Intermittent Theta-Burst Stimulation for Depressive Symptoms in Parkinson Disease
A Randomized Clinical Trial
JAMA Netw Open
Published Online: May 20, 2026
2026;9;(5):e2613580. doi:10.1001/jamanetworkopen.2026.13580
Miaomiao Hou, MD1; Bingjie Tian, PhD2; Chen Qi, PhD1 et al
Key Points
Question Can the ultra-brief intermittent theta-burst stimulation (iTBS) protocol provide a time-efficient and effective alternative to standard high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) for treating depressive symptoms in Parkinson disease (PD)?
Findings In this randomized clinical trial including 54 patients with PD and depressive symptoms, both iTBS and HF-rTMS produced significant and comparable reductions in depressive symptoms compared with sham stimulation.
Meaning This study suggests that the ultra-brief iTBS protocol achieved antidepressant efficacy comparable with that of standard HF-rTMS in PD while reducing treatment time, offering a pragmatic and patient-centered advancement for clinical management.
Importance Depressive symptoms in patients with Parkinson disease (PD) are common and burdensome. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) targeting the left dorsolateral prefrontal cortex (DLPFC-L) is effective but time intensive, limiting practicality.
Objective To evaluate the antidepressant efficacy and neurofunctional effects of the ultra-brief intermittent theta-burst stimulation (iTBS) protocol for patients with PD depression (PD-D) compared with active HF-rTMS and sham stimulation.
Design, Setting, and Participants This triple-arm, randomized, sham-controlled single-center clinical trial was conducted at Xinhua Hospital, Shanghai Jiao Tong University School of Medicine in China from August 1, 2024, to January 31, 2025. Patients with PD aged 50 to 80 years with 24-item Hamilton Depression Rating Scale (HAMD-24) scores of 8 to 20 were randomized 1:1:1 to iTBS, HF-rTMS, or sham iTBS. Outcomes were assessed at baseline, week 1, week 2, and week 6. Data analysis was finalized in February 2026.
Interventions Ten daily sessions over 2 weeks: active iTBS (3 minutes and 20 seconds), active HF-rTMS (20 minutes), or sham iTBS.
Main Outcomes and Measures The primary outcome was the HAMD-24 score at week 2. Secondary outcomes included anxiety (measured by the 14-item Hamilton Anxiety Rating Scale [HAMA-14]), motor symptoms (measured by the Movement Disorder Society–Unified Parkinson Disease Rating Scale), quality of life (measured by the 8-item Parkinson’s Disease Questionnaire [PDQ-8]), and prefrontal hemodynamics (measured using functional near-infrared spectroscopy). Primary analysis followed the principle of intention to treat.
Results Of 54 randomized participants (mean [SD] age, 70.1 [5.3] years; 29 men [53.7%]), 50 (92.6%) completed the trial. Linear mixed-effects models revealed a significant group × time interaction for the HAMD-24 (F6,145 = 4.84; P < .001). At week 2, both active interventions were superior to sham (HAMD-24 score mean difference: iTBS, −4.97 [95% CI, −7.71 to −2.23]; P < .001; and HF-rTMS, −5.73 [95% CI, −8.95 to −2.51]; P < .001). Effects persisted at week 6 (HAMD-24 score mean difference: iTBS vs sham, −6.05 [95% CI, −9.26 to −2.83]; P < .001; and HF-rTMS vs sham, −5.57 [95% CI, −9.36 to −1.78]; P = .002), with no between-group differences. Both interventions improved PDQ-8 scores at week 2 (mean difference: iTBS vs sham, −2.33 [95% CI, −3.33 to −1.33]; P < .001; and HF-rTMS vs sham, −2.43 [95% CI, −4.60 to −0.26]; P = .02). iTBS also alleviated anxiety (mean difference: HAMA-14 score vs sham, −4.04 [95% CI, −7.73 to −0.35; P = .03). Active stimulations increased DLPFC-L activation (estimated adjusted difference: iTBS vs sham, 151.18 [95% CI, 51.24-251.11]; P = .004; and HF-rTMS vs sham, 173.26 [95% CI, 71.92-274.60]; P = .001) and reduced time in low-efficiency connectivity states (iTBS: median change, −0.12 [IQR, −0.29 to 0.02]; false discovery rate–corrected P = .045; and HF-rTMS: −0.12 [IQR, −0.32 to 0]; false discovery rate–corrected P = .02).
Conclusions and Relevance In this randomized clinical trial of patients with PD-D, the ultra-brief iTBS achieved antidepressant efficacy comparable with that of standard HF-rTMS while markedly reducing treatment time, supporting its use as a pragmatic therapy for PD-D. This study suggests the promise of symptom-stratified neuromodulation for personalized treatment protocols.
Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2100044421
Depressive symptoms affect 20% to 50%1 of patients with Parkinson disease (PD), worsening quality of life, motor function, and cognitive trajectory.2 Although selective serotonin reuptake inhibitors are first-line pharmacotherapy, their adverse effects (eg, nausea and headache) often limit tolerability.3,4 High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the left dorsolateral prefrontal cortex (DLPFC-L) offers an effective alternative with guideline support.5-7 However, the standard 20-minute session duration of HF-rTMS poses a practical barrier for patients with PD, who frequently contend with complex medication regimens, mobility challenges, and time-intensive care schedules.
Intermittent theta-burst stimulation (iTBS) condenses therapeutic stimulation into an ultra-brief 3-minute session while using potent plasticity mechanisms.8 Although iTBS has demonstrated efficacy comparable with that of HF-rTMS in major depressive disorder,9 its use for PD depression (PD-D) remains unknown.
Therefore, we conducted this 3-arm, randomized, sham-controlled clinical trial to evaluate the clinical use of iTBS for PD-D. We aimed to determine whether the ultra-brief iTBS protocol could achieve antidepressant efficacy comparable with that of the standard HF-rTMS and to examine the underlying neural mechanisms. Using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task (VFT),10 we measured prefrontal cortical activation via oxygenated hemoglobin (HbO) concentration changes, and we complemented this with dynamic functional connectivity analysis to capture temporal network dynamics. We hypothesized that both active interventions would be superior to sham stimulation in alleviating depressive symptoms and that the clinical response to iTBS would be underpinned by measurable modulation of prefrontal network dynamics. Confirmation of these hypotheses would position iTBS as a pragmatic, patient-centered advancement in the management of PD-D.
This double-blind, 3-arm, randomized, sham-controlled clinical trial compared iTBS, HF-rTMS, and sham stimulation for PD-D (trial protocol in Supplement 1). The protocol consisted of 10 daily sessions over 2 consecutive weeks, with clinical assessments at baseline, on the day of session 5 (week 1) and session 10 (week 2), as well as 4 weeks after session 10 ended (week 6) (eFigure 1A in Supplement 2). This study was conducted at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine in China from August 1, 2024, to January 31, 2025. The Ethics Committee of Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine approved the experiments, and written informed consent was obtained from all the participants. The study protocol was preregistered with the Chinese Clinical Trial Register (ChiCTR2100044421). This 3-arm, randomized, sham-controlled clinical trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Recent Comments