M1-iTBS in Mid-Stage PD
(2026)Objective
Test whether 5 daily sessions of bilateral intermittent theta-burst stimulation (iTBS) over the primary motor cortex improve motor symptoms, depression, and anxiety in mid-stage Parkinson's disease.
Study Summary
• Responders (11/15) improved by 17.70 ± 7.82 points (37.2%); bradykinesia subscore improved 35.3% (p=0.048 vs sham at post-3)
• Hamilton Depression dropped 47.6% (p=0.002) and Anxiety 37.9% (p=0.007) from baseline after real iTBS
• rs-fMRI showed increased cerebello-thalamo-cortical connectivity; medial geniculate-precuneus FC inversely correlated with bradykinesia (r=-0.718, p=0.013)
• Adverse events were not systematically reported; no SAEs described
Intervention
Bilateral primary-motor-cortex intermittent theta-burst stimulation (M1-iTBS) at 80% active motor threshold for 5 consecutive daily sessions
Inclusion Criteria
UK PD Brain Bank criteria, disease duration ≥5 yrs, H&Y II-III on medication, stable therapy ≥2 months, age 45-75, TMS-naïve
Study Design
Arms: Crossover RCT: real bilateral M1-iTBS vs sham (AirFilm coil), 5 daily sessions per phase, ≥3-month washout
Patients per Arm: 15 completers (same patients in both arms due to crossover)
Outcome
• Secondary: HDRS −47.6% (p=0.002), HARS −37.9% (p=0.007); bradykinesia subscore −35.3% in responders (p=0.048 vs sham)
• Functional MRI: increased cerebello-thalamo-cortical FC correlated with motor improvement
Clinical Question
Do 5 consecutive daily sessions of bilateral primary-motor-cortex iTBS improve motor and mood-related symptoms in mid-stage Parkinson's disease compared with sham?
Bottom Line
Bilateral M1-iTBS produced a 30.7% reduction in MDS-UPDRS Part III at 2 weeks (vs 14.3% sham, p=0.036) plus large improvements in depression (-47.6%) and anxiety (-37.9%), accompanied by increased cerebello-thalamo-cortical connectivity in responders.
Major Points
- First crossover, double-blind, sham-controlled RCT of 5-session M1-iTBS in mid-stage PD showing combined motor and affective benefit
- Maximal motor improvement at 2 weeks: 8.90 ± 6.11 points on MDS-UPDRS Part III (30.7%) vs 2.87 ± 5.33 (14.3%) with sham; condition×time interaction p=0.014
- 11/15 patients met responder criteria with 37.2% MDS-UPDRS-III improvement; bradykinesia was the most responsive subdomain
- HDRS fell 47.6% (p=0.002) and HARS 37.9% (p=0.007) — supports M1-iTBS as a dual motor/affective intervention
- Resting-state fMRI implicates cerebello-thalamo-cortical reintegration as a candidate mechanism (medial geniculate-precuneus FC inversely correlated with bradykinesia, r=-0.718)
Study Design
- Study Type
- Randomized, double-blind, sham-controlled crossover trial
- Randomization
- Yes
- Blinding
- Double-blind (patients and evaluators blinded; only randomization investigator unblinded; AirFilm SHAM coil)
- Sample Size
- 15
- Follow-up
- 1 month after final session (post-1 immediate, post-2 1 wk, post-3 2 wk, post-4 1 mo); rs-fMRI on day 8; ≥3-month washout between phases
- Centers
- 1
- Countries
- Spain
Primary Outcome
Definition: Change in MDS-UPDRS Part III (motor) score from baseline across 4 follow-up timepoints (immediate, 1 wk, 2 wk, 1 mo)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Small sample (n=15 from 24 recruited) limits generalizability and precision; post-hoc power ~60%
- Single-center study (Puerta del Mar Hospital, Cádiz) restricts external validity
- Excluded patients with cognitive impairment — a clinically meaningful subgroup
- Mood outcomes vulnerable to expectation effects (sham also improved mood scores)
- Assessments performed only in ON-medication state
- Short follow-up (1 month) limits durability assessment
- Exploratory rs-fMRI ROI analyses lacked across-ROI correction — hypothesis-generating only
- Adverse events not systematically reported
- Imbalanced responder subgroup analyses (only real-iTBS responders analyzed due to limited sham responders)
Citation
Neurotherapeutics. 2026 Apr 28;e00911. DOI:10.1016/j.neurot.2026.e00911