Acupuncture for Migraine Without Aura and Connection-Based Efficacy Prediction: A Randomized Clinical Trial.

Importance: Connectome-based predictive modeling (CPM) uses a data-driven whole-brain framework to identify connectivity patterns predicting clinical outcomes. However, CPM's application to acupuncture in migraine without aura (MWOA) remains novel. Objective: To evaluate the clinical efficacy of real acupuncture and sham acupuncture in MWOA, and to identify acupuncture-response brain connectivity patterns using CPM analysis of baseline functional magnetic resonance imaging (fMRI) data. Design, Setting, and Participants: This single-blinded randomized clinical trial was conducted from June 2021 to June 2023 at Beijing Hospital of Traditional Chinese Medicine in China. It enrolled participants aged 18 to 65 years who met the MWOA criteria of the International Classification of Headache Disorders, 3rd edition. Eligible participants were randomly assigned to receive real acupuncture or sham acupuncture, and underwent baseline clinical assessments and baseline fMRI scans. Data analyses were performed between October 2024 and March 2025 following intention-to-treat and per-protocol principles. Interventions: Both treatment groups received 12 sessions of 30-minute acupuncture over 4 weeks. Real acupuncture involved 8 acupoints with deqi sensation, while sham acupuncture used sham acupoints without deqi. Main Outcomes and Measures: Primary outcome was the change from baseline in monthly migraine days (MMDs) during weeks 1 to 4. Secondary outcomes included 50% or greater reduction in MMDs and change from baseline in monthly headache days (MHDs), acute medication use days, pain score (visual analog scale [VAS] score range: 0 [indicating no pain] to 10 [indicating severe pain]), disability score (6-item Headache Impact Test [HIT-6] score range: 36 to 78, with the higher scores indicating severe headache effect), and quality-of-life score (Migraine-Specific Quality of Life Questionnaire [MSQ] score range: 0 to 100, with the higher scores indicating superior quality of life) during 4 weeks. Neuroimaging analyses used fMRI data to predict outcome changes via CPM. Results: Among the 120 participants (mean [SD] age, 36.8 [10.0] years; 95 females [79.2%]), 60 were randomly assigned to real acupuncture and 60 to sham acupuncture. The change from baseline in MMDs significantly improved for the real acupuncture group compared with the sham acupuncture group (median difference, -1.0; 95% CI, -2.0 to 0; P = .02). Significant differences were also observed in MHDs (median difference, -1.0; 95% CI, -2.0 to 0; P = .01), acute medication use days (median difference, -1.0; 95% CI, -2.0 to 0; P = .02), VAS score (median difference, -1.0; 95% CI, -1.0 to 0; P = .02), HIT-6 score (mean difference, -2.9; 95% CI, -5.4 to -0.5; P = .02), and MSQ score (Role Function-Restrictive domain: median difference, 8.6; 95% CI, 3.7-14.3; P < .001; Role Function-Preventive domain: median difference, 5.0; 95% CI, 0-10.0; P = .02; Emotional Function domain: median difference, 6.7; 95% CI, 0-13.3; P = .001). CPM revealed distinct neural signatures: negative connectivity predicted VAS score reduction (r = 0.23, P = .04) and positive connectivity predicted HIT-6 score improvement (r = 0.29, P = .02). Feature selection identified robust networks (12 connections for VAS score; 120 for HIT-6 score), in which default mode network and subcortical-cerebellum (DMN-SC) hypoconnectivity and SC-motor hyperconnectivity were identified as key connectivity patterns in predictive models of VAS and HIT-6 scores, respectively. Conclusions and Relevance: This trial demonstrated acupuncture's efficacy for MWOA pain relief and functional improvement. CPM identified DMN-SC hypoconnectivity as predicting pain relief and SC-motor hyperconnectivity as predicting reduced disability, providing a personalized treatment framework. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100044251.