Low-Intensity Focused Ultrasound Targeting the Dorsolateral Prefrontal Cortex for Preventive Treatment of Chronic Migraine

Chronic migraine is a disabling neurological disorder characterized by frequent headache attacks and significant impairment of quality of life. Low-intensity focused ultrasound (LIFUS) is a non-invasive neuromodulation technique that can precisely target deep brain regions. This study aims to evaluate the efficacy, safety, and tolerability of LIFUS targeting the left dorsolateral prefrontal cortex (DLPFC) for preventive treatment of chronic migraine in adults. This is a randomized, single-blind, sham-controlled clinical trial. Eligible participants with chronic migraine will be randomly assigned to receive either active LIFUS stimulation targeting the left DLPFC or sham stimulation. Participants will receive 10 stimulation sessions over 2 weeks and will be followed for 3 months after intervention. The primary outcome is the change in monthly migraine days from baseline to 1 month after intervention. Secondary and exploratory outcomes include headache-related disability, quality of life, psychological assessments, electrophysiological measurements, neuroimaging changes, and safety outcomes.

Inclusion Criteria: * Participants diagnosed with chronic migraine according to the International Classification of Headache Disorders, 3rd edition (ICHD-3), with a history of migraine for at least 12 months before screening. * Migraine onset at or before 50 years of age. * During the 3 months before screening, participants have headache occurring on at least 15 days per month, with migraine features or migraine-specific treatment on at least 8 days per month. * During the baseline prospective electronic headache diary period, participants record at least 8 migraine days and 15 to 27 headache days. * Participants are able to comply with electronic headache diary recording requirements, with data recorded for at least 24 of the 28 days during the screening period. * Age between 18 and 65 years at screening visit. * Participants are willing and able to provide written informed consent and comply with study procedures. Exclusion Criteria: * History of epilepsy, brain tumor, or traumatic brain injury. * History of transcranial magnetic stimulation, transcranial direct current stimulation, or electroconvulsive therapy within the past 3 months. * Presence of MRI-incompatible metallic implants, including but not limited to vascular stents, cardiac pacemakers, or ventriculoperitoneal shunts. * Clinically significant comorbid chronic pain conditions, such as fibromyalgia, chronic low back pain, or complex regional pain syndrome. * Diagnosis of acute or active temporomandibular disorder. * History or diagnosis of other primary headache disorders, including chronic tension-type headache, hypnic headache, cluster headache, hemicrania continua, new daily persistent headache, or atypical migraine subtypes. * Use of opioid-containing analgesics for more than 4 days within 1 month before baseline or during baseline period. * Use of any migraine preventive medication within 1 month prior to screening. * Use of devices or surgical interventions for migraine treatment within 1 month before baseline, including transcranial magnetic stimulation, greater occipital nerve block, or invasive/non-invasive neuromodulation procedures. * History of malignant tumors within the past 5 years, except adequately treated localized basal cell carcinoma or carcinoma in situ of the cervix. * History of severe psychiatric disorders, including schizophrenia, other psychotic disorders, bipolar disorder, obsessive-compulsive disorder, or post-traumatic stress disorder. * Severe anxiety, depression, or manic symptoms according to predefined scale thresholds (SAS, SDS, and BRMS). * Significant risk of self-harm or harm to others based on the Columbia Suicide Severity Rating Scale (C-SSRS) assessment or investigator judgment. * History of myocardial infarction, stroke, transient ischemic attack, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months before screening. * Pregnancy or breastfeeding. * Claustrophobia or inability to undergo MRI examination.