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The Value of Deep Brain Stimulation in Difficult-To-Treat and Treatment-Refractory Depression Abstract: Deep Brain Stimulation ("DBS") is a minimally invasive, neurosurgical and hypothesis-driven therapeutic procedure for permanent local regulation of pathological circuits. While depression represents a heterogeneous syndrome with multifactorial etiopathogenesis, neuroscience research is advancing evidence to identify network-level mechanisms that play an important role in the pathophysiology of depression. In the following article, we will review the role of DBS in treatment-resistant or difficult-to-treat depression. The aim is to increase the awareness of DBS and to discuss the challenges of its therapy and implementation.

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OBJECTIVES: We investigated changes of impulsivity after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients, distinguishing functional from dysfunctional impulsivity and their contributing factors. METHODS: Data of 33 PD patients treated by STN-DBS were studied before and 6 months after surgery: motor impairment, medication (dose and dopaminergic agonists), cognition, mood and occurrence of impulse control disorders. Impulsivity was assessed by the Dickman Impulsivity Inventory, which distinguishes functional impulsivity (FI), reflecting the potential for reasoning and rapid action when the situation requires it, and dysfunctional impulsivity (DI), reflecting the lack of prior reasoning, even when the situation demands it. The location of DBS leads was studied on postoperative MRI using a deformable histological atlas and by compartmentalization of the STN. RESULTS: After STN-DBS, DI was significantly increased (mean pre- and postoperative DI scores 1.9±1.6 and 3.5±2.4, P<0.001) although FI was not modified (mean pre- and postoperative FI scores 6.2±2.7 and 5.8±2.6). Factors associated with a DI score's increase≥2 (multivariable logistic regression model) were: low preoperative Frontal Assessment Battery score and location of the left active contact in the ventral part of the STN. CONCLUSION: Our study suggests that STN-DBS may have a different impact on both dimensions of impulsivity, worsening pathological impulsivity without altering physiological impulsivity. The increase in dysfunctional impulsivity may be favoured by the location of the electrode in the ventral part of the STN.

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Movement Disorders: What Are You Doing? What Can We Do? Abstract. Disturbances of movement are common and varied. Frequent causes are systemic diseases such as Parkinson's syndromes and the essential tremor. Treatment options in practice and hospital include conservative, predominantly drug strategies such as oral administration of dopamine precursors or agonists, and pharmacological or non-pharmacological escalation strategies such as intramuscular botulinum toxin A injections, the subcutaneous or enteral drug pumps for apomorphine or levodopa and carbidopa, the effective deep brain stimulation and the novel focused ultrasound therapy, which are bound to highly specialized centers and should be considered as treatment option quite earlier and more frequently.

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Stereotactic surgery is an increasingly popular option for disabling tremors whenever it is insufficiently improved by drug treatment. Surgical approaches are expanding. Thalamic deep brain stimulation is one of the most efficacious treatments. Its recent technological advances with adaptive stimulation and new electrodes configuration will allow a more physiological stimulation. However, a reappraisal of less invasive, new lesioning procedures is underway. Gamma Knife thalamotomy and magnetic resonance-guided focused ultrasounds encounter very few contraindications. Recent studies reported their efficacy on tremor control and safety profile. Besides the ventralis intermedius nucleus of the thalamus, alternative targets are also emerging. The effectiveness of surgical therapies on essential tremor and Parkinson's disease tremor is well established. For more uncommon tremors, preliminary studies are encouraging. All these surgical therapies can be proposed as treatment option for medically refractory tremors.

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Movement disorders (tremor, chorea, dystonia, tics, and myoclonus) are related to basal ganglia and/or interconnected brain areas dysfunction. Clinical examination is a key point in order to characterize the abnormal movement and identify associated signs that can guide etiological approach. Iatrogenic diseases will be systematically ruled out before conducting additional investigations (brain MRI, electrophysiological studies). Wilson disease, but also other treatable metabolic and/or genetic diseases, and auto-immune diseases will be systematically considered. Therapeutic management is symptomatic and based on specific oral drugs appropriate to each movement disorders. In some cases, radiosurgery and deep brain stimulation should be helpful, especially for tremor and generalized dystonia.

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Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system, characterized by the accumulation of numerous neurological symptoms and signs throughout its course. Fatigue is one of the most distressing complaints that MS patients may experience over their lifetime. In spite of its high prevalence, the pathophysiology of MS fatigue is far from being fully elucidated and a constellation of mechanisms seems implicated in this setting. Several factors could contribute to its development and/or exacerbation, and this requires a careful workup in order to search for all possible underlying causes, such as sleep disturbances, endocrine dysfunction and mood disorders, to cite a few. The aim of this review is to revisit the definition of MS fatigue, provide an overview of its pathophysiology, and reappraise its clinical, structural and functional correlates. Additionally, we discuss the available assessment tools, as well as the various management strategies including pharmacological and non-pharmacological interventions. Special emphasis will be placed on the role of noninvasive brain stimulation techniques in this field. Finally, we propose a "road map" to facilitate the diagnosis and guide the therapeutic regimens of this multifactorial and multidimensional construct.

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The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson's disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.

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Transcranial direct current stimulation (tDCS) is a technique of noninvasive cortical stimulation allowing significant modification of brain functions. Clinical application of this technique was reported for the first time in March 2005. This paper presents a detailed list of the 340 articles (excluding single case reports) which have assessed the clinical effect of tDCS in patients, at least when delivered to cortical targets. The reviewed conditions were: pain syndromes, Parkinson's disease, dystonia, cerebral palsy, post-stroke limb motor impairment, post-stroke neglect, post-stroke dysphagia, post-stroke aphasia, primary progressive aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer's disease and other types of dementia, tinnitus, depression, auditory hallucinations and negative symptoms of schizophrenia, addiction and craving, autism, and attention disorders. The following data were collected: (i) clinical condition; (ii) study design; (iii) sample size; (iv) anode and cathode locations; (v) stimulation intensity and electrode area; (vi) number and duration of sessions; (vii) clinical outcome measures and results. This article does not include any meta-analysis and aims simply at providing a comprehensive overview of the raw data reported in this field to date, as an aid to researchers.

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INTRODUCTION: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Psychiatric comorbidity is frequent but does not enter into the official classification of the syndrome. In the present article, we will focus on treatment options for tics. METHODS: We have reviewed the relevant literature on treatment of tics and GTS, especially in the period from 2011-2016 since the publication of the European Society for the Study of Tourette Syndrome (ESSTS) treatment guidelines in 2011. RESULTS: We present current and up-to-date approaches in psychotherapy, pharmacotherapy and neurosurgery for GTS with an outlook for the upcoming years. CONCLUSIONS: Although many patients and health-care professionals seem to view tics and/or GTS as difficult to treat, or believe that treatment requires severe side effects with reduction in quality of life, we wish to convey that there is cause for optimism, both with regard to available treatment modalities and future therapeutic developments.

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OBJECTIVE: Since 2006 transcranial direct current stimulation (tDCS) has been investigated in the treatment of depression. In this review, we discuss the implications and clinical perspectives that tDCS may have as a therapeutic tool in depression from the results reported in this domain. METHODS: A comprehensive literature review has found nearly thirty articles - all in English - on this topic, corresponding to clinical studies, placebo-controlled or not, case reports and reviews. RESULTS: Several meta-analyses showed that the antidepressant effects of active tDCS are significant against placebo, but variable, mainly due to the heterogeneity of the patients included in the studies, for example regarding the resistance to antidepressant treatment. CONCLUSIONS: Specific recommendations for the use of tDCS in treating depression may not yet be available, but some elements of good practice can be highlighted. Of particular note is that anodal tDCS of the left prefrontal cortex at 2mA for 20 minutes per day has a potential therapeutic value without risk of significant side effects: tDCS offers safe conditions for clinical use in the treatment of depression.

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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) provides an efficient treatment for the alleviation of motor signs in patients with Parkinson's disease. The effects of DBS on gait and balance disorders are less successful and may even lead to an aggravation of freezing of gait and imbalance. The identification of a substantia nigra pars reticulata (SNr)-mesencephalic locomotor region (MLR) network in the control of locomotion and postural control and of its dysfunction/lesion in PD patients with gait and balance disorders led to suggestion that DBS should be targeting the SNr and the pedunculopontine nucleus (part of the MLR) for PD patients with these disabling axial motor signs. However, the clinical results to date have been disappointing. In this review, we discuss the effects of DBS of these basal ganglia and brainstem structures on the neurophysiological parameters of gait and balance control in PD patients. Overall, the data suggest that both STN and GPi-DBS improve gait parameters and quiet standing postural control in PD patients, but have no effect or may even aggravate dynamic postural control, in particular with STN-DBS. Conversely, DBS of the SNr and PPN has no effect on gait parameters but improves anticipatory postural adjustments and gait postural control.

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At the Paris Colloquium held forty years ago, and which this paper celebrates, the issue of psychosurgery had not been tackled yet. At that time psychosurgery was tainted by the controversial history of lobotomy and leucotomy. Supporters of psychosurgery at the time of the Colloquium were preparing their fourth International Conference, which was held in Madrid the following year. This represented a key characteristic of the collective, institutional and symbolic action of psychosurgery practitioners. At the end of the seventies, their strategy changed as noted below. Furthermore, we focus on the special importance of the results presented and commented on by psychosurgery supporters, including its conception and classification throughout the rhetoric historically involved (its supposed ventriloquism, its persuasive strength). Based on this view, we suggest a critical reflection encompassing old and new psychosurgery, while questioning the value of new rhetorical devices for the assessment and presentation of psychosurgery results after the surge of Deep Brain Stimulation.

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Innovative technologies for sensorimotor rehabilitation after stroke have dramatically increased these past 20 years. Based on a review of the literature on "Medline" and "Web of Science" between 1990 and 2013, we offer an overview of available tools and their current level of validation. Neuromuscular electric stimulation and/or functional electric stimulation are widely used and highly suspected of being effective in upper or lower limb stroke rehabilitation. Robotic rehabilitation has yielded various results in the literature. It seems to have some effect on functional capacities when used for the upper limb. Its effectiveness in gait training is more controversial. Virtual reality is widely used in the rehabilitation of cognitive and motor impairments, as well as posture, with admitted benefits. Non-invasive brain stimulation (rTMS and TDCS) are promising in this indication but clinical evidence of their effectiveness is still lacking. In the same manner, these past five years, neurofeedback techniques based on brain signal recordings have emerged with a special focus on their therapeutic relevance in rehabilitation. Technological devices applied to rehabilitation are revolutionizing our clinical practices. Most of them are based on advances in neurosciences allowing us to better understand the phenomenon of brain plasticity, which underlies the effectiveness of rehabilitation. The acceptation and "real use" of those devices is still an issue since most of them are not easily available in current practice.

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OBJECTIVE: O-arm(®) now gives us the opportunity not only to perform 2D but also 3D scans during deep brain stimulation (DBS) procedures. We present our experience with the intraoperative use of this device. Our objective was to measure the geometrical accuracy of electrode placement during surgical procedures driven under O-arm(®) control. METHODS: Fifteen patients underwent STN-DBS. For the first 4 patients, 3D scans were performed at the end of the procedure. We calculated the accuracy of electrode positioning, i.e. the distance between final electrode positioning and the planned trajectory. For the next 11 patients, who underwent both intraoperative and final 3D scan, we also calculated the accuracy of the microelectrode positioning. RESULTS: Average stimulation-induced improvement of UPDRS-III score was 52.5±15%. For the first 4 patients, the mean electrode positioning accuracy was 1.46±0.56mm. For the 11 patients who underwent intraoperative 3D scan, the mean microelectrodes positioning accuracy was 1.59±1.1mm. Aberrant positioning was detected in two cases, and was analyzed by fusing 3D scan with preoperative MR images. The definite electrodes positioning accuracy was 1.05±0.54mm. CONCLUSION: Intraoperative 3D scan is feasible, and can help us detect and correct early aberrant trajectories.

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Thanks to advances in medical care, an increased number of patients recover from coma. However, some remain in vegetative/unresponsive wakefulness syndrome or in a minimally conscious state. Detection of awareness in severely brain-injured patients is challenging because it relies on behavioral assessments, which can be affected by motor, sensory and cognitive impairments of the patients. Other means of evaluation are needed to improve the accuracy of the diagnosis in this challenging population. We will here review the different altered states of consciousness occurring after severe brain damage, and explain the difficulties associated with behavioral assessment of consciousness. We will then describe a non-invasive technique, transcranial magnetic stimulation combined with high-density electroencephalography (TMS-EEG), which has allowed us to detect the presence or absence of consciousness in different physiological, pathological and pharmacological states. Some potential underlying mechanisms of the loss of consciousness will then be discussed. In conclusion, TMS-EEG is highly promising in identifying markers of consciousness at the individual level and might be of great value for clinicians in the assessment of consciousness.

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Six clinical studies of chronic electrical modulation of deep brain circuits published between 1968 and 2010 have reported effects in 55 vegetative or minimally conscious patients. The rationale stimulation was to activate the cortex through the reticular-thalamic complex, comprising the tegmental ascending reticular activating system and its thalamic targets. The most frequent intended target was the central intralaminar zone and adjacent nuclei. Hassler et al. also proposed to modulate the pallidum as part of the arousal and wakefulness system. Stimulation frequency varied from 8Hz to 250Hz. Most patients improved, although in a limited way. Schiff et al. found correlations between central thalamus stimulation and arousal and conscious behaviours. Other treatments that have offered some clinical benefit include drugs, repetitive magnetic transcranial stimulation, median nerve stimulation, stimulation of dorsal column of the upper cervical spinal cord, and stimulation of the fronto-parietal cortex. No one treatment has emerged as a gold standard for practice, which is why clinical trials are still on-going. Further clinical studies are needed to decipher the altered dynamics of neuronal network circuits in patients suffering from severe disorders of consciousness as a step towards novel therapeutic strategies.

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