Transcranial Ultrasound Stimulation of the Motor Networks in Parkinson's Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and has shown a rapid rise globally over the past three decades. As of 2019, the global incidence and prevalence of PD reached approximately 1.08 million and 8.5 million cases, respectively, with both showing significant increases since 1990. The primary approach to managing PD focuses on symptomatic relief through medications that enhance dopamine availability or activate dopamine receptors. As the disease advances, patients often require escalating doses and dosing frequency. In later stages, advanced interventions such as deep brain stimulation (DBS) and ablative procedures may be considered. However, these interventions are invasive, resource-intensive, and remain inaccessible to a large proportion of patients. Transcranial ultrasound stimulation (TUS) is a novel, non-invasive neuromodulation technique capable of targeting deep brain structures and holds potential for symptom management in PD. This study had three main objectives: (i) to evaluate the safety and clinical effect size of TUS in patients with PD; (ii) to assess the safety and feasibility of recording LFPs during and after TUS; and (iii) to use LFPs to explore stimulation targets and characterize TUS effects, including frequency-band-specific modulation, direction, and duration. I demonstrated that TUS can be safely applied in patients with PD. While the clinical effect size was small and not statistically significant, TUS successfully increased motor excitability, as measured by transcranial magnetic stimulation. Subsequently, I tested the effects of TUS on DBS electrodes ex vivo and found no evidence of detrimental displacement or heating. I safely recorded LFPs in DBS-implanted patients with PD before, during, and after TUS, and demonstrated that its effects are specific to the stimulation target, frequency band, and brain state. While TUS has demonstrated neuromodulatory effects, the current effect size is insufficient for clinical translation. Further optimization of stimulation parameters and identification of inhibitory protocols are warranted to advance its therapeutic potential.