN stimulation are significant providing that the electrodes are correctly placed into the target. There is strong improvement of the symptoms of the triad in which akinesia, rigidity, and tremor are reduced on average to 41. 6, 48.6, and 27%, respectively, when compared with the previous preoperative level. From our experience, HFS of the STN could be considered the surgical therapy of choice at advanced stages of Parkinson's disease.

IntroductionL’accumulation de preuves avant une prise de décision, et la capacité d’attendre avant d’agir, respectivement nommées « impulsivité décisionnelle » et « impulsivité différée », sont des formes du contrôle du comportement, dysfonctionnel dans le trouble obsessionnel compulsif (TOC). Ce travail a exploré les effets de la stimulation cérébrale profonde (SCP) du noyau sous thalamique (NST) chez ces patients et sur ces deux types d’impulsivité.Matériel et méthodesDouze patients souffrant d’un TOC traités par SCP du NST ont été inclus dans une étude randomisée en double aveugle utilisant un design croisé au cours de laquelle chacun a réalisé une évaluation comportementale en condition de stimulation ON et OFF. Leurs performances ont été comparées à celles d’un groupe de 24 sujets témoins sains appariés (âge, sexe). « L’impulsivité différée » était évaluée par la tâche de « temps de réaction en série à quatre choix », requérant une réponse motrice après avoir détecté un stimulus cible, et « l’impulsivité décisionnelle » via le « test des perles » impliquant une décision après un cumul variable d’informations laissé à l’appréciation du sujet.RésultatsLa tâche de « temps de réaction en série à quatre choix » a montré que les sujets sains avaient un nombre moindre de réponses prématurées que les patients en condition ON (p = 0,007), différence non retrouvée en condition OFF (p = 0,073), suggérant une augmentation de « l’impulsivité différée » en ON. Le test des perles a montré que les patients en condition OFF accumulaient davantage de preuves que les sujets sains avant une prise de décision (p = 0,021), et que cette différence disparaissait en condition ON (p = 0,017), témoignant d’une augmentation de « l’impulsivité décisionnelle » en ON.ConclusionL’augmentation retrouvée de ces deux types d’impulsivité pourrait être impliquée dans l’effet thérapeutique de la SCP du NST.

Before the introduction of high frequency stimulation of the subthalamic nucleus (STN), many disabled tremor dominant parkinsonian patients underwent lesioning or chronic electrical stimulation of the thalamus. We studied the effects of STN stimulation in patients with previous ventral intermediate nucleus (VIM) surgery whose motor state worsened. Fifteen parkinsonian patients were included in this study: nine with unilateral and two with bilateral VIM stimulation, three with unilateral thalamotomy, and one with both unilateral thalamotomy and contralateral VIM stimulation. The clinical evaluation consisted of a formal motor assessment using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests encompassing a 50 point frontal scale, the Mattis Dementia Rating Scale, and the Beck Depression Inventory. The first surgical procedure was performed a mean (SD) of 8 (5) years after the onset of disease. STN implantation was carried out 10 (4) years later, and duration of follow up after beginning STN stimulation was 24 (20) months. The UPDRS motor score, tremor score, difficulties in performance of activities of daily living, and levodopa equivalent daily dose significantly decreased after STN stimulation. Neither axial symptoms nor neuropsychological status significantly worsened after the implantation of the STN electrodes. The parkinsonian motor state is greatly improved by bilateral STN stimulation even in patients with previous thalamic surgery, and STN stimulation is more effective than VIM stimulation in tremor dominant parkinsonian patients.

Models of action selection postulate the critical involvement of the subthalamic nucleus (STN), especially in reactive inhibition processes when inappropriate responses to a sudden stimulus must be overridden. The STN could also play a key role during proactive inhibition, when subjects prepare to potentially suppress their actions. Here, we hypothesized that STN responses to reactive and proactive inhibitory control might be driven by different underlying mechanisms with specific temporal profiles. Direct neural recordings in twelve Parkinson's disease patients during a modified stop signal task (SST) revealed a decrease of beta band activity (βA, 13-35Hz) in the STN during reactive inhibition of smaller amplitude and shorter duration than during motor execution. Crucially, the onset latency of this relative increase of βA took place before the stop signal reaction time. It could thus be thought of as a "stop" signal inhibiting thalamo-cortical activity that would have supported motor execution. Finally, results also revealed a higher level of βA in the STN during proactive inhibition, which correlated with patient's inhibitory performances. We propose that βA in the STN would here participate in the implementation of a "hold your horse" signal to delay motor responses, thus prioritizing accuracy as compared to speed. In brief, our results provide strong electrophysiological support for the hypothesized role of the STN during executive control underlying proactive and reactive response suppression.

Summary Purpose Failure of anterior temporal lobectomy for temporal lobe epilepsy has raised the question of insular cortex involvement in these seizures. Because of difficulties in exploring the insula with invasive electroencephalography (EEG) recordings, only few studies have been performed and this question remains unanswered. Methods Here, we studied 17 patients who underwent surgery for drug-resistant temporal lobe epilepsy, explored with intracerebral electrodes, with at least one electrode coplanar to the insula. We analyzed seizure propagation patterns from temporal lobe structures to the insula, and their effect on outcome. We used an objective measure of the epileptogenicity of the insula for individual cases and group analysis between patients who were seizure-free after surgery and the others. Key Findings All temporal lobe seizures propagated to the insular cortex, with a shorter propagation delay in the case of mesiolateral temporal lobe seizures, thus supporting the existence of a perilimbic network. Epileptogenicity of the insular cortex was not a prognostic factor for outcome after surgery. Significance Insular involvement in temporal lobe seizure is not per se a prognostic factor for surgical outcome. Prognosis may be correlated with larger epileptogenic zones that our stereoelectroencephalography spatial sampling could have underestimated.

International audience; Access to cerebral tissue is essential to better understand the molecular mechanisms associated with neurodegenerative diseases. In this study, we present, for the first time, a new tool designed to obtain molecular and cellular cerebral imprints in the striatum of anesthetized monkeys. The imprint is obtained during a spatially controlled interaction of a chemically modified micro-silicon chip with the brain tissue. Scanning electron and immunofluorescence microscopies showed homogeneous capture of cerebral tissue. Nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analysis of proteins harvested on the chip allowed the identification of 1158 different species of proteins. The gene expression profiles of mRNA extracted from the imprint tool showed great similarity to those obtained via the gold standard approach, which is based on post-mortem sections of the same nucleus. Functional analysis of the harvested molecules confirmed the spatially controlled capture of striatal proteins implicated in dopaminergic regulation. Finally, the behavioral monitoring and histological results establish the safety of obtaining repeated cerebral imprints in striatal regions. These results demonstrate the ability of our imprint tool to explore the molecular content of deep brain regions in vivo. They open the way to the molecular exploration of brain in animal models of neurological diseases and will provide complementary information to current data mainly restricted to post-mortem samples.

Because of its reversibility and adaptability, deep brain stimulation (DBS) has recently gained interest in psychiatric disorders, such as obsessive-compulsive disorders (OCD) and depression. In OCD, DBS is now an alternative procedure to lesions of fascicles such as the anterior capsule, which links the orbitofrontal cortex, the cingulum, and the thalamus, and has been applied to new target such as the nucleus accumbens, with promising results. However, a recent interest has been developed toward the subthalamic nucleus (STN), a key structure of the basal ganglia that connects the motor, limbic, and associative systems. It is known from patients with Parkinson disease that STN-DBS can have significant effects on mood and cognition. Those transient effects are usually seen as "side effects" in Parkinson disease, but are clues to the underappreciated role that STN plays in the limbic circuitry, a role whose precise details are as yet unknown and under active investigation. We present the rationale supporting the use of nonmotor STN as a therapeutic target to treat OCD. In particular, we discuss the recent experience and preliminary results of our group after 6 months of nonmotor STN-DBS in patients with severe OCD.

Apathy is one of the most common symptoms encountered in Parkinson's disease, and is defined as a lack of motivation accompanied by reduced goal-directed cognition, behaviour and emotional involvement. In a previous study we have described a delayed withdrawal syndrome after successful motor improvement related to subthalamic stimulation allowing for a major decrease in dopaminergic treatment. This withdrawal syndrome correlated with a diffuse mesolimbic dopaminergic denervation. To confirm our hypothesis of parkinsonian apathy being related to mesolimbic dopaminergic denervation, we performed a randomized controlled study using piribedil, a relatively selective D2/D3 dopamine agonist to treat parkinsonian apathy, using the model of postoperative apathy. A 12-week prospective, placebo-controlled, randomized, double-blinded trial was conducted in 37 patients with Parkinson's disease presenting with apathy (Starkstein Apathy Scale score > 14) following subthalamic nucleus stimulation. Patients received either piribedil up to 300 mg per day (n = 19) or placebo (n = 18) for 12 weeks. The primary end point was the improvement of apathy under treatment, as assessed by the reduction of the Starkstein Apathy Scale score in both treatment groups. Secondary end points included alleviation in depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), improvement of quality of life (PDQ39) and anhedonia (Snaith-Hamilton Pleasure Scale). Exploratory endpoints consisted in changes of the Robert Inventory score and Hamilton depression scales. An intention to treat analysis of covariance analysis was performed to compare treatment effects (P < 0.05). The number of premature study dropouts was seven in the placebo and five in the piribedil groups, mostly related to intolerance to hypodopaminergic symptoms. At follow-up evaluation, the apathy score was reduced by 34.6% on piribedil versus 3.2% on placebo (P = 0.015). With piribedil, modifications in the Beck depression and anxiety scores were -19.8% and -22.8%, respectively versus +1.4% and -8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life (-16.2% versus +6.7% on placebo; P = 0.08) and anhedonia (-49% versus -5.6% on the placebo; P = 0.08). Apathy, assessed by the Robert Inventory score, improved by 46.6% on piribedil and worsened by 2.3% on placebo (P = 0.005). Depression, measured by the Hamilton score, improved in the piribedil group (P = 0.05). No significant side effects were observed. The present study provides a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment of apathy in Parkinson's disease.

International audience; The pedunculopontine area (PPNa) including the pedunculopontine and cuneiform nuclei, belongs to the mesencephalic locomotor region. Little is known about the oscillatory mechanisms underlying the function of this region in postural and gait control. We examined the modulations of the oscillatory activity of the PPNa and cortex during stepping, a surrogate of gait, and stance in seven Parkinson's disease patients who received bilateral PPNa implantation for disabling freezing of gait (FOG). In the days following the surgery, we recorded behavioural data together with the local field potentials of the PPNa during sitting, standing and stepping-in-place, under two dopaminergic medication conditions (OFF and ON levodopa). Our results showed that OFF levodopa, all subjects had FOG during step-in-place trials, while ON levodopa, stepping was effective (mean duration of FOG decreasing from 61.7±36.1% to 7.3±10.1% of trial duration). ON levodopa, there was an increase in PPNa alpha (5-12 Hz) oscillatory activity and a decrease in beta (13-35 Hz) and gamma (65-90 Hz) bands activity. PPNa activity was not modulated during quiet standing and sitting. Our results confirm the role of the PPNa in the regulation of gait and suggest that, in Parkinson disease, gait difficulties could be related to an imbalance between low and higher frequencies.

High-frequency deep brain stimulation of the subthalamic nucleus can be used to treat severe obsessive-compulsive disorders that are refractory to conventional treatments. The mechanisms of action of this approach possibly rely on the modulation of associative-limbic subcortical–cortical loops, but remain to be fully elucidated. Here in 12 patients, we report the effects of high-frequency stimulation of the subthalamic nucleus on behavior, and on electroencephalographic responses and inferred effective connectivity during motor inhibition processes involved in the stop signal task. First, we found that patients were faster to respond and had slower motor inhibition processes when stimulated. Second, the subthalamic stimulation modulated the amplitude and delayed inhibition-related electroencephalographic responses. The power of reconstructed cortical current densities decreased in the stimulation condition in a parietal–frontal network including cortical regions of the inhibition network such as the superior parts of the inferior frontal gyri and the dorsolateral prefrontal cortex. Finally, dynamic causal modeling revealed that the subthalamic stimulation was more likely to modulate efferent connections from the basal ganglia, modeled as a hidden source, to the cortex. The connection from the basal ganglia to the right inferior frontal gyrus was significantly decreased by subthalamic stimulation. Beyond motor inhibition, our study thus strongly suggests that the mechanisms of action of high-frequency subthalamic stimulation are not restricted to the subthalamic nucleus, but also involve the modulation of distributed subcortical–cortical networks.

En France, 300 000 personnes souffrent d’un trouble de la parole et plus de 5 millions de par le monde. Ces troubles surviennent le plus souvent suite a un accident vasculaire cerebral ayant endommage le reseau cortical du langage. Cependant, des aphasies severes sont egalement observees chez des personnes ou ce reseau n’a pas ete endommage, notamment dans le cas d’un syndrome d’enfermement (« locked-in »), de maladies neurodegeneratives telles que la sclerose laterale amyotrophique ou la maladie de Parkinson, de myopathies, ou encore de comas. Dans ce cas, il est possible d’envisager de restaurer la parole par un paradigme d’interface cerveau–machine (BCI) ou les activites corticales sont decodees pour predire ce que souhaite dire la personne [3] . Dans cette perspective, nous developpons une strategie visant a enregistrer les aires motrices de la parole controlant les articulateurs du conduit vocal, et a decoder leurs activites pour controler un synthetiseur vocal articulatoire. Les differentes etapes de ce projet seront discutees, ainsi que les premiers resultats deja obtenus en termes de synthese vocale artificielle en temps reel [1] et de decodage des activites corticales des aires de la parole. Nous soulignerons egalement certaines questions ethiques associees au projet et plus largement au developpement de neuroprotheses et d’interfaces cerveau-machine en general [2] .

Objectif Les singes parkinsoniens presentent des troubles de sommeil s’apparentant a ceux des parkinsoniens caracterises entre autres par une somnolence diurne (Barraud, 2009). La depletion en dopamine pourrait etre a l’origine de ces troubles en alterant le fonctionnement des centres d’eveil qui ne seraient alors plus suffisamment actifs pour maintenir un eveil diurne. Pour verifier cette hypothese nous avons etudie l’activite des neurones de la region pedunculopontine (PPNa) chez des singes sains puis rendus parkinsoniens. Methodes Chez 2 macaques, une chambre d’enregistrement a ete positionnee sur le crâne de facon a pouvoir enregistrer les neurones de la region du PPNa. Des vis fixees dans le crâne ont permis d’enregistrer l’EEG. Les recueils ont ete realises pendant des sessions comportant un eveil et un endormissement chez l’animal sain puis lors de l’eveil chez l’animal rendu parkinsonien. Resultats Chez l’animal sain, 68 % (pour n = 38) des neurones ont presente une diminution de leur frequence de decharge durant l’endormissement. Chez les singes rendus parkinsoniens, une augmentation significative de la part de neurones ayant un pattern burste a ete observe allant de 28,9 % (pour n = 245 neurones a l’etat sain) a 45,1 % (pour n = 152 ; [p Conclusion Les neurones du PPNa sont majoritairement plus actifs pendant l’eveil, et leur pattern se modifie a l’etat parkinsonien. Cette deregulation neuronale du PPNa pourrait expliquer la somnolence diurne et faire de cette region une cible pour la stimulation cerebrale profonde en vue d’ameliorer les troubles du sommeil.