PROJECT ABSTRACT Dystonia is a debilitating movement disorder characterized by involuntary muscle contractions with abnormal and repetitive movements, postures, or both. The current treatments for dystonia, consisting of oral medications, botulinum toxin injections, and deep brain stimulation surgery, fail to improve symptoms in more than a third of patients despite optimal management. The improvements are often unpredictable. Recent studies found exercise therapy primarily involving muscle stretching, muscle relaxation, and range of motion exercises, when added to optimal medical management, further improved symptoms of focal cervical dystonia. But the clinical outcomes were noted to be variable and modest. These studies did not investigate the pathophysiological underpinnings that could explain the variability of treatment outcomes. They did not include progressive resistance training that has the potential to induce central brain changes. The main goal of this proposal is to investigate the brain adaptation effects for progressive resistance exercise-focused cervical and shoulder training (PERFECT) in patients with focal cervical dystonia, which is the most common form of dystonia. We will use functional MRI (fMRI) and transcranial magnetic stimulation (TMS) techniques for understanding the pathophysiological underpinnings. We will randomize patients into PERFECT plus standard-of-care (SOC) group and SOC alone group. Participants in the PERFECT + SOC group will perform personal-trainer-guided exercises twice a week for six months. Participants in the SOC group will continue receiving standard pharmacological therapies at stable doses, and they will not exercise. We will use fMRI and TMS techniques to examine brain effects. We hypothesize that the PERFECT program in focal cervical dystonia will improve the functioning of dystonia circuitries involving the sensorimotor cortex. In Aim 1, we will determine the brain adaptation changes in response to PERFECT at six months compared to baseline with fMRI. We will record seed-based functional connectivity and bold oxygen level-dependent signal in the sensorimotor network. In Aim 2, we will determine the brain adaptation changes in response to PERFECT at six months compared to baseline with TMS. We will use a TMS-based paired associative stimulation protocol to measure sensorimotor plasticity and compare. We will monitor the TMS-based resting motor threshold; motor evoked potential, intracortical inhibition, and intracortical facilitation as additional measures. In Aim 3, we will determine whether the brain adaptation response relates to clinical and functional change. We will assess with blinded dystonia ratings, cognition and mood measures, muscle strength, physical functioning capacity. The outcomes of this proposal will (1) test whether a 6-month long resistance exercise is viable, (2) identify physiological brain markers that are responsive to effects of resistance exercise and are specific to dys...