Targeting fronto-limbic dysfunctions via intermittent theta burst stimulation as a novel treatment for Functional Movement Disorders

Abstract

Background. Neuroimaging studies suggest that corticolimbic dysfunctions, including increased amygdala reactivity to emotional stimuli and heightened fronto-amygdala coupling, play a central role in the pathophysiology of functional movement disorders (FMD), although there is no direct causal evidence of this relationship. Transcranial magnetic stimulation (TMS) has the potential to probe and modulate brain networks implicated in neuropsychiatric disorders, including FMD. Therefore, in this proof-of-concept study, we investigated safety, tolerability and preliminary efficacy of fronto-amygdala neuromodulation via targeted left prefrontal intermittent theta burst stimulation (iTBS) on brain and behavioral manifestations of FMD. Methods. Six subjects with a clinically defined diagnosis of FMD received three open-label iTBS sessions per day, for two consecutive study visits. Safety and tolerability were assessed throughout the trial. Amygdala reactivity to emotionally valenced stimuli presented during an fMRI task and fronto-amygdala connectivity at rest were evaluated at baseline and after each stimulation visit, together with subjective levels of arousal and valence in response to affective stimuli. FMD symptom severity was assessed at baseline, during treatment and 24 hours after receiving the last iTBS session. Results. Multiples doses of iTBS were well-tolerated by all participants. Intermittent TBS significantly decreased fronto-amygdala connectivity and also influenced amygdala reactivity to emotional stimuli. These neurocircuitry changes were associated to a significant decrease in negative valence and an increase in positive valence levels following iTBS. Furthermore, we also observed a marked reduction in FMD symptom severity post stimulation. Conclusions. Corticolimbic modulation via iTBS represents a promising treatment for FMD that warrants additional research.