Cerebellar Neuromodulation to Enhance Fear extinction and Predict Response to Exposure Therapy

PROJECT ABSTRACT Despite enormous financial and person-power investments into functional neuroimaging studies in anxiety, the results from these investigations have had limited actionable impact on clinical practice. In particular, few studies have been designed to predict which patients will benefit from a particular intervention, which could result in enormous cost-savings and increased efficiency in delivering mental health care. The goal of exposure-based therapies for anxiety is to present the fear inducing stimulus to the patient in a safe setting in order to extinguish (fear extinction) the previously conditioned (fear conditioned) association. Abnormalities in the fear extinction process characterize many anxiety disorders such as social phobias, panic disorder, and post-traumatic stress disorder. Fear conditioning studies in anxious individuals implicate both enhanced and overgeneralized conditioned fear responses as well as deficits in fear extinction learning. We hypothesize that an acute intervention such as transcranial magnetic stimulation (TMS) may be able to probe the plasticity of a neural network relevant to exposure therapy outcome and help aid early decision points regarding who is most likely to benefit from exposure therapy. Both animals and human investigations have supported an important role for the cerebellum in fear conditioning and fear extinction, with the lateral cerebellar hemispheres involved in the associative and emotional aspects and the cerebellar vermis involved in the sensory and autonomic ones. Functional connectivity between the cerebellum and cerebral hemispheres suggests that cerebral structures too difficult to reach by the cortex with TMS may be accessible via their cerebellar connectivity, a relationship that is slowly becoming recognized. The lateral cerebellar hemisphere is accessible by TMS and is conveniently functionally connected to the medial prefrontal cortex. Ventromedial prefrontal cortex (vmPFC) activation is a key component to effective fear extinction. Accordingly, vmPFC is hypoactive in fear extinction learning in anxious individuals, a finding explicitly determined for those with phobias. Opportunities to explore the contribution of neural pathways that may enhance fear extinction through modulation of vmPFC activity remain wide open and modulation via the cerebellum is an underexplored one. Our investigative model uses fear of public speaking, a prevalent social phobia that is amenable to exposure based therapy and which is typically less complicated by comorbidities than other anxiety disorders. This study will be among the first to clearly delineate the role of the cerebellum in fear extinction. Clarifying the particular function of the cerebellum is important because 1] it enables one to modulate a brain structure that is accessible using TMS and other neuromodulation tools, and 2] it may provide a severity indicator to help identify subsets of individuals with severe difficulties with fear extinction. The results from this study may lead to a program of research aimed at synergizing neuromodulation with behavioral therapy to increase treatment efficacy.