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

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.

Neurostimulation for the treatment of functional neurological disorder: A systematic review

“…A further critical source of variability was represented by the stimulation target. In the majority of studies, the motor cortex was selected as target site, despite lack of motor cortex abnormalities in patients with FND based on a large body of neurophysiological and neuroimaging studies (for a review see Spagnolo, Garvey and Hallett, 2021 [56] ). Current evidence suggests that functional neurological symptoms are associated with abnormalities in activity and connectivity in motor-limbic circuitry (i.e., amygdala, insula, supplementary motor area) as well brain areas implicated in agency (right temporoparietal junction – rTPJ– and precuneus) [60] , [61] .…”

“… Table 1.2. Open Label Studies Parameters of stimulation Results Study (author/year) FND Phenotype Design N Anatomical Target Frequency* Intensity (% MT) Total pulses/ session # Sessions Outcome Measures Outcome Time point 1** Outcome Time point 2*** Open label Spagnolo et al [56] Movement disorder -unspecified Open label 6 Left DLPFC Individualized fMRI imaging guided iTBS 120%RMT 3600pulses total of 6 sessions 2 visits- 24h interval 3 iTBS sessions each visit, >20min between sessions Functional MRI data S-FMDRS Decrease functional connectivity between the left amygdala and DLPFCSignificant FMDRS decrease within each stimulation visit (pre and post treatment) Significant FMDRS decrease between baseline (pre TMS) and 24h after last stimulation Peterson et al [62] Functional seizures Open label 7 Right TPJ rTMS 10Hz 5 sec trains ITI 30sec 110% MT 3000pulses 30 sessions in 3 weeks 2 sessions/day-15min between sessions Functional seizures count Decrease in weekly functional seizures frequency in all subjects throughout treatment. All participants sustained improvement up to 3 months post-treatment.…”

“…Five studies (1 RCT, 2 case series and 2 case reports) used high-frequency (>5Hz) rTMS –generally considered excitatory–; and 6 studies (5 case series and 1 case report) used single pulse TMS. Lastly, 2 studies (a case report and a proof-of-concept study) used iTBS – an accelerated excitatory protocol using short bursts of stimulation at high frequencies [55] , [56] .…”

“…Five studies investigated TMS efficacy on FMD with hyperkinetic motor symptoms (2 RCTs, 1 pilot study and 2 case series – Table 1 ), and they all used the primary motor cortex as the stimulation site, except for one study using an individualized, functional neuroimaging-guided stimulation target within the left dorsolateral prefrontal cortex [56] . Although the TMS protocol used was different between studies (single pulse TMS, low frequency rTMS and iTBS), all reported positive outcomes that persisted through their follow-up timepoint.…”

“…Several studies also assessed secondary outcome measures related to mood, pain, functioning, and cognitive complaints. Imaging and/or physiological measures (e.g., functional MRI, EEG) to evaluate target engagement were not included in the studies identified, with the exception of a recent pilot study which used resting-state functional connectivity data to identify an individualized stimulation target and evaluate neurocircuitry engagement [56] .…”