Somatotopic Organization of Hyperdirect Pathway Projections From the Primary Motor Cortex in the Human Brain.

Background: The subthalamic nucleus (STN) is an effective neurosurgical target to improve motor symptoms in Parkinson's Disease (PD) patients. MR-guided Focused Ultrasound (MRgFUS) subthalamotomy is being explored as a therapeutic alternative to Deep Brain Stimulation (DBS) of the STN. The hyperdirect pathway provides a direct connection between the cortex and the STN and is likely to play a key role in the therapeutic effects of MRgFUS intervention in PD patients. Objective: This study aims to investigate the topography and somatotopy of hyperdirect pathway projections from the primary motor cortex (M1). Methods: We used advanced multi-fiber tractography and high-resolution diffusion MRI data acquired on five subjects of the Human Connectome Project (HCP) to reconstruct hyperdirect pathway projections from M1. Two neuroanatomy experts reviewed the anatomical accuracy of the tracts. We extracted the fascicles arising from the trunk, arm, hand, face and tongue area from the reconstructed pathways. We assessed the variability among subjects based on the fractional anisotropy (FA) and mean diffusivity (MD) of the fibers. We evaluated the spatial arrangement of the different fascicles using the Dice Similarity Coefficient (DSC) of spatial overlap and the centroids of the bundles. Results: We successfully reconstructed hyperdirect pathway projections from M1 in all five subjects. The tracts were in agreement with the expected anatomy. We identified hyperdirect pathway fascicles projecting from the trunk, arm, hand, face and tongue area in all subjects. Tract-derived measurements showed low variability among subjects, and similar distributions of FA and MD values among the fascicles projecting from different M1 areas. We found an anterolateral somatotopic arrangement of the fascicles in the corona radiata, and an average overlap of 0.63 in the internal capsule and 0.65 in the zona incerta. Conclusion: Multi-fiber tractography combined with high-resolution diffusion MRI data enables the identification of the somatotopic organization of the hyperdirect pathway. Our preliminary results suggest that the subdivisions of the hyperdirect pathway projecting from the trunk, arm, hand, face, and tongue motor area are intermixed at the level of the zona incerta and posterior limb of the internal capsule, with a predominantly overlapping topographical organization in both regions. Subject-specific knowledge of the hyperdirect pathway somatotopy could help optimize target definition in MRgFUS intervention.

Anterior pallidal deep brain stimulation for Tourette's syndrome: a randomised, double-blind, controlled trial.

BACKGROUND: Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. METHODS: In this randomised, double-blind, controlled trial, we recruited patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. FINDINGS: Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR -23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [-10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). INTERPRETATION: 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. FUNDING: French Ministry of Health.

Acute severe depression induced by stimulation of the right globus pallidus internus.

Depressive symptoms may occur after Deep Brain Stimulation (DBS) in the subthalamic nucleus. This is often explained by reduced pharmacological treatment after surgery, and not as a direct effect of DBS. Pallidal DBS seems not to be associated with such side effects and have not, to our knowledge, previously been reported. We present a patient with acute depressive symptoms induced by pallidal DBS. We believe this case strengthen the hypothesis that the basal ganglia and structures involved in the functional connectome of these nucleuses play a role not only in regulation of movement but also in regulation of mood.

PPNa-DBS for gait and balance disorders in Parkinson's disease: a double-blind, randomised study.

Gait and balance disorders are the major source of motor disabilities in advanced forms of Parkinson's disease (PD). Low-frequency stimulation of the pedunculopontine nucleus area (PPNa-DBS) has been recently proposed to treat these symptoms with variable clinical results. To further understand the effects of PPNa-DBS on resistant gait and balance disorders, we performed a randomised double-blind cross-over study in six PD patients. Evaluation included clinical assessment of parkinsonian disability, quality of life and neurophysiological recordings of gait. Evaluations were done 1 month before, 4 and 6 months after surgery with four double-blinded conditions assessed: with and without PPNa-DBS, with and without levodopa treatment. Four patients completed the study and two patients were excluded from the final analysis because of peri-operative adverse events (haematoma, infection). Clinically, the combination of PPNa-DBS and levodopa treatment produced a significant decrease of the freezing episodes. The frequency of falls also decreased in three out of four patients. From a neurophysiological point of view, PPNa-DBS significantly improved the anticipatory postural adjustments and double-stance duration, but not the length and speed of the first step. Interestingly, step length and speed improved after surgery without PPNa-DBS, suggesting that the lesioning effect of PPNa-DBS surgery alleviates parkinsonian akinesia. Quality of life was also significantly improved with PPNa-DBS. These results suggest that PPNa-DBS could improve gait and balance disorders in well-selected PD patients. However, this treatment may be riskier than others DBS surgeries in these patients with an advanced form of PD.

Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate.

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.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease.

OBJECTIVE: To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS: Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS: Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION: In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

Neuronal activity correlated with checking behaviour in the subthalamic nucleus of patients with obsessive-compulsive disorder.

Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.

Thalamic stimulation for tremor: can target determination be improved?

High frequency stimulation of the ventral intermedius nucleus (Vim) of the thalamus is successfully used for the treatment of postural tremor. Target coordinates are most commonly calculated using a statistical method. Here, we compare a statistical and an individual targeting method, using an histology-based three-dimensional deformable brain atlas which allows localization of the Vim on individual patient's MR images by adaptation of the atlas onto the patient's brain. Twenty-nine consecutive patients had electrodes implanted in the Vim uni-or bilaterally for severe essential tremor. Thirty-five targets were determined by calculating the statistical target and then using the deformable atlas to compute the individual target. Pythagorean distance between these targets was calculated. Statistical and individual targets were compared by double blind evaluation of perioperative stimulation effects. For most cases (n = 24), the Pythagorean distance was higher than 1.5 mm. In 79% of these cases, the definitive electrode was implanted using the position of the individual target. For the remaining cases (n = 11, distance < 1.5 mm), the definitive electrode was implanted according to the statistical target location in 73% of the cases. As a whole, when individual target was used, it was located at least 2 mm more medial than the statistical one in 86% cases. These results suggest that Vim target determination based on a statistical method might be inaccurate. In particular, laterality might be overestimated, leading to nonoptimal clinical results. In clinical practice, this means that microelectrode exploration during Vim surgery should include at least one trajectory more medial than the statistical target.

Bilateral deep brain stimulation of the pallidum for myoclonus-dystonia due to ε-sarcoglycan mutations: a pilot study.

OBJECTIVE: To assess the efficacy of bilateral deep brain stimulation of the internal pallidum in patients with myoclonus-dystonia due to genetically proved ε-sarcoglycan (SGCE-M-D) deficiency. DESIGN: Patients with documented SGCE-M-D undergoing bilateral deep brain stimulation of the internal pallidum were recruited. Standardized assessments of M-D were videorecorded before surgery and 6 to 9 months and 15 to 18 months after surgery, using the movement and disability subscales of the Burke-Fahn-Marsden Dystonia Rating Scale and the Unified Myoclonus Rating Scale. The analysis was based on blinded evaluation of the recordings. SETTING: Movement disorder unit in a university hospital in Paris. PATIENTS: Five consecutive patients with documented SGCE-M-D. MAIN OUTCOME MEASURES: Myoclonus and dystonia scores at follow-up. RESULTS: The median myoclonus score decreased from 76 before surgery (range, 38-116) to 10 at 6 to 9 months after surgery (range, 6-31). The median dystonia score decreased from 30.0 before surgery (range, 18.5-53.0) to 4.5 after surgery (range, 3.5-16.0). Disability was also improved and symptoms remained stable between the postoperative evaluations. No adverse effects occurred. CONCLUSIONS: Bilateral deep brain stimulation of the internal pallidum is safe and highly effective in this homogeneous population of patients with SGCE-M-D. This therapeutic option should therefore be considered for patients with severe, drug-resistant forms of the disorder.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.

BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study.

BACKGROUND: We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. METHODS: We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. FINDINGS: Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. INTERPRETATION: Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.