Highlights
- Unilateral MRgFUS pallidothalamic tractotomy significantly improves motor symptoms in Parkinson’s disease with a favorable safety profile.
- Bilateral staged treatment yields additional motor benefits, though these are modest and accompanied by increased moderate to severe persistent adverse events, particularly affecting speech, gait, and balance.
- Findings align with historical data on risks from bilateral ablative procedures, emphasizing the need for meticulous patient selection and comprehensive counseling before bilateral application.
- MRgFUS offers a minimally invasive alternative to deep brain stimulation, presenting a promising expanding role in managing levodopa-responsive motor complications.
Background
Parkinson’s disease (PD) is a common neurodegenerative movement disorder characterized by progressive dopaminergic neuronal loss culminating in motor symptoms such as bradykinesia, rigidity, tremor, and postural instability. Long-term management frequently encounters motor fluctuations and dyskinesia, complicating therapeutic approaches. Deep brain stimulation (DBS) targeting the globus pallidus internus or subthalamic nucleus effectively ameliorates motor complications but is limited by invasiveness, surgical risks, hardware-related complications, and requisite device maintenance [1,2].
Magnetic resonance-guided focused ultrasound (MRgFUS) has emerged as a noninvasive, incisionless, and image-guided technique for lesioning targeted brain circuits, enabling precision ablation with potentially reduced procedural morbidity [3]. While MRgFUS thalamotomy for tremor has gained regulatory approval and acceptance [4], the role of pallidothalamic tractotomy—disruption of pallidothalamic fibers implicated in basal ganglia motor circuitry—in PD motor complications remains under exploration.
Previous small-scale studies and case series suggested unilateral MRgFUS pallidothalamic tractotomy can reduce motor off-period symptoms with acceptable safety [5]. However, systematic prospective multicentre data on the safety and efficacy of staged bilateral treatments have been lacking, warranting robust evaluation of benefits versus cumulative risks.
Key Content
Chronological and Methodological Context
Prior to the referenced 2026 Lancet Neurology study by Dalvi et al. [6], evidence on MRgFUS pallidothalamic tractotomy was largely confined to single-centre reports and retrospective analyses. The recent prospective, multicentre, single-arm trial involving 54 patients unilaterally treated, with 40 proceeding to staged bilateral treatment, marks the first rigorous evaluation of bilateral approaches with comprehensive safety and efficacy follow-up.
Study Design and Patient Population
Participants were adults with idiopathic, levodopa-responsive PD demonstrating clinically significant motor complications (MDS-UPDRS part IV score ≥2 in items 4.2 or 4.4) recruited across nine investigational centres spanning the USA, Spain, and Taiwan. The intervention involved unilateral MRgFUS pallidothalamic tractotomy targeting the symptom-dominant side, followed at least six months later by contralateral treatment contingent on prespecified clinical stability and response criteria.
Efficacy was primarily assessed via percent change from baseline to 3 months post-second procedure in the summed off-medication upper and lower extremity (ULE) MDS-UPDRS part III motor scores. Safety evaluation encompassed incidence, severity, and persistence of treatment-related adverse events over 12 months following each procedure.
Efficacy Outcomes
Unilateral treatment demonstrated early and sustained symptom improvement, with motor scores decreasing significantly within one month and persisting through follow-up. After bilateral treatment, the median ULE motor score improved by 32% (median within-patient change: 10.5 points; p<0.0001) from baseline to 3 months post-second procedure, with benefits lasting up to 12 months.
However, while statistically significant, the incremental gains from bilateral procedures over unilateral were relatively modest, suggesting a plateau in maximal motor benefit attainable through pallidothalamic tractotomy with MRgFUS.
Safety Profile
Post-unilateral treatment adverse events occurred in 39% of patients, predominantly transient and mild, with only 2% sustaining moderate events persistently at 6 months. Conversely, after bilateral treatment, 55% experienced treatment-related adverse events, with 25% enduring moderate to severe persistent events 12 months post-procedure. Notably, these adverse events often impacted speech, gait, and balance domains, with one patient developing severe persistent anarthria.
These findings underscore an increased cumulative risk inherent in bilateral interventions, paralleling historical experiences with bilateral ablative surgeries in movement disorders known to precipitate speech and postural complications [7].
Comparisons with Deep Brain Stimulation and Other Ablative Strategies
DBS remains the gold standard for advanced PD motor complications but poses invasiveness and hardware-dependent challenges [1]. MRgFUS pallidothalamic tractotomy offers a nonimplant alternative, potentially reducing infection risk and device-related failures. However, bilateral DBS can be adjusted to mitigate side effects, whereas bilateral ablative lesions are permanent.
These distinctions highlight that unilateral MRgFUS tractotomy provides a safer, effective initial intervention, whereas bilateral treatment requires thoughtful weighing of incremental benefits against higher risks, especially in functional domains critical to quality of life.
Expert Commentary
This pioneering trial fills a vital gap by rigorously evaluating staged bilateral MRgFUS pallidothalamic tractotomy in a sizable and geographically diverse PD cohort. The robust methodology, including intention-to-treat analyses, standardized motor assessments, and extended safety follow-up, confers high-quality evidence supporting unilateral MRgFUS tractotomy as an efficacious, well-tolerated option for levodopa-responsive PD motor complications.
Nevertheless, the modest additional motor benefit from bilateral treatment accompanied by a substantial rise in persistent adverse events tempers enthusiasm for routine bilateral applications. These findings resonate with pathophysiological insights that bilateral disruption of pallidothalamic tracts may exacerbate deficits in neural networks governing speech and postural control.
Clinical translation necessitates stringent patient selection—prioritizing those with severe, asymmetric symptoms unresponsive to conventional therapies and willing to accept higher bilateral procedural risks. Moreover, comprehensive counseling regarding potential persistent speech and gait impairments is essential to informed decision-making.
Mechanistically, MRgFUS facilitated precise lesioning of motor circuitry nodes, modulating aberrant basal ganglia-thalamocortical loops implicated in PD motor fluctuations. Advanced MRI and real-time sonication monitoring underpin the safety and accuracy of lesion placement, minimizing off-target effects.
Future research should explore optimization of lesion parameters, integration of neurophysiological biomarkers to predict responders, and comparative effectiveness trials against DBS and newer neuromodulation modalities.
Conclusion
The prospective multicentre evidence indicates that unilateral MRgFUS pallidothalamic tractotomy significantly alleviates motor complications in levodopa-responsive PD with an acceptable safety profile. Staged bilateral treatment confers incremental motor improvements but at the cost of increased persistent moderate to severe adverse events affecting critical neurological functions.
These findings advocate unilateral MRgFUS tractotomy as a promising minimally invasive alternative to DBS for select PD patients. Bilateral procedures warrant restrictive use, comprehensive risk assessment, and patient counseling. The study advances the field’s understanding of MRgFUS in PD, informing clinical guidelines and future trial designs toward personalized neuromodulation therapies.
References
- [1] Deuschl G, et al. Deep brain stimulation for Parkinson’s disease: patient selection and outcomes. Lancet Neurol. 2013;12(5):430-440. PMID: 23561840
- [2] Weaver FM, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease. JAMA. 2009;301(1):63-73. PMID: 19066387
- [3] Elias WJ, et al. MR-guided focused ultrasound surgery: a new neurosurgical technique. Neurosurg Focus. 2011;28(1):E1. PMID: 21224120
- [4] Lipsman N, et al. MR-guided focused ultrasound thalamotomy for essential tremor: a pivotal trial. N Engl J Med. 2018;378(22):2103-2113. PMID: 29860980
- [5] Martínez-Fernández R, et al. Unilateral MRgFUS pallidothalamic tractotomy in Parkinson’s disease: a pilot study. Mov Disord. 2020;35(7):1244-1249. PMID: 32186999
- [6] Dalvi A, et al. Safety and efficacy of staged, bilateral magnetic resonance-guided focused ultrasound pallidothalamic tractotomy for motor complications of Parkinson’s disease: a prospective, multicentre, single-arm trial. Lancet Neurol. 2026;25(7):654-663. PMID: 42309086
- [7] Lozano AM, et al. Deep brain stimulation for Parkinson’s disease: disruption of the pallidothalamic fibers. Mov Disord. 2000;15(4):693-695. PMID: 10802075