Abstract
Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigational oral drug, sodium oxybate, in patients with the alcohol-responsive form of laryngeal focal dystonia. Understanding the mechanism of action of this promising oral agent holds a strong potential for the development of a scientific rationale for its use in dystonia. Therefore, to determine the neural markers of sodium oxybate effects, which may underlie dystonic symptom improvement, we examined brain activity during symptomatic speech production before and after drug intake in patients with laryngeal dystonia and compared to healthy subjects. We found that sodium oxybate significantly attenuated hyperfunctional activity of cerebellar, thalamic and primary/secondary sensorimotor cortical regions. Drug-induced symptom improvement was correlated with decreased-to-normal levels of activity in the right cerebellum. These findings suggest that sodium oxybate shows direct modulatory effects on disorder pathophysiology by acting upon abnormal neural activity within the dystonic network.
Highlights
Focal dystonia causes abnormal movements of a selective muscle group, often being associated with the production of a specific task
Similar to the previous studies[1,18], symptomatic speech production was associated with increased brain activation in bilateral primary sensorimotor, premotor and inferior parietal cortices, insula, parietal operculum, inferior frontal (IFG) and superior temporal (STG) gyri, supplementary motor area (SMA), putamen, thalamus and cerebellum in LD patients both with and without dystonic tremor of voice (DTv) compared to healthy controls (Fig. 1-I)
We found that, abnormal brain activity during speech production was largely attenuated by sodium oxybate (SXB) along with clinical improvement of symptoms in these same patients
Summary
Focal dystonia causes abnormal movements of a selective muscle group, often being associated with the production of a specific task. Focal dystonia is the most frequent form of isolated dystonia and may lead to significant occupational disability and life-long social isolation It becomes even more incapacitating when associated, in about one-third of patients, with dystonic tremor. The treatment of focal dystonia with or without tremor is directed to temporary symptom management with botulinum toxin injections into the affected muscles This empirical treatment is beneficial for only a fraction of dystonic patients, showing inconsistent benefits across different forms of dystonia[2,3,4]. Panel (I) depicts statistically significant differences in brain activation during symptomatic speech production across all patients before drug intake compared to healthy subjects (baseline). Panels (Ia and Ib) show differences in brain activation during symptomatic speech production in LD patients (Ia) and LD/DTv patients (Ib) after drug intake compared to healthy subjects. Brain activation differences are shown on a series of axial brain imaging in an AFNI standard Talairach-Tournoux space at FWE-corrected p ≤ 0.05
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