The Effects of Neuromodulation on Phonatory Function in Laryngeal Dystonia

The cause of LD is largely unknown and there are no treatments that produce long-term benefits. The investigators' long-term goal is to elucidate the pathophysiology of laryngeal dystonia as a crucial step towards the development of sensitive testing and novel interventions to treat this devastating disease. Neuroimaging studies have suggested that LD is associated with abnormal patterns of activation and excessive plasticity in sensorimotor areas in the brain, however, an understanding of the cortical excitability in this disorder is lacking. This information is important because it provides a more comprehensive understanding of the pathophysiology of the disorder, opening potential investigation into novel tests or treatments. The investigators have begun to address this gap in knowledge by developing a novel transcranial magnetic stimulation (TMS) paradigm to assess intracortical excitability and inhibition of targeted laryngeal muscles. Although similar paradigms have been fruitful for explicating the neural mechanisms of dystonia in the limbs, to our knowledge TMS has not been used to assess pathophysiology in laryngeal dystonia, thus similarities and differences in brain state between the limb and laryngeal dystonias could not be assessed. The investigators' current NIDCD project (R01DC015216) with which this proposed project synergizes, uses TMS and functional neuroimaging in people with LD and focal hand dystonia to determine the brain excitability and connectivity, distinctive of, and common to the two disorders. This approach is based on the investigators' recently completed NIDCD grant (R21DC012344) which supported the development of a valid and reliable TMS method to determine the cortical representation and excitability of the thyroarytenoid, a muscle affected in LD. Utilizing this approach, the investigators have recently demonstrated that people with LD have reduced intracortical inhibition compared to healthy controls. These results provide a compelling basis for the clinical application of this finding to determine if an intervention that increases intracortical inhibition can produce clinical improvements.

Aim 1: Determine the phonatory effects of 5-days of daily rTMS vs sham in people with LD. The effects of rTMS on phonatory function will be measured using (a) auditory-perceptual assessment (b) acoustic analysis including smoothed cepstral peak prominence (CPPS) of running speech and sustained vowel, and (c) patient self-ratings of vocal effort (response to voice demand). (H1) The investigators will observe large favorable intervention effect sizes in measures of phonatory function following rTMS compared to sham.

Aim 2: Determine the neurophysiologic changes associated with 5 days of rTMS vs sham in people with LD. The intervention effects on TMS-measured neurophysiology including intracortical excitatory and inhibitory measures from the laryngeal motor cortex will be assessed pre and post intervention. (H2) The investigators will observe significant decreases in cortical excitability [motor evoked potential (MEP)] and/or increases in inhibition [cortical silent period (cSP)] following rTMS compared to sham.

Aim 3: Explore characteristics associated with responders vs non-responders to rTMS in people with LD. This exploratory aim will stratify participants as responders or non-responders based on each person's acoustic (CPPS) changes. A multivariate regression will explore factors associated with positive response to intervention. (H3) Certain factors such as age, time since symptom onset, clinical severity, and/or baseline cortical excitability and inhibition will be associated with treatment responsiveness.

Procedures: Qualified participants will provide informed consent and receive on-site screening to determine eligibility. On Day 1, baseline (Pre) acoustic, perceptual and patient-reported assessments of voice production and TMS-measured neurophysiology will be performed. Participants will then receive the first rTMS intervention. On Day 2, 3 and 4, participants will receive rTMS (real or sham) intervention solely, with no testing. On Day 5, the same acoustic, perceptual, patient-reported and neurophysiologic assessments will be performed after rTMS intervention. At least 3 months after Post1, participants will cross-over to receive the other intervention (rTMS or Sham). The timing of the assessments in the cross-over phase of the experiment, Pre2 and Post2, will mirror the timing of Pre1 and Post1 in the first phase.