A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity

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.

Trial registration: ClinicalTrials.gov NCT01961297.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1

The main effect of sodium oxybate (Xyrem ®) in patients with LD and LD/DTv before and after drug intake compared to healthy subjects. 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. Graph (II) shows individual speech symptoms as measured by a number of LD-characteristic voice breaks before and after drug intake in LD and LD/DTv patients. 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.

Figure 2

(A) Modulatory effect of botulinum toxin alone (I) and in combination with sodium oxybate (II) in patients with LD and LD/DTv. A series of axial brain images depict brain regions that were modulated by the respective treatment in pre vs. post treatment comparisons at FWE-corrected p ≤ 0.01. (B) A bar chart shows number of voice breaks per sentence in LD and LD/DTv patients at a baseline as well as following botulinum toxin treatment alone and in combination with sodium oxybate. The diamond indicates the median of response. The p values indicate the difference between the baseline and post-botulinum toxin assessment as well as between baseline and post-combined botulinum toxin and sodium oxybate assessment. Sagittal and axial brain slices show brain regions where statistically significant relationships were observed between respective treatment and improvement of voice symptoms at a corrected p ≤ 0.025. Color bars depict the t-level statistics.

Figure 3

(A) A bar chart shows the clinical effects of sodium oxybate in drug-nonresponders and drug-responders, which were assessed based on perceptual analysis of voice symptoms at a baseline and following sodium oxybate treatment. (B) A series of axial brain slices show regions of common (in purple) and distinct (in green) action of sodium oxybate in drug-responders and non-responders at FWE-corrected p ≤ 0.05.