Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study.

BACKGROUND: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities. OBJECTIVE: We conducted a proof-of-concept, open-label phase II study to examine the efficacy and central effects of sodium oxybate in patients with alcohol-responsive ETv. METHODS: All subjects received 1.0 to 1.5 g of oral sodium oxybate and underwent brain functional magnetic resonance imaging. The primary endpoint was the number of patients (% from total) with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. The secondary endpoint included changes in brain activity after sodium oxybate intake compared to baseline. RESULTS: Sodium oxybate reduced ETv symptoms on average by 40.8% in 92.9% of patients. Drug effects were observed about 40 to 45 minutes after intake, lasting about 3.5 hours, and gradually wearing off by the end of the fifth hour. The central effects of sodium oxybate were associated with normalized activity in the cerebellum, inferior/superior parietal lobules, inferior frontal gyrus, and insula and re-established functional relationships between these regions. CONCLUSIONS: Sodium oxybate showed high efficacy in ETv patients, with a likely central action on disorder pathophysiology. Sodium oxybate may be an effective novel oral drug for treatment of alcohol-responsive ETv patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sensory processing in the auditory and olfactory domains is normal in laryngeal dystonia.

Abnormal sensory discriminatory processing has been implicated as an endophenotypic marker of isolated dystonia. However, the extent of alterations across the different sensory domains and their commonality in different forms of dystonia are unclear. Based on the previous findings of abnormal temporal but not spatial discrimination in patients with laryngeal dystonia, we investigated sensory processing in the auditory and olfactory domains as potentially additional contributors to the disorder pathophysiology. We tested auditory temporal discrimination and olfactory function, including odor identification, threshold, and discrimination, in 102 laryngeal dystonia patients and 44 healthy controls, using dichotically presented pure tones and the extended Sniffin' Sticks smell test protocol, respectively. Statistical significance was assessed using analysis of variance with non-parametric bootstrapping. Patients had a lower mean auditory temporal discrimination threshold, with abnormal values found in three patients. Hyposmia was found in 64 patients and anosmia in 2 patients. However, there were no statistically significant differences in either auditory temporal discrimination threshold or olfactory identification, threshold, and discrimination between the groups. A significant positive relationship was found between olfactory threshold and disorder severity based on the Burke-Fahn-Marsden dystonia rating scale. Our findings demonstrate that, contrary to altered visual temporal discrimination, auditory temporal discrimination and olfactory function are likely not candidate endophenotypic markers of laryngeal dystonia.

DystoniaBoTXNet: Novel Neural Network Biomarker of Botulinum Toxin Efficacy in Isolated Dystonia.

OBJECTIVE: Isolated dystonia is characterized by abnormal, often painful, postures and repetitive movements due to sustained or intermittent involuntary muscle contractions. Botulinum toxin (BoTX) injections into the affected muscles are the first line of therapy. However, there are no objective predictive markers or standardized tests of BoTX efficacy that can be utilized for appropriate candidate selection prior to treatment initiation. METHODS: We developed a deep learning algorithm, DystoniaBoTXNet, which uses a 3D convolutional neural network architecture and raw structural brain magnetic resonance images (MRIs) to automatically discover and test a neural network biomarker of BoTX efficacy in 284 patients with 4 different forms of focal dystonia, including laryngeal dystonia, blepharospasm, cervical dystonia, and writer's cramp. RESULTS: DystoniaBoTXNet identified clusters in superior parietal lobule, inferior and middle frontal gyri, middle orbital gyrus, inferior temporal gyrus, corpus callosum, inferior fronto-occipital fasciculus, and anterior thalamic radiation as components of the treatment biomarker. These regions are known to contribute to both dystonia pathophysiology across a broad clinical spectrum of disorder and the central effects of botulinum toxin treatment. Based on its biomarker, DystoniaBoTXNet achieved an overall accuracy of 96.3%, with 100% sensitivity and 86.1% specificity, in predicting BoTX efficacy in patients with isolated dystonia. The algorithmic decision was computed in 19.2 seconds per case. INTERPRETATION: DystoniaBoTXNet and its treatment biomarker have a high translational potential as an objective, accurate, generalizable, fast, and cost-effective algorithmic platform for enhancing clinical decision making for BoTX treatment in patients with isolated dystonia. ANN NEUROL 2023;93:460-471.

Multimodal collaborative brain-computer interfaces aid human-machine team decision-making in a pandemic scenario.

Objective.Critical decisions are made by effective teams that are characterized by individuals who trust each other and know how to best integrate their opinions. Here, we introduce a multimodal brain-computer interface (BCI) to help collaborative teams of humans and an artificial agent achieve more accurate decisions in assessing danger zones during a pandemic scenario.Approach.Using high-resolution simultaneous electroencephalography/functional MRI (EEG/fMRI), we first disentangled the neural markers of decision-making confidence and trust and then employed machine-learning to decode these neural signatures for BCI-augmented team decision-making. We assessed the benefits of BCI on the team's decision-making process compared to the performance of teams of different sizes using the standard majority or weighing individual decisions.Main results.We showed that BCI-assisted teams are significantly more accurate in their decisions than traditional teams, as the BCI is capable of capturing distinct neural correlates of confidence on a trial-by-trial basis. Accuracy and subjective confidence in the context of collaborative BCI engaged parallel, spatially distributed, and temporally distinct neural circuits, with the former being focused on incorporating perceptual information processing and the latter involving action planning and executive operations during decision making. Among these, the superior parietal lobule emerged as a pivotal region that flexibly modulated its activity and engaged premotor, prefrontal, visual, and subcortical areas for shared spatial-temporal control of confidence and trust during decision-making.Significance.Multimodal, collaborative BCIs that assist human-artificial agent teams may be utilized in critical settings for augmented and optimized decision-making strategies.

Short- and Long-term Central Action of Botulinum Neurotoxin Treatment in Laryngeal Dystonia.

BACKGROUND AND OBJECTIVES: Laryngeal dystonia (LD) is isolated task-specific focal dystonia selectively impairing speech production. The first choice of LD treatment is botulinum neurotoxin (BoNT) injections into the affected laryngeal muscles. However, whether BoNT has a lasting therapeutic effect on disorder pathophysiology is unknown. We investigated short-term and long-term effects of BoNT treatment on brain function in patients with LD. METHODS: A total of 161 participants were included in the functional MRI study. Statistical analyses examined central BoNT effects in patients with LD who were stratified based on the effectiveness and duration of treatment. RESULTS: Patients with LD who were treated and benefited from BoNT injections had reduced activity in the left precuneus compared with BoNT-naive and treatment nonbenefiting patients. In addition, BoNT-treated patients with adductor LD had decreased activity in the right thalamus, whereas BoNT-treated abductor patients with LD had reduced activity in the left inferior frontal cortex. No statistically significant differences in brain activity were found between patients with shorter (1-5 years) and longer (13-28 years) treatment durations. However, patients with intermediate treatment duration of 6-12 years showed reduced activity in the right cerebellum compared with patients with both shorter and longer treatment durations and reduced activity in the right prefrontal cortex compared with patients with shorter treatment duration. DISCUSSION: Our findings suggest that the left precuneus is the site of short-term BoNT central action in patients with LD, whereas the prefrontal-cerebellar axis is engaged in the BoNT response in patients with intermediate treatment duration of 6-12 years. Involvement of these structures points to indirect action of BoNT treatment on the dystonic sensorimotor network through modulation of motor sequence planning and coordination.