Resting state functional connectivity signature of treatment effects of rTMS in Mal de Debarquement Syndrome

Repetitive transcranial magnetic stimulation (rTMS) has been used in experimental protocols to treat Mal de Debarquement Syndrome (MdDS), a neurological condition that represents a maladaptive brain state resulting from entrainment to external oscillating motion. Medical treatments and biomarkers for MdDS remain limited but neuromodulation with rTMS has shown evidence for therapeutic effects. The current study took a neuroimaging approach to examine the neuromodulatory effect of rTMS on MdDS. Twenty individuals with MdDS underwent five daily treatments of rTMS over bilateral dorsolateral prefrontal cortex (DLPFC). Participants received 1Hz over right DLPFC (1200 pulses) followed by 10Hz over left DLPFC (2000 pulses). Resting state fMRI was acquired before and after treatments to determine functional connectivity changes associated with a positive treatment effect. A single-subject based analysis protocol was developed to capture the degree of resting state functional connectivity between the rTMS target and the entorhinal cortex, an area previously shown to be hypermetabolic in MdDS. Our results showed that rocking motion perception in subjects were modulated by rTMS over the DLPFC. Improvements in symptoms correlated most strongly with a post-rTMS reduction in functional connectivity between the left entorhinal cortex and the precuneus, right inferior parietal lobule, and the contralateral entorhinal cortex, which are part of the posterior default mode network. Positive response to rTMS correlated with higher baseline resting state functional connectivity between the DLPFC and the entorhinal cortex. Our findings suggest that baseline prefrontal-limbic functional connectivity may serve as a predictor of treatment response to prefrontal stimulation in MdDS and that resting state functional connectivity may serve as a dynamic biomarker of symptom status.