Optimizing Parameters of Low-Intensity Focused Ultrasound for Pallidal Modulation in Huntington's Disease

DLT refers to the occurrence of any of the following six events during LIFU treatment:

• Second-degree scalp burn;
• Clinical seizure;
• Worsening of chorea or new movement disorder;
• Significant deterioration of the patient's mood or mental status (e.g., anxiety, depression, hallucinations, excessive sleepiness);
• Severe autonomic dysfunction, such as marked blood pressure fluctuations, abnormal heart rate, or respiratory distress;
• Imaging-related safety events: new or significantly enlarged brain edema, new microbleeds, new infarcts, or structural abnormalities in the treatment area on post-treatment cranial MRI compared with baseline, deemed clinically significant by both radiologists and clinicians.

The Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) evaluates motor impairment in Huntington's disease.

Score range: 0-124 Higher scores indicate more severe motor impairment

Response is defined as a reduction of ≥4 points from baseline.

Utility is a composite measure integrating dose-limiting toxicity (DLT) and efficacy response to quantify the overall benefit-risk balance for each dose group.

During the trial, the Utility value for each dose group is dynamically calculated using the U-BOIN design platform. In Stage II, the Utility value determines dose allocation for subsequent cohorts. At study completion, the dose group with the highest Utility value is identified as the optimal biological dose.

The Patient Global Impression of Change (PGI-C) is a patient-reported scale assessing perceived change in overall condition after treatment.

Score range: 1-7 Lower scores indicate greater improvement

The Clinical Global Impression of Change (CGI-C) is a clinician-rated scale assessing overall change in the patient's clinical status.

Score range: 1-7 Lower scores indicate greater improvement

The UHDRS Chorea Score evaluates severity of choreiform movements.

Score range: 0-28 Higher scores indicate more severe chorea

The Symbol Digit Modalities Test (SDMT) is a cognitive assessment of processing speed and attention.

Score range: 0-110 (number of correct matches within 90 seconds)

Higher scores indicate better cognitive function

The Controlled Oral Word Association Test (COWAT) assesses verbal fluency and executive function.

Score range: 0-unlimited (total number of words generated across three trials, each 60 seconds)

Higher scores indicate better verbal fluency and executive function

The Stroop Interference Test assesses cognitive inhibition and executive function.

Score range: 0-unlimited (number of correct responses on the interference task within a time limit)

Higher scores indicate better cognitive function

The Functional Independence Scale assesses a patient's level of independence in daily activities.

Score range: 0-100

Higher scores indicate greater independence

The Total Functional Capacity (TFC) scale is a component of the Unified Huntington's Disease Rating Scale (UHDRS) that assesses functional capacity.

Score range: 0-13

Higher scores indicate better functional capacity

The Functional Assessment Score is a component of the Unified Huntington's Disease Rating Scale (UHDRS) that assesses the patient's ability to perform specific tasks.

Score range: 0-25

Higher scores indicate better functional ability

Serum Neuron-Specific Enolase (NSE) is a biomarker of neuronal injury.

Unit of measure: ng/mL

Higher levels indicate more neuronal damage

Change from baseline in structural and functional brain connectivity metrics as assessed by multimodal MRIto evaluate the neuromodulatory effects of LIFU.