Selective striatal fast-spiking interneuron inhibition induces cortical seizure.

Whether striatal fast-spiking interneurons are involved in cortical synchronization remains elusive. We performed acute microinjections of a selective FSI-AMPA receptor antagonist into the sensorimotor striatum of non-human primates to verify whether selective FSI inhibition within the sensorimotor striatum could potentially modify cortical excitability, thereby triggering focal seizures. Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of IEM-1460 (4-8 µL) were injected slowly at 1 µL/min. Spontaneous behavioral changes were classified according to the Racine scale modified for primates. These induced motor behaviors were correlated with electroencephalographic (EEG and EMG) measures. Power spectrum and time-frequency analysis were performed and compared between each period of interest. Pharmacological selective inhibition of striatal fast-spiking INs induced focal motor seizures. Back averaging confirmed that myoclonic activity was closely linked to cortical spikes-and-waves epileptic activity, with a significant increase in cortical EEG power in all studied frequency bands (p < .0001). Thus, striatal FSIs likely play a role in controlling cortical excitability through the cortico-striato-thalamo-cortical pathway. They may contribute to the pathophysiology of focal motor epilepsies by modulating the threshold at which focal motor seizures are triggered.

Usefulness of thalamic beta activity for closed-loop therapy in essential tremor.

A partial loss of effectiveness of deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) has been reported in some patients with essential tremor (ET), possibly due to habituation to permanent stimulation. This study focused on the evolution of VIM local-field potentials (LFPs) data over time to assess the long-term feasibility of closed-loop therapy based on thalamic activity. We performed recordings of thalamic LFPs in 10 patients with severe ET using the ACTIVA™ PC + S (Medtronic plc.) allowing both recordings and stimulation in the same region. Particular attention was paid to describing the evolution of LFPs over time from 3 to 24 months after surgery when the stimulation was Off. We demonstrated a significant decrease in high-beta LFPs amplitude during movements inducing tremor in comparison to the rest condition 3 months after surgery (1.91 ± 0.89 at rest vs. 1.27 ± 1.37 µV2/Hz during posture/action for N = 8/10 patients; p = 0.010), 12 months after surgery (2.92 ± 1.75 at rest vs. 2.12 ± 1.78 µV2/Hz during posture/action for N = 7/10 patients; p = 0.014) and 24 months after surgery (2.32 ± 0.35 at rest vs 0.75 ± 0.78 µV2/Hz during posture/action for 4/6 patients; p = 0.017). Among the patients who exhibited a significant decrease of high-beta LFP amplitude when stimulation was Off, this phenomenon was observed at least twice during the follow-up. Although the extent of this decrease in high-beta LFPs amplitude during movements inducing tremor may vary over time, this thalamic biomarker of movement could potentially be usable for closed-loop therapy in the long term.

How does Tourette syndrome impact adolescents' daily living? A text mining study.

Tourette syndrome is a neurodevelopmental disease in which clinical manifestations are essentially present during childhood and adolescence, corresponding to one of the critical development phases. However, its consequences on the daily lives of young patients have been insufficiently investigated. Here, we aimed to investigate this using a statistical text mining approach, allowing for the analysis of a large volume of free textual data. Sixty-two adolescents with Tourette syndrome participated in an interview in which they discussed their daily life (i) in school, (ii) at home, and (iii) with strangers, (iv) the aspect of Tourette syndrome which caused the most difficulty, and (v) their thoughts regarding their future as adults. Following data pre-processing, these corpora were analyzed separately using the IRAMUTEQ software through factorial correspondence analysis to identify the most commonly recurring topics of each corpus, and their relations with clinical features. The main difficulty corpus was directly related to comorbidities of Tourette syndrome. Daily life at home was correlated with executive functioning. Difficulties at school were related to a higher severity of tics. Thoughts regarding future daily life were worst for the youngest patients and were correlated with executive functioning and a higher depression score. Taken altogether, our results highlighted that social stigma was a pervasive topic among our corpora. From a clinical standpoint, tic severity was especially related to difficulties at school, while comorbidities had a high impact on social daily living and cost for managing both tics and symptoms of comorbidities. TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04179435.

Prediction of Clinical Deep Brain Stimulation Target for Essential Tremor From 1.5 Tesla MRI Anatomical Landmarks.

Background: Deep brain stimulation is an efficacious treatment for refractory essential tremor, though targeting the intra-thalamic nuclei remains challenging. Objectives: We sought to develop an inverse approach to retrieve the position of the leads in a cohort of patients operated on with optimal clinical outcomes from anatomical landmarks identifiable by 1.5 Tesla magnetic resonance imaging. Methods: The learning database included clinical outcomes and post-operative imaging from which the coordinates of the active contacts and those of anatomical landmarks were extracted. We used machine learning regression methods to build three different prediction models. External validation was performed according to a leave-one-out cross-validation. Results: Fifteen patients (29 leads) were included, with a median tremor improvement of 72% on the Fahn-Tolosa-Marin scale. Kernel ridge regression, deep neural networks, and support vector regression (SVR) were used. SVR gave the best results with a mean error of 1.33 ± 1.64 mm between the predicted target and the active contact position. Conclusion: We report an original method for the targeting in deep brain stimulation for essential tremor based on patients' radio-anatomical features. This approach will be tested in a prospective clinical trial.

Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.

A Phase 2 Randomized Trial of Asleep versus Awake Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Asleep deep brain stimulation (DBS) for Parkinson's disease (PD) is being performed more frequently; however, motor outcomes and safety of asleep DBS have never been assessed in a prospective randomized trial. METHODS: We conducted a prospective, randomized, noncomparative trial to assess the motor outcomes of asleep DBS. Leads were implanted in the subthalamic nucleus (STN) according to probabilistic stereotactic coordinates with a surgical robot under O-arm© imaging guidance under either general anesthesia without microelectrode recordings (MER) (20 patients, asleep group) or local anesthesia with MER and clinical testing (9 patients, awake group). RESULTS: The mean motor improvement rates on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-3) between OFF and ON stimulation without medication were 52.3% (95% CI: 45.4-59.2%) in the asleep group and 47.0% (95% CI: 23.8-70.2%) in the awake group, 6 months after surgery. Except for a subcutaneous hematoma, we did not observe any complications related to the surgery. Three patients (33%) in the awake group and 8 in the asleep group (40%) had at least one side effect potentially linked with neurostimulation. CONCLUSIONS: Owing to its randomized design, our study supports the hypothesis that motor outcomes after asleep STN-DBS in PD may be noninferior to the standard awake procedure.

A new phenotype of choreic syndrome associating severe freezing of gait and chorea.

The early onset of gait akinesia should not rule out the diagnosis of hereditary chorea. It would be helpful to proceed to a whole-genome and long-read sequencing in order to track a new pathogenic variant including noncoding repeat expansion.

Acute Striato-Cortical Synchronization Induces Focal Motor Seizures in Primates.

OBJECTIVE: Whether the basal ganglia are involved in the cortical synchronization during focal seizures is still an open question. In the present study, we proposed to synchronize cortico-striatal activities acutely inducing striatal disinhibition, performing GABA-antagonist injections within the putamen in primates. METHOD: Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of bicuculline (0.5-4 µL) were injected at a slow rate of 1 µL/min. Spontaneous behavioral changes were classified according to Racine's scale modified for primates. These induced motor behaviors were correlated with electromyographic, electroencephalographic, and putaminal and pallidal local field potentials changes in activity. RESULTS: acute striatal desinhibition induced focal motor seizures. Seizures were closely linked to cortical epileptic activity synchronized with a striatal paroxysmal activity. These changes in striatal activity preceded the cortical epileptic activity and the induced myoclonia, and both cortical and subcortical activities were coherently synchronized during generalized seizures. INTERPRETATION: Our results strongly suggest the role of the sensorimotor striatum in the regulation and synchronization of cortical excitability. These dramatic changes in the activity of this "gating" pathway might influence seizure susceptibility by modulating the threshold for the initiation of focal motor seizures.

Increased diagnostic yield in complex dystonia through exome sequencing.

INTRODUCTION: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing. MATERIAL AND METHODS: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature. RESULTS: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002). CONCLUSION: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.

Dystonia and dopamine: From phenomenology to pathophysiology.

A line of evidence suggests that the pathophysiology of dystonia involves the striatum, whose activity is modulated among other neurotransmitters, by the dopaminergic system. However, the link between dystonia and dopamine appears complex and remains unclear. Here, we propose a physiological approach to investigate the clinical and experimental data supporting a role of the dopaminergic system in the pathophysiology of dystonic syndromes. Because dystonia is a disorder of motor routines, we first focus on the role of dopamine and striatum in procedural learning. Second, we consider the phenomenology of dystonia from every angle in order to search for features giving food for thought regarding the pathophysiology of the disorder. Then, for each dystonic phenotype, we review, when available, the experimental and imaging data supporting a connection with the dopaminergic system. Finally, we propose a putative model in which the different phenotypes could be explained by changes in the balance between the direct and indirect striato-pallidal pathways, a process critically controlled by the level of dopamine within the striatum. Search strategy and selection criteria References for this article were identified through searches in PubMed with the search terms « dystonia ¼, « dopamine", « striatum ¼, « basal ganglia ¼, « imaging data ¼, « animal model ¼, « procedural learning ¼, « pathophysiology ¼, and « plasticity ¼ from 1998 until 2018. Articles were also identified through searches of the authors' own files. Only selected papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.

Effect of Trunk Muscle Strengthening on Gait Pattern and Falls in Parkinson's Disease.

BACKGROUND: The course of Parkinson's disease is characterized by gait disturbance and falls, which affect patients' quality of life and engender high healthcare costs. These factors are not greatly improved by levodopa therapy or deep brain stimulation of the subthalamic nuclei. Indeed, the symptoms may even worsen with these treatment. Physiotherapy may be the most appropriate treatment to reduce the incidence of falls in these cases; however, its benefits are modest. OBJECTIVE: To assess the effectiveness of trunk muscle strengthening in 10 patients with Parkinson's disease being treated with deep brain stimulation of the subthalamic nuclei who are affected by gait disturbances and falls. METHOD: A standardized physiotherapy programme centred on trunk muscle strengthening was conducted. Its effectiveness was assessed using a clinical approach combined with video-based motion analysis. RESULTS: After 4 weeks of trunk muscle strengthening, the gait item on the Unified Parkinson's Disease Rating Scale (UPDRS, part 3) together with several gait kinematic parameters (step length, walking cycle duration variability, gait speed) were significantly improved and the number of falls decreased. CONCLUSION: These preliminary findings suggest that physiotherapy centred on rachis mobility improves the quality of gait and reduces the number of falls in patients with Parkinson's disease who are being treated with deep brain stimulation of the subthalamic nuclei. This is a potentially useful supplement to the traditional physiotherapy approach, in addition to the pharmacological and surgical treatment of Parkinson's disease.

Localization of Deep Brain Stimulation Electrode by Image Registration Is Software Dependent: A Comparative Study between Four Widely Used Software Programs.

BACKGROUND: The control of the anatomic position of the active contacts is essential to understand the effects and adapt the settings of the neurostimulation. The localization is commonly assessed by a registration between the preoperative MRI and the postoperative CT scan. However, its accuracy depends on the quality of the registration algorithm and many software programs are available. OBJECTIVE: To compare the localization of implanted deep brain stimulation (DBS) leads in the subthalamic nucleus (STN) between four registration devices. METHODS: The preoperative stereotactic MRI was co-registered and fused with the 3-month postoperative CT scan in 27 patients implanted in the STN for Parkinson's disease (53 leads). Localizations of the active contacts were calculated in the stereotactic frame space and compared between software programs. RESULTS: The coordinates of the active contacts were different between software programs in the 3 axes (p < 0.001) with a mean vectorial error between the deepest contact locations of 1.17 mm (95% CI 1.09-1.25). CONCLUSION: We found a small but significant difference in the coordinates calculated on four different devices. These results have to be considered when performing studies comparing active contact locations or when following patients with an implanted DBS lead.