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The pedunculopontine nucleus (PPN) included in the caudal mesencephalic reticular formation (cMRF) plays a key role in the control of locomotion and wake state. Regarding its involvement in the neurodegenerative process observed in Parkinson disease (PD), deep brain stimulation of the PPN was proposed to treat levodopa-resistant gait disorders. However, the precise role of the cMRF in the pathophysiology of PD, particularly in freezing of gait and other non-motor symptoms is still not clear. Here, using micro electrode recording (MER) in 2 primates, we show that dopamine depletion did not alter the mean firing rate of the overall cMRF neurons, particularly the putative non-cholinergic ones, but only a decreased activity of the regular neurons sub-group (though to be the cholinergic PPN neurons). Interestingly, a significant increase in the relative proportion of cMRF neurons with a burst pattern discharge was observed after MPTP intoxication. The present results question the hypothesis of an over-inhibition of the CMRF by the basal ganglia output structures in PD. The decreased activity observed in the regular neurons could explain some non-motor symptoms in PD regarding the strong involvement of the cholinergic neurons on the modulation of the thalamo-cortical system. The increased burst activity under dopamine depletion confirms that this specific spike discharge pattern activity also observed in other basal ganglia nuclei and in different pathologies could play a mojor role in the pathophysiology of the disease and could explain several symptoms of PD including the freezing of gait. The present data will have to be replicated in a larger number of animals and will have to investigate more in details how the modification of the spike discharge of the cMRF neurons in the parkinsonian state could alter functions such as locomotion and attentional state. This will ultimely allow a better comprehension of the pathophysiology of freezing of gait.

Background Although the mechanisms by which deep brain stimulation (DBS) modifies the activity of the ictal network are mostly undefined, recent studies have suggested that DBS of the anterior nucleus of the thalamus (ANT) can be an effective treatment for mesial temporal lobe epilepsy (MTLE) when resective surgery cannot be performed. In a nonhuman primate (NHP) model of MTL seizures, we showed that the ANT was actively involved during interictal and ictal periods through different patterns and that the hippocampus (HPC) and ANT synchronously oscillate in the high beta-band during seizures. Objective Based on those findings, we evaluated whether the frequency of stimulation is an important parameter that interferes with seizures and how to adapt stimulation protocols to it. Methods We investigated the effects of low-frequency (40 Hz - determined as the ictal frequency of correlation between structures) and high-frequency (130 Hz - as commonly used in clinic) ANT stimulation in three monkeys in which MTLE seizures were initiated. Results Low-frequency stimulation had a strong effect on the number of seizures and the total time spent in seizure, whereas high-frequency stimulation had no effect. The coherence of oscillations between the HPC and the ANT was significantly correlated with the success of low-frequency stimulation: the greater the coherence was, the greater the antiepileptic effect of ANT-DBS. Conclusion Our results suggest that low-frequency stimulation is efficient in treating seizures in a nonhuman primate model. More importantly, the study of the coherence between the ANT and HPC during seizures can help to predict the anti-epileptic effects of ANT stimulation. Furthermore, the DBS paradigm could be customized in frequency for each patient on the basis of the coherence spectral pattern.

BackgroundObsessive–compulsive disorder (OCD) is a major cause of disability in western country and responsible for severe impairment of quality of life. About 10% of patients present with severe OCD symptoms and require innovative treatment such as deep brain stimulation (DBS). Among possible targets, the non-motor subthalamic nucleus (STN) is a key node of the basal ganglia circuitry, strongly connected to limbic cortical areas known to be involved in OCD.MethodWe analysed, in a prospective, observational, monocentric, open label cohort, the effect of chronic non-motor STN-DBS in 19 patients with treatment-resistant OCD consecutively operated in a single centre. Severity of OCD was evaluated using the Yale and Brown Obsessive–Compulsive Scale (YBOCS). YBOCS scores at 6, 12 and 24 months postoperatively were compared with baseline. Responders were defined by >35% improvement of YBOCS scores. Global Assessment Functioning (GAF) scale was used to evaluate the impact of improvement.ResultsAt a 24-month follow-up, the mean YBOCS score improved by 53.4% from 33.3±3.5 to 15.8±9.1 (95% CI 11.2–20.4; pConclusionChronic DBS of the non-motor STN is an effective and relatively safe procedure to treat severe OCD resistant to conventional management.

Background The third ventricle (3rd V) is surrounded by centers related to satiety, homeostasis, hormones, sleep, memory, and pain. Stimulation of the wall of the 3rd V could be useful to treat disorders related to dysfunction of the hypothalamus. Objective To assess safety and efficacy of endoventricular electrical stimulation of the hypothalamus using a floating deep brain stimulation (DBS) lead laid on the floor of the 3rd V to treat refractory cluster headaches (CH). Methods Seven patients, aged 24 to 60 years, experiencing chronic CH (mean chronic duration 5.8 ± 2.5 years) were enrolled in this pilot, prospective, open study assessing the safety and potential efficacy of chronic DBS of the 3rd V. Number of attacks was collected during baseline and was compared with those occurring at 3, 6, and 12 months postoperation. Any side effects that occurred during or after surgery were reported. Effect on mood was assessed using the Hospital Anxiety and Depression scale during baseline and at 6 and 12 months postoperation. Results Insertion of the lead into the posterior 3rd V and chronic stimulation was feasible and safe in all patients. The voltage ranged from 0.9 to 2.3 volts. The most common side effect was transient trembling vision during stimulation. At 12 months, 3 of 7 patients were pain free, 2 had 90% improvement, 1 of 7 had 75% improvement, and 1 of 7 was not significantly improved. Conclusion This proof of concept demonstrates the feasibility, safety, and potential efficacy of 3rd V DBS using an endoventricular road that could be applied to treat various diseases involving hypothalamic areas. Abbreviations CCH, chronic cluster headacheCH, cluster headacheDBS, deep brain stimulationHAD, hospital anxiety depressionONS, occipital nerve stimulationPAG, periaqueductal gray matterPH, posterior hypothalamusPVG, periventricular gray matter3rd V, third ventricle.

The subthalamic nucleus (STN) plays a critical role during action inhibition, perhaps by acting like a fast brake on the motor system when inappropriate responses have to be rapidly suppressed. However, the mechanisms involving the STN during motor inhibition are still unclear, particularly because of a relative lack of single-cell responses reported in this structure in humans. In this study, we used extracellular microelectrode recordings during deep brain stimulation surgery in patients with Parkinson's disease (PD) to study STN neurophysiological correlates of inhibitory control during a stop signal task. We found two neuronal subpopulations responding either during motor execution (GO units) or during motor inhibition (STOP units). GO units fired selectively before patients' motor responses whereas STOP units fired selectively when patients successfully withheld their move at a latency preceding the duration of the inhibition process. These results provide electrophysiological evidence for the hypothesized role of the STN in current models of response inhibition.

Deep brain stimulation of the anterior nucleus of the thalamus has been proposed as novel therapy to treat intractable epilepsy. To optimize this approach, we proposed to study the involvement of this nucleus in a non-human primate model of mesial temporal lobe seizure. Two macaques were implanted with one chronic electrode into the hippocampus allowing to monitor the ictal activity. Neurons of the anterior nucleus of the thalamus were recorded with a microelectrode inserted acutely. To induce seizures, penicillin was injected into the hippocampus and neuronal activities of the anterior nucleus were analyzed during ictal and interictal periods. The effects of the chemical neuromodulation of the anterior nucleus on the ictal hippocampal activities were studied and electron microscopy analysis was carried out to study morphological modifications induced in the anterior nucleus of the thalamus. Our results demonstrate that the anterior nucleus of the thalamus is directly involved in the pathophysiology of induced seizures since: (1) Electrophysiological study showed an heterogenous excitation during seizure characterized by the appearance of 2 types of neuronal firing response; (2) chemical neuromodulation of the anterior nucleus of the thalamus changed the severity of seizures; (3) morphological modification of the ultrastructure as well as a reduction of synapse density were observed within the ipsilateral anterior nucleus of the thalamus. This study demonstrates that the anterior nucleus of the thalamus is part of the epileptic network activated during temporal lobe seizures and suggests that this nucleus would be valid target for seizure control using deep brain stimulation.

International audience; BACKGROUND Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. OBJECTIVE To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. METHODS We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as "bad responders" (2 patients), "mild responders" (1 patient) and "good responders" (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. RESULTS Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. CONCLUSION In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF.

Background and objective: Generating and characterizing primate models of epileptic seizures are important for understanding pathophysiology of diseases and establishing preclinical efficacy of novel therapies like Deep Brain Stimulation. A focal motor epilepsy model is described here. Method: Seizures were obtained after intracortical penicillin injection into the motor strip through a cannula in two awake monkeys and electrocorticograms were recorded by epidural screws. Seizures were analyzed and compared for number, average duration of each seizure and total duration of ictal activity. Pharmaco-resistance for antiepileptic drug was tested by administration of Diazepam during seizures. Results: A motor status with seizures mimicking those seen in Kojevnikov’s syndrome was easily generated several minutes after penicillin injection and lasted 24 h on an average. The model thus characterized appears stable and consistent. There is no significant variation between experiments in individual primate as well as between two specimens. Diazepam though reduced the total duration of seizures, failed to abolish behavioural seizures. Conclusion: This model represents a good alternative model for preclinical research aiming at testing novel therapies because seizures are obtained on demand, last up to 24 h after a single penicillin injection, are stable and resistant to Diazepam.

The authors proposed an intraventricular 'floating' electrode inserted in the third ventricle (V3) adjacent to the ventromedian hypothalamus (VMH) in a freely moving Macaca fascicularis to modulate food intake (FI), body fat (BF), body weight (BW) and body mass index (BMI), as a potential treatment of obesity.Five adult Macaca fascicularis monkeys were implanted stereotactically in the V3 contiguous to the VMH with one deep brain stimulation (DBS) electrode. The study was divided in two phases: (a) acute 24 h-fasting trials: different electrical stimulation parameters were applied to a fasting primate to determine the best combination in reducing FI; and (b) chronic 8-week stimulation trials: three cycles of intraventricular-VMH DBS lasting 8-10 weeks were performed at 130 Hz, 80 Hz (most effective frequency reducing FI) and 30 Hz, respectively. BMI, BW, BF content, skinfolds and hormones were measured during baseline and at the end of each session of stimulation.Acute 24 h-fasting trials: there was a decrease in FI in all subjects at 80 Hz, (11-19%, mean 15%). Chronic 8-week stimulation trials: a significant decrease in BW and BMI was observed in three out of four monkeys at 80 Hz (mean 8 ± 4.4%). Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. The sham monkey remained stable. No significant adverse effects were recorded.The stimulation of the VMH region through an intraventricular approach might acutely modulate FI and induce a sustained decrease in BW and fat mass in normal non-human primate.

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.

Objective Almost 30 years after the start of the modern era of deep brain stimulation (DBS), the subthalamic nucleus (STN) still constitutes a standard stimulation target for advanced Parkinson's disease (PD), but the use of STN-DBS is also now supported by level I clinical evidence for treatment-refractory obsessive-compulsive disorder (OCD). Disruption of neural synchronization in the STN has been suggested as one of the possible mechanisms of action of standard and alternative patterns of STN-DBS at a local level. Meanwhile, recent experimental and computational modeling evidence has signified the efficiency of alternative patterns of stimulation; however, no indications exist for treatment-refractory OCD. Here, we comparatively simulate the desynchronizing effect of standard (regular at 130 Hz) versus temporally alternative (in terms of frequency, temporal variability and the existence of bursts or pauses) patterns of STN-DBS for PD and OCD, by means of a stochastic dynamical model and two microelectrode recording (MER) datasets. Approach The stochastic model is fitted to subthalamic MERs acquired during eight surgical interventions for PD and eight surgical interventions for OCD. For each dynamical system simulated, we comparatively assess the invariant density (steady-state phase distribution) as a measure inversely related to the desynchronizing effect yielded by the applied patterns of stimulation. Main results We demonstrate that high (130 Hz)-and low (80 Hz)-frequency irregular patterns of stimulation, and low-frequency periodic stimulation interrupted by bursts of pulses, yield in both pathologic conditions a significantly stronger desynchronizing effect compared with standard STN-DBS, and distinct alternative patterns of stimulation. In PD, values of the invariant density measure are proven to be optimal at the dorsolateral oscillatory region of the STN including sites with the optimal therapeutic window. Significance In addition to providing novel insights into the efficiency of low-frequency nonregular patterns of STN-DBS for advanced PD and treatment-refractory OCD, this work points to a possible correlation of a model-based outcome measure with clinical effectiveness of stimulation and may have significant implications for an energy- and therapeutically-efficient configuration of a closed-loop neuromodulation system.

We present a novel closed-loop subthalamic nucleus (STN) deep brain stimulation (DBS) scheme for Parkinson's disease (PD) and obsessive-compulsive disorder (OCD). The algorithm is designed to effectuate real-time, adaptive stimulation employing the outcome of the 0–1 test for chaos as a state-specific biomarker. In case of a null outcome, the system identifies optimal patterns of stimulation desynchronizing pathologic neuronal activity with minimal energy consumption, on grounds of a stochastic dynamical model and an appropriately formulated cost function. Simulations are performed utilizing microelectrode recordings (MERs) acquired during 8 and 2 DBS surgical interventions for PD and OCD, respectively.

International audience; The electrical effects on the nervous system have been known for long. The excitatory effect has been used for diagnostic purposes or even for therapeutic applications, like in pain using low-frequency stimulation of the spinal cord or of the thalamus. The discovery that High-Frequency Stimulation (HFS) mimics the effect of lesioning has opened a new field of therapeutic application of electrical stimulation in all places where lesion of neuronal structures, such as nuclei of the basal ganglia, had proven some therapeutic efficiency. This was first applied to the thalamus to mimic thalamotomy for the treatment of tremor, then to the subthalamic nucleus and the pallidum to treat some advanced forms of Parkinson's disease and control not only the tremor but also akinesia, rigidity and dyskinesias. The field of application is increasingly growing, currently encompassing dystonias, epilepsy, obsessive compulsive disease, cluster headaches, and experimental approaches are being made in the field of obesity and food intake control. Although the effects of stimulation are clear-cut and the therapeutic benefit is clearly recognized, the mechanism of action of HFS is not yet understood. The similarity between HFS and the effect of lesions in several places of the brain suggests that this might induce an inhibition-like process, which is difficult to explain with the classical concept of physiology where electrical stimulation means excitation of neural elements. The current data coming from either clinical or experimental observations are providing elements to shape a beginning of an understanding. Intra-cerebral recordings in human patients with artefact suppression tend to show the arrest of electrical firing in the recorded places. Animal experiments, either in vitro or in vivo, show complex patterns mixing inhibitory effects and frequency stimulation induced bursting activity, which would suggest that the mechanism is based upon the jamming of the neuronal message, which is by this way functionally suppressed. More recent data from in vitro biological studies show that HFS profoundly affects the cellular functioning and particularly the protein synthesis, suggesting that it could alter the synaptic transmission by reducing the production of neurotransmitters. It is now clear that this method has a larger field of application than currently known and that its therapeutical applications will benefit to several diseases of the nervous system. The understanding of the mechanism has opened a new field of research, which will call for reappraisal of the basic effects of electricity on the living tissues.

Parkinson’s disease (PD) is characterized by nigral degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. Rather than treating only the symptomatic aspects of Parkinson’s disease, one may also consider treatments designed to retard, arrest, or even reverse this degenerative process. Such strategies could include preventive or restorative treatments instead of purely palliative treatments. A recent hypothesis states that glutamate output from the subthalamic nucleus (STN) to the substantia nigra contributes to the neurotoxic process underlying dopaminergic cell death in Parkinson’s disease. Furthermore, high-frequency stimulation (HFS) of the STN inhibits neurons resulting in the suppression of their glutamate output. Experiments in both rats and monkeys provide preliminary data supporting this hypothesis. Kainic acid (KA) lesions of the STN prevent the loss of dopaminergic neurons in the substantia nigra after intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats, and after systemic administration of MPTP in monkeys. In PD patients, the background level of their disease is evaluated in the off medication/off stimulation state (UPDRS III score), over a period of 5 years. Thirty percent of the patients are stabilized and 18% have persistent improvement of their disease-related impairment. Further experiments are needed, including controlled clinical trials utilizing functional imaging of the dopamine transporters and post-synaptic receptors.

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.

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.

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; OBJECTIVE: Although electrophysiologic dysfunction of the subthalamic nucleus is putative, deep brain stimulation of this structure has recently been reported to improve obsessions and compulsions. In Parkinson disease, sensorimotor subthalamic neurons display high-frequency burst firing, which is considered as an electrophysiologic signature of motor loop dysfunction. We addressed whether such neuronal dysfunction of the subthalamic nucleus also exists in the nonmotor loops involved in patients with obsessive-compulsive disorder. METHODS: We compared the neuronal activity of the subthalamic nucleus recorded in 9 patients with obsessive-compulsive disorder with that of 11 patients with Parkinson disease measured during intraoperative exploration for deep brain stimulation. RESULTS: The mean subthalamic neuron discharge rate was statistically lower in patients with obsessive-compulsive disorder than in patients with Parkinson disease (20.5 ± 11.0 Hz, n = 100 and 30.8 ± 15.6 Hz, n = 93, respectively, p < 0.001). The relative proportion of burst neurons did not differ significantly between the 2 diseases (75% vs 73%). Interestingly, burst neurons were predominantly left-sided in obsessive-compulsive disorder. INTERPRETATION: The recording of burst neurons within the nonmotor subthalamic nucleus in patients with obsessive-compulsive disorder is a novel finding that suggests the existence of deregulation of the nonmotor basal ganglia loop, possibly left-sided. Potentially, burst activity might interfere with normal processes occurring within nonmotor loops.

International audience; Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive-compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1-8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative-limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative-limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.

In advanced Parkinson’s disease, several therapeutical option including not only lesional surgery (VIM, GPi) and deep brain stimulation (STN, GPi, VIM) but also continuous subcutaneous apomorphine infusion therapy can be proposed to the patient. The choice depends on the hope of the patient, patient’s general health condition and the experience and choice of the neurosurgical and neurologist team. Here we report our experience based on 400 STN-DBS cases and we discuss, on the basis of our experience and on the literature, the advantage and disadvantage of DBS strategy as compared with non-surgical option such as continuous subcutaneous apomorphine infusion therapy.

International audience; Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

International audience; Since the 1960s, deep brain stimulation and spinal cord stimulation at low frequency (30 Hz) have been used to treat intractable pain of various origins. For this purpose, specific hardware have been designed, including deep brain electrodes, extensions, and implantable programmable generators (IPGs). In the meantime, movement disorders, and particularly parkinsonian and essential tremors, were treated by electrolytic or mechanic lesions in various targets of the basal ganglia, particularly in the thalamus and in the internal pallidum. The advent in the 1960s of levodopa, as well as the side effects and complications of ablative surgery (e.g., thalamotomy and pallidotomy), has sent functional neurosurgery of movement disorders to oblivion. In 1987, the serendipitous discovery of the effect of high-frequency stimulation (HFS), mimicking lesions, allowed the revival of the surgery of movement disorders by stimulation of the thalamus, which treated tremors with limited morbidity, and adaptable and reversible results. The stability along time of these effects allowed extending it to new targets suggested by basic research in monkeys. The HFS of the subthalamic nucleus (STN) has profoundly challenged the practice of functional surgery as the effect on the triad of dopaminergic symptoms was very significant, allowing to decrease the drug dosage and therefore a decrease of their complications, the levodopa-induced dyskinesias. In the meantime, based on the results of previous basic research in various fields, HFS has been progressively extended to potentially treat epilepsy and, more recently, psychiatric disorders, such as obsessive-compulsive disorders, Gilles de la Tourette tics, and severe depression. Similarly, suggested by the observation of changes in PET scan, applications have been extended to cluster headaches by stimulation of the posterior hypothalamus and even more recently, to obesity and drug addiction. In the field of movement disorders, it has become clear that STN stimulation is not efficient on the nondopaminergic symptoms such as freezing of gait. Based on experimental data obtained in MPTP-treated parkinsonian monkeys, the pedunculopontine nucleus has been used as a new target, and as suggested by the animal research results, its use indeed improves walking and stability when stimulation is performed at low frequency (25 Hz). The concept of simultaneous stimulation of multiple targets eventually at low or high frequency, and that of several electrodes in one target, is being accepted to increase the efficiency. This leads to and is being facilitated by the development of new hardware (multiple-channel IPGs, specific electrodes, rechargeable batteries). Still additional efforts are needed at the level of the stimulation paradigm and in the waveform. The recent development of nanotechnologies allows the design of totally new systems expanding the field of deep brain stimulation. These new techniques will make it possible to not only inhibit or excite deep brain structures to alleviate abnormal symptoms but also open the field for the use of recording cortical activities to drive neuroprostheses through brain-computer interfaces. The new field of compensation of deficits will then become part of the field of functional neurosurgery.

International audience; In animals, the pedunculopontine (PPN) and the sub-cuneiform (SCU) nuclei located in the upper brainstem are involved during the processing of gait. Similar functional nuclei are suspected in humans but their role in gait is unclear. Here we show that, using extra-cellular recordings of the PPN/SCU region obtained in two parkinsonian patients, the SCU neurons increased their firing rate without modifying their firing pattern during mimicked steps. We conclude that SCU neurons are activated during gait processes.

The present paper is devoted to the suppression of spurious signals (artifacts) in records of neural activity during deep brain stimulation. An algorithm of adaptive filtering based on the signals synchronization in phase space is presented. The algorithm was implemented and tested using synthetic data and recordings collected from patients during the stimulation.