Corticolimbic Modulation via Intermittent Theta Burst Stimulation as a Novel Treatment for Functional Movement Disorder: A Proof-of-Concept Study

Primavera A Spagnolo, Jacob Parker, Silvina Horovitz, Mark Hallett, Primavera A Spagnolo, Jacob Parker, Silvina Horovitz, Mark Hallett

Abstract

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). Transcranial magnetic stimulation (TMS) has the potential to probe and modulate brain networks implicated in neuropsychiatric disorders, including FMD. Therefore, the objective of this proof-of-concept study was to investigate the 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. 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. The FMD symptom severity was assessed at baseline, during treatment and 24 h after the last iTBS session. Multiple doses of iTBS were well-tolerated by all participants. Intermittent TBS significantly decreased fronto-amygdala connectivity and influenced amygdala reactivity to emotional stimuli. These neurocircuitry changes were associated to a marked reduction in FMD symptom severity. Corticolimbic modulation via iTBS represents a promising treatment for FMD that warrants additional research.

Keywords: amygdala; corticolimbic connectivity; functional movement disorders; intermittent theta burst stimulation; neuromodulation; valence.

Conflict of interest statement

The authors declare no relevant conflict of interest. M.H. is an inventor of patents held by NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he received license fee payments from the NIH (from Brainsway). He is on the medical advisory boards of CALA Health and Brainsway (both unpaid positions). He is on the editorial board of approximately 15 journals and receives royalties and/or honoraria from publishing from Cambridge University Press, Oxford University Press, Springer, and Elsevier. He has research grants from Medtronic, Inc. for a study of DBS for dystonia and CALA Health for studies of a device to suppress tremor.

Figures

Figure 1
Figure 1
Schematic representation of the study design.
Figure 2
Figure 2
Individualized left dorsolateral prefrontal cortex targets.
Figure 3
Figure 3
Imaging results. Panel (A) shows changes in rsFC between the individualized DLPFC target and the left amygdala. The y axis represents changes in z-transformed region-to-region correlation strength as a result of iTBS. Panel (B) shows changes in the left amygdala reactivity to fearful to neutral (F–N) vs. happy–neutral (H–N) faces during the fMRI task. The y axis represents left amygdala beta values. Error bars represent SEM.
Figure 4
Figure 4
Changes in valence levels. Panel (A) shows an increase in positive valence ratings from Visit 1(V1) to Visit 3 (V3); panel (B) shows a decrease in valence ratings in response to fearful faces from V1 to V3. Participants received iTBS (3 daily session) on V2 and V3.
Figure 5
Figure 5
Changes in Simplified-Functional Movement Disorder Rating Scale (S-FMDRS) scores.

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