Personalized Neuromodulation for Persistent Post-Concussive Symptoms: Preliminary Findings and Trial Protocol
Kevin Bickart1, Christopher Giza3, Andrew Leuchter2, Colleen Hanlon4
1Neurology, UCLA, 2UCLA, 3UCLA, Depts of Pediatrics and Neurosurgery, 4BrainsWay
Objective:
To investigate frontoamygdala neuromodulation as a novel mechanism and treatment target for fear avoidance in patients with persistent post-concussive symptoms (PPCS).
Background:
PPCS are heterogeneous, nonspecific, and subjective, making their etiology complex and difficult to target. One promising target is fear avoidance, or avoiding stimuli and activities that trigger symptoms, because it accounts for substantial variance in PPCS and relies on well-studied circuitry. Fear regulation relies on a dynamic interaction between ventromedial prefrontal cortex (vmPFC) and amygdala. This interaction is disrupted in animal and human models of traumatic brain injury (TBI) towards vmPFC and amygdala hyperconnectivity or hyperactivity concurrent with enhanced and persistent fear behavior. Here, we examined whether this circuitry could be modulated using transcranial magnetic stimulation (TMS) to the vmPFC.
Design/Methods:
Participants with substance use disorder underwent blinded, sham-controlled TMS to the left frontal pole (FP1) for 20 sessions using continuous theta burst stimulation (cTBS), which is traditionally inhibitory. We assessed resting-state fMRI connectivity (rsFC) between the vmPFC and medial amygdala from baseline to immediately and 1 month after treatment using repeated measures ANOVA.
Results:
vmPFC to medial amygdala rsFC decreased significantly in participants receiving real (N=9) but not sham (N=8) cTBS (Time-x-Treatment Interaction: F=6.78, p=0.02, Partial eta sq= 0.31). The effect persisted up to 1 month after treatment, greatest for participants who had the strongest baseline connectivity (R2=0.50, p<0.05). This effect was specific to the medial amygdala, not seen for the ventrolateral or dorsal amygdala subregions, which are functionally distinct.
Conclusions:
This is the first evidence that ventromedial frontoamygdala circuitry can be specifically and durably modulated noninvasively in humans. It sets the stage for our DOD-funded trial using personalized circuit-based frontoamygdala cTBS to reduce fear avoidance and persistent symptoms in patients with PPCS, but may also be transdiagnostic to any condition marked by similar fear and emotion dysregulation mechanisms.