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GPi tbTUS in PD

Transcranial Ultrasound Stimulation of Internal Globus Pallidus Region and Motor Cortex in Parkinson's Disease

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Year of Publication: 2026

Authors: Lin YY et al.

Journal: Movement Disorders

Citation: Mov Disord. 2026 Feb; DOI:10.1002/mds.70095

Link: https://doi.org/10.1002/mds.70095

Bottom Line

Bilateral GPi tbTUS produced a clinically meaningful 4.1-point reduction in MDS-UPDRS-III at 30 min post-sonication (p=0.002), driven primarily by bradykinesia improvement; M1-only and dual-site M1+GPi stimulation showed no significant motor benefit, and dual-site was not additive.

Major Points

  • First proof-of-concept that non-invasive bilateral GPi tbTUS produces an acute clinical motor benefit in PD
  • Effect size (4.1 points) exceeded the MCID for MDS-UPDRS-III (3.25) and was apparent in 12/13 participants
  • Bradykinesia was the most responsive subdomain (p=0.003); M1-only and dual-site sonication did not improve motor scores
  • Mechanistically, GPi tbTUS increased the TMS intensity needed to elicit 1 mV MEP (consistent with subcortical inhibition), while M1 tbTUS instead raised MEP amplitudes
  • Safety profile favorable: only transient mild headache (23%), no SAEs, intensities below FDA limits

Design

Study Type: Randomized, sham-controlled, within-subject crossover proof-of-concept trial

Randomization: 1

Blinding: Single-blind (video-based MDS-UPDRS-III scoring by blinded second rater; condition order partly constrained for safety in first 7 participants)

Enrollment Period: Not reported

Follow-up Duration: 60 min post-sonication (TMS at T10, T45, T60; MDS-UPDRS-III at T30); ≥1 week between sessions

Centers: 1

Countries: Canada

Sample Size: 13

Analysis: ART rmANOVA, Wilcoxon signed-rank (per-condition contrast)

Inclusion Criteria

  • Diagnosis of Parkinson's disease per 2015 MDS clinical diagnostic criteria, confirmed by a neurologist
  • Stable dopaminergic medication doses for at least 4 weeks
  • Tested in on-medication state on regular medications
  • Underwent MRI for neuronavigation targeting
  • Able to tolerate TMS procedures
  • Provided written informed consent

Exclusion Criteria

  • History of seizure
  • Intracranial implants or devices
  • Contraindications to MRI
  • Pregnancy
  • Major psychiatric disorders
  • Severe tremor or dyskinesia that could interfere with TMS recordings

Baseline Characteristics

CharacteristicActiveControl
Mean Age62.6 ± 9.3 years
Sex - Male8/13 (61.5%)
Disease Duration7.5 ± 3.6 years
Hoehn & Yahr stage2.0 ± 0.4
LEDD654 ± 330 mg/day
Baseline MDS-UPDRS-III (real M1/sham GPi)16.1 ± 4.0
Baseline MDS-UPDRS-III (real GPi/sham M1)18.9 ± 6.9
Baseline MDS-UPDRS-III (dual-site)15.3 ± 5.0
Estimated ISPPA at GPi target (R/L)4.05 ± 0.80 / 3.91 ± 0.70 W/cm²
NoteWithin-subject sham crossover; no separate control cohort

Arms

FieldReal M1 / Sham GPiReal GPi / Sham M1Dual-site (Real M1 + Real GPi)
InterventionBilateral M1 tbTUS (active), bilateral GPi tbTUS (sham)Bilateral GPi tbTUS (active), bilateral M1 tbTUS (sham)Simultaneous bilateral M1 and bilateral GPi tbTUS
DurationSingle session, evaluated to 60 minSingle session, evaluated to 60 minSingle session, evaluated to 60 min

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in MDS-UPDRS-III at 30 min post-sonication across the three conditionsPrimaryReal GPi/sham M1: −4.1 points from baseline (p=0.002); 12/13 improved · Real M1/sham GPi: No significant change (6/13 improved) · Dual-site M1+GPi: No significant change (8/13 improved) · Statistics: ART rmANOVA main effect of time p=0.011; condition×time interaction p=0.204 (NS); main effect of condition p=0.076 (NS) · Clinical relevance: Exceeded MCID of 3.25 for MDS-UPDRS-III
Bradykinesia subscore at T30 (GPi tbTUS)Secondary0.003 (z=-2.996)
MEP amplitude ratio to baseline at T10 (M1 tbTUS)SecondaryCondition×time interaction p=0.007
TMS intensity to elicit 1 mV MEP at T10 (GPi tbTUS)Secondary0.022 vs baseline; condition×time interaction p=0.015
Resting motor threshold (RMT)SecondaryInteraction p=0.553
Short-interval intracortical inhibition (SICI)SecondaryInteraction p=0.756
Intracortical facilitation (ICF)SecondaryInteraction p=0.628
OverallAdverse4/15 (26.7%) enrolled / 3/13 (23.1%) completers reported headache
HeadacheAdverse23% of completers — transient mild-to-moderate, resolved within 1-3 days
Slight head tightness leading to dropoutAdverse1/15 (6.7%)
TMS intolerance leading to dropoutAdverse1/15 (6.7%)
Serious AEAdverseNone reported
IntensitiesAdverseBelow FDA guideline limits

Subgroup Analysis

Acoustic field simulations showed sonication covered not only GPi but also external GP and putamen, so observed effects cannot be attributed solely to GPi

Criticisms

  • Very small sample (n=13 completers) limits power and generalizability
  • Single-center (Toronto, Canada); cohort clinically heterogeneous
  • On-medication state only — effects in off-medication state unknown; dopaminergic therapy may have limited observable improvement
  • Excluded patients with severe tremor or dyskinesia, narrowing generalizability
  • Acoustic field also covered external GP and putamen — effects cannot be solely attributed to GPi
  • Short follow-up (30 min for motor outcome) — durability unknown
  • ANOVA condition×time interaction for MDS-UPDRS-III was non-significant (p=0.204); GPi benefit demonstrated only by within-condition contrast
  • Participant blinding to sonication condition not explicitly described
  • Condition order partially constrained (dual-site last in first 7 patients)

Funding

Parkinson's Foundation fellowship (A.B.); University Health Network REB #20-5740

Based on: GPi tbTUS in PD (Movement Disorders, 2026)

Authors: Lin YY et al.

Citation: Mov Disord. 2026 Feb; DOI:10.1002/mds.70095

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