A Prospective Study on the Effects of Percutaneous Patent Foramen Ovale Closure on Multimodal Brain Function, Cognition, and Emotion in Patients With Migraine and Patent Foramen Ovale
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 45
- 主要终点
- Change in whole-brain network connectivity strength (FCN and MCN) from baseline to 12 months
研究概览
简要总结
This investigator-initiated, single-center prospective study is designed to clarify how patent foramen ovale (PFO) relates to brain function abnormalities in patients with drug-refractory migraine with aura (MA), and whether percutaneous PFO closure is associated with measurable, longitudinal improvements in neurophysiological and neuroimaging markers as well as clinical symptoms.
The study addresses two core questions: (1) Do MA patients with clinically significant right-to-left shunt due to PFO demonstrate distinct resting-state brain function patterns-captured by high-density EEG (hdEEG), resting-state functional MRI (rs-fMRI), and standardized cognitive testing-compared with MA patients without PFO? (2) In MA patients with PFO who undergo clinically indicated percutaneous PFO closure, do these multimodal brain function measures change over time after closure (pre-procedure vs 1, 6, and 12 months), and are such changes accompanied by improvement in migraine burden, quality of life, and mood/anxiety symptoms? The protocol includes two phases. In Phase 1 (cross-sectional comparison), two groups are evaluated at baseline: MA with PFO (PFO+/MA+) and MA without PFO (PFO-/MA+). Participants complete hdEEG and rs-fMRI to characterize whole-brain power spectral density and connectivity, and undergo MATRICS Consensus Cognitive Battery (MCCB) testing and validated symptom/psychological assessments (e.g., MIDAS, MSQ v2.1, PHQ-9, GAD-7, RoPE). In Phase 2 (prospective self-controlled cohort), eligible PFO+/MA+ participants who proceed to percutaneous PFO closure as part of routine clinical care are followed longitudinally with repeated multimodal assessments at pre-closure baseline and post-closure 1, 6, and 12 months. This phase evaluates within-person trajectories of resting-state brain function (hdEEG, rs-fMRI) and cognition/emotion measures, together with migraine diary-based outcomes and patient-reported quality of life/disability and mood/anxiety scales. Key eligibility focuses on adults aged 18-65 years with ICHD-3-defined migraine with aura and a history of frequent migraine (≥4 migraine days/month during screening) despite prior preventive therapy trials; the PFO group requires echocardiographic confirmation of PFO with at least moderate right-to-left shunt (e.g., during Valsalva on contrast TEE), consistent with the study's focus on clinically meaningful shunt physiology.
The primary endpoints are multimodal brain function and cognition measures. In Phase 1, the main outcomes include between-group differences in MCCB composite score, rs-fMRI whole-brain functional connectivity strength, and hdEEG spectral power across frequency bands (delta/theta/alpha/beta/gamma) and theta-band connectivity quantified by whole-brain phase-lag index (PLI). In Phase 2, the primary outcome is the 12-month post-closure change in these multimodal resting-state brain function measures, reflecting dynamic neural recovery or reorganization after PFO closure.
Secondary outcomes include changes in migraine clinical metrics (monthly migraine days, attack frequency and duration, and complete remission rate), migraine-specific quality of life (MSQ v2.1), disability (MIDAS), and depression/anxiety symptom scores (PHQ-9 and GAD-7) over follow-up. Safety outcomes include adverse events potentially related to the closure procedure and routine post-procedural anti-thrombotic therapy, captured throughout follow-up.
详细描述
This is an investigator-initiated, single-center, prospective, longitudinal, self-controlled cohort study evaluating multimodal brain function changes in adults with migraine with aura and echocardiographically confirmed patent foramen ovale (PFO) who undergo clinically indicated percutaneous PFO closure as part of routine care. The study is designed to characterize within-person trajectories of resting-state neurophysiology, brain network organization, and neurocognitive performance from pre-closure baseline through post-closure follow-up, using standardized acquisition and analytic pipelines for high-density electroencephalography (hdEEG), resting-state functional MRI (rs-fMRI), and cognitive testing.
Overall design and clinical workflow integration
Participants are identified through routine clinical pathways (cardiology/structural heart disease and headache/neurology services). Study procedures are embedded within the standard pre-procedural assessment and post-procedural follow-up schedule whenever feasible to reduce participant burden and improve data completeness. The PFO closure procedure itself, device selection, peri-procedural management, and post-procedure antithrombotic therapy follow local clinical practice and are not assigned by the study.
Participants complete a pre-closure baseline assessment and then undergo repeated assessments during follow-up. Study visits are time-locked to clinically meaningful recovery phases after PFO closure and are intended to capture early neurophysiologic changes, intermediate adaptation, and longer-term stabilization of brain network measures.
Multimodal assessments and acquisition procedures Resting-state fMRI acquisition and quality control
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years and <60 years at Screening/Baseline.
- •Diagnosis of migraine with aura established by a neurologist according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria.
- •Migraine history ≥1 year AND, during the 3-month screening/run-in period, an average of ≥4 migraine days per month; participant is willing and able to complete a headache diary, which will be reviewed by the investigator prior to enrollment.
- •Patent foramen ovale (PFO) identified by transthoracic echocardiography (TTE) and confirmed by contrast transesophageal echocardiography (cTEE), with at least moderate atrial-level right-to-left shunt (RLS) during Valsalva maneuver.
- •RLS grading by microbubbles in the left-sided cardiac chambers per frame on single-frame images:
- •No RLS: 0 microbubbles
- •Grade I (small): 1-10 microbubbles/frame
- •Grade II (moderate): 11-30 microbubbles/frame
- •Grade III (large): >30 microbubbles/frame or near-complete opacification of the left chambers ("hazy" appearance)
- •Prior use of at least three different classes of migraine preventive therapies with either <50% improvement in migraine frequency during treatment OR intolerable adverse effects.
- •At least two therapies must be from different categories among (a-f); the third may be one of (g-j):
- •Beta-blockers
- •Tricyclic antidepressants
- •Verapamil or flunarizine
- •Sodium valproate (or divalproex sodium)
- •Other anticonvulsants
- •Any therapy supported as effective by at least one positive randomized controlled trial
- •Nonsteroidal anti-inflammatory drugs (NSAIDs)
- •Metabolic agents (e.g., vitamin B2 or coenzyme Q10)
- •Traditional Chinese medicine
- •Participant has been on a stable daily dose regimen of preventive headache medication for ≥3 consecutive months prior to enrollment (to be verified during screening).
- •Written informed consent provided and willingness to comply with study procedures and follow-up schedule.
排除标准
- •Expected life expectancy ≤1 year at Screening/Baseline.
- •Secondary migraine attributable to other causes.
- •History of transient ischemic attack (TIA), stroke, or intracranial hemorrhage.
- •Investigator-determined anatomical findings on TEE that are unfavorable for successful PFO occluder deployment or any contraindication to device implantation, including (but not limited to):
- •Inability to undergo/complete TEE
- •Vascular access unable to accommodate the delivery system
- •Requirement for transseptal puncture
- •Requirement for implantation of more than one occluder
- •Defect size estimated too large for successful closure
- •Potential interference between the occluder and other intracardiac structures
- •Anatomy preventing adequate apposition of the occluder discs to the atrial septum
- •Allergy to any component/material of the AMPLATZER™ PFO Occluder (e.g., nickel allergy).
- •Current or past diagnosis of severe psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depressive disorder), or unstable psychiatric illness defined as psychiatric hospitalization, medication dose adjustment, or marked symptom fluctuation within the past 6 months.
- •Neurological and/or neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis), uncontrolled epilepsy/seizures within the past 1 year, central nervous system tumor, or history of traumatic brain injury.
- •History of myocardial infarction.
- •History of pacemaker implantation, atrial septal defect (ASD) closure, or left atrial appendage (LAA) closure.
- •Intracardiac right-to-left shunt due to causes other than PFO.
- •Contraindications to aspirin and/or clopidogrel, including significant thrombocytopenia, major trauma, acute clinically significant bleeding, or allergy to study medications.
- •Hepatic impairment defined as PT and/or APTT >2× the upper limit of normal (ULN) OR total bilirubin ≥3 mg/dL.
- •Poorly controlled diabetes mellitus at Screening/Baseline (as judged by the investigator).
- •Poorly controlled atrial fibrillation at Screening/Baseline (as judged by the investigator).
- •Poorly controlled hypertension at Screening/Baseline, defined as blood pressure >160/90 mmHg despite appropriate pharmacologic treatment.
- •Active autoimmune disease at Screening/Baseline (e.g., systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, central nervous system granulomatous vasculitis).
- •Active infection at Screening/Baseline that cannot be fully resolved prior to enrollment.
- •Alcohol abuse or drug dependence at Screening/Baseline.
- •Ongoing anticoagulation therapy that cannot be discontinued.
- •Unable to accurately describe headache status and/or unable to complete/maintain a headache diary.
- •Currently participating in another device or drug clinical trial in which the primary endpoint has not been reached, or that may clinically confound this study's endpoints, or that prohibits co-enrollment.
- •Pregnant or planning pregnancy during the study period.
- •Planned elective surgery during the study period.
- •Any medical condition or circumstance that, in the investigator's opinion, poses a significant risk to participant safety, confounds study results, or interferes with study participation.
- •Any other medical or non-medical reason that, in the investigator's opinion, makes the participant unsuitable (e.g., inability to comply with study procedures/visits, plans to relocate during the study period).
结局指标
主要结局
Change in whole-brain network connectivity strength (FCN and MCN) from baseline to 12 months
时间窗: from enrollment to the end of postoperative followup at 3 years
Connectivity matrices will be constructed using a predefined brain parcellation; whole-brain connectivity strength will be summarized as a prespecified global network strength metric (and/or network-level strength within canonical systems).
次要结局
未报告次要终点