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Therapy resistance of approximately one-third of patients with Gilles de la Tourette syndrome ( GTS) requires consideration of alternative therapeutic interventions. The article demonstrates the role of the cerebellum in neuropsychiatric disorders and GTS in particular, specifically its role in functions relating to motor and cognitive symptoms. Certain circuits in the cerebellum have been shown to undergo learning-induced changes during conditioning, with cells in the cortex of the cerebellum appearing to decrease their activity whilst those in deep nuclei seem to do the inverse. Evidence exists showing that abnormal excitability of the motor cortex via the cerebellum could be expected to participate in motor tics in GTS possibly due to aberrations in certain structures of involved circuits. The role of the cerebellum in learning and plasticity processes renders it a strategic and valuable structure to consider for brain stimulation when investigating potential treatment options for neuropsychiatric disorders such as GTS. This article puts forth the concept of using non-invasive and invasive brain stimulation techniques as a novel platform for non-pharmacological neuromodulation of GTS symptoms. [ABSTRACT FROM AUTHOR]

Corticospinal excitation is mediated by polysynaptic pathways in several vertebrates, including dexterous monkeys. However, indirect non-monosynaptic excitation has not been clearly observed following transcranial electrical stimulation (TES) or cervicomedullary stimulation (CMS) in humans. The present study evaluated indirect motor pathways in normal human subjects by recording the activities of single motor units (MUs) in the biceps brachii (BB) muscle. The pyramidal tract was stimulated with weak TES, CMS, and transcranial magnetic stimulation (TMS) contralateral to the recording side. During tasks involving weak co-contraction of the BB and hand muscles, all stimulation methods activated MUs with short latencies. Peristimulus time histograms (PSTHs) showed that responses with similar durations were induced by TES (1.9 ± 1.4 ms) and CMS (2.0 ± 1.4 ms), and these responses often showed multiple peaks with the PSTH peak having a long duration (65.3% and 44.9%, respectively). Such long-duration excitatory responses with multiple peaks were rarely observed in the finger muscles following TES or in the BB following stimulation of the Ia fibers. The responses obtained with TES were compared in the same 14 BB MUs during the co-contraction and isolated BB contraction tasks. Eleven and three units, respectively, exhibited activation with multiple peaks during the two tasks. In order to determine the dispersion effects on the axon conduction velocities (CVs) and synaptic noise, a simulation study that was comparable to the TES experiments was performed with a biologically plausible neuromuscular model. When the model included the monosynaptic-pyramidal tract, multiple peaks were obtained in about 34.5% of the motoneurons (MNs). The experimental and simulation results indicated the existence of task-dependent disparate inputs from the pyramidal tract to the MNs of the upper limb. These results suggested that intercalated interneurons are present in the spinal cord and that these interneurons might be equivalent to those identified in animal experiments. [ABSTRACT FROM AUTHOR]

Background: Obsessive compulsive disorder (OCD) has a lifetime prevalence of 1-2%. Standard treatments are ineffective in up to 40% of cases. Even with the best treatments, there remains a subgroup with severe symptoms and significant disability. Studies of deep brain stimulation (DBS) for OCD have shown improvement in both symptoms and quality of life in severe OCD. Two targets in particular have shown promise: the anteromedial subthalamic nucleus (STN) and the ventral capsule/ventral striatum (VC/VS) [1-3]. It is not clear however if one site has advantages over the other and, with regard to the VC/VS site, whether stimulation of the anterior capsule white matter or ventral striatum/ nucleus accumbens grey matter is critical for improvement [2, 3]. Aims: We report a within subject comparison of the effect of DBS on OCD symptoms at STN and VC/VS sites both individually and together (ClinicalTrials.gov #NCT02655926). The aims of the study were to determine: a) the efficacy of DBS at each site; b) whether stimulation of both sites improves the response compared to either site alone; and c) the critical stimulation contacts at the VC/VS site. Methods: Six participants, with severe treatment refractory OCD, were recruited via the UK specialist OCD service and underwent implantation of bilateral electrodes at both the VC/VS and anteromedial STN sites. A Leksell frame-based MRI-guided and MRI-verified approach under general anaesthesia was used. The subthalamic nucleus was localised on axial T2-weighted stereotactic images and the VC/VS localised on coronal and axial proton density images (Siemens, 1.5T). Using a double blind cross-over design, 12-weeks stimulation at STN and VC/VS sites was compared, followed by stimulation at both sites for 12 weeks. The primary outcome measure was YBOCS: an improvement of greater than or equal to 35% was the predefined response. Results: Accurate stereotactic and anatomical lead location was confirmed on immediate postoperative stereotactic MR images in all patients. For the VC/VS target, the deepest DBS lead contact was within the nucleus accumbens, the one superior to that in the 'shell' of the nucleus accumbens while the superior two contacts were within the inferior aspect of the anterior limb of the internal capsule. The response rates (defined as the number of patients with >35% reduction in YBOCS) were: STN 3/6; VC/VS: 5/6; STN + VC/VS: 5/6. In the one non-responder YBOCS reduction was 32% after the combined STN+VC/VS stimulation phase. For the whole group, the mean reduction in YBOCS scores were: STN 16.3; VC/ VS: 19.2; STN + VC/VS: 22.0 which represents a mean reduction of 42%, 53%, 62% from their own baseline scores and a reduction to predefined mild/subclinical symptoms of 0%, 50% 50% respectively. The top two DBS contacts of the quadripolar lead were found to be the most effective at the VC/VS target in all 6 patients. Conclusion: These results suggest that: a) The VC/VS site may be superior to the STN site for the amelioration of severe OCD symptoms; b) There is only a modest advantage of stimulating both sites together; and c) The effective stimulation site for the VC/VS target is the inferior aspect of the anterior limb of the internal capsule and not the ventral striatum/nucleus accumbens grey matter. The study was funded by the MRC (MR/J012009/1). [ABSTRACT FROM AUTHOR]

Introduction: MRI-guided focused ultrasound (MRgFUS) thalamotomy provides an exciting development in the field of minimally invasive stereotactic neurosurgery. Current treatment options for focal hand dystonia are limited, with potentially more effective invasive stereotactic interventions, such as deep brain stimulation or lesional therapies, rarely used. The advent of minimally invasive brain lesioning provides a potentially safe and effective treatment approach with a recent pilot study establishing MRgFUS Vo-complex thalamotomy as an effective treatment option for focal hand dystonia. In this study, we undertake an open-label clinical trial to further establish MRgFUS Vo-complex thalamotomy as an effective treatment for focal hand dystonia with greater attention paid to potential motor costs associated with this treatment. To elucidate pathophysiology of dystonia and treatment mechanisms, neurophysiological and MRI analysis will be performed longitudinally to explore the hypothesis that neuroplastic and structural changes that may underlie this treatment benefit., Methods and Analysis: A total of 10 participants will be recruited into this open-label clinical trial. All participants will undergo clinical, kinemetric, neurophysiological and radiological testing at baseline, followed by repeated measures at predesignated time points post MRgFUS Vo-complex thalamotomy. Further, to identify any underlying structural or neurophysiological abnormalities present in individuals with focal hand dystonia, 10 age and gender matched control participants will be recruited to undergo comparative investigation. These results will be compared with the intervention participants both at baseline and at 12 months to assess for normalisation of these abnormalities, if present., Ethics and Dissemination: This trial was reviewed and approved by the St Vincent's Health Network Sydney Human Research Ethics Committee (2022/ETH00778). Study results will be published in peer-reviewed journals and presented at both national and international conferences., Trial Registration Number: CTRN12622000775718., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Status dystonicus (SD) is a life-threatening condition., Objective and Methods: In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to-, via status dystonicus episodes, and evolution following them., Results: Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 ± 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes., Conclusion: Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses., Competing Interests: The authors have declared that no competing interests exist.