Journal Club · Functional Neurosurgery

Staged Bilateral Focused Ultrasound for Parkinson Disease

The pivotal multicentre trial behind the FDA approval of staged bilateral treatment, and an unusually candid account of what the second side costs.

A trainee reading of the prospective, multicentre, single-arm trial of staged bilateral MR-guided focused ultrasound (MRgFUS) pallidothalamic tractotomy for Parkinson disease (Dalvi and colleagues, Lancet Neurology 2026), the study that supported FDA approval of staged bilateral treatment, and what it does, and does not, license us to offer.

Dalvi, Lancet Neurol 2026 NCT04728295

Why This Trial

The FDA approved staged bilateral pallidothalamic tractotomy (PTT) for selected patients with Parkinson disease in July 2025. This was not the first staged bilateral focused-ultrasound approval: staged bilateral thalamotomy for essential tremor was approved in December 2022. This trial helps frame the potential benefit and persistent speech, gait, and balance problems associated with a second PTT procedure.

One-Line Takeaway

In this single-arm study, unilateral treatment was associated with improvement in Parkinson motor complications. The authors reported smaller additional motor gains after the second procedure and more persistent adverse events. The unilateral and bilateral safety observations use different follow-up times and selected, overlapping cohorts; they do not provide a directly comparable relative-risk estimate.

Part I

The Question and the Design

1.The target and the rationale

The pallidothalamic tract carries the inhibitory output of the internal globus pallidus (GPi) toward the motor thalamus: the ansa and fasciculus lenticularis converging in the field of Forel. Lesioning it (a modern revival of the historical campotomy) interrupts excessive pallidal outflow and releases thalamocortical motor activity, the same physiologic goal as GPi DBS or pallidotomy but at a smaller, deeper target. Unilateral PTT was already known to help; the open question this trial set out to answer was whether the second side could be added with an acceptable risk–benefit balance, given the long, hard-won lesson that bilateral basal-ganglia ablation tends to harm speech, gait, and swallowing.

PTT Targeting in Brief: Forel's Field H1 The target is white matter, not a nucleus: the pallidothalamic tract as it passes through Forel's field H1 (the thalamic fasciculus) just below the thalamus, at or ~1 mm below the AC–PC plane. It is found indirectly: anchored to two structures visible on T2, the mammillothalamic tract (MTT) medially and the subthalamic nucleus (STN) inferolaterally (the tract sits above the STN, lateral to the MTT), with an atlas overlay refining a coordinate estimate (~8–10 mm lateral) that must be re-anchored per patient. With MRgFUS the lesion is assembled from 5–7 small sub-units (~1.5 × 1.5 × 3 mm) along the tract, each tested at sub-ablative temperature for benefit and for side effects from the neighbors (paresthesia = sensory thalamus/lemniscus; pull or slurring = internal capsule; diplopia = red nucleus) before the permanent lesion. There is no standard DBS version of PTT: the same circuit is engaged at GPi upstream, or with a caudal-zona-incerta / posterior-subthalamic-area lead near Forel's field H. (Full step-by-step on the Focused Ultrasound for Parkinson Disease reference page.)

2.Study design and population

This was a prospective, multicentre, single-arm trial at 9 centres (six in the USA, two in Spain, one in Taiwan), enrolling adults with idiopathic, levodopa-responsive (≥ 30% improvement) Parkinson disease and motor complications (MDS-UPDRS part IV item 4.2 or 4.4 score ≥ 2). Patients underwent unilateral PTT to the symptom-dominant side; those meeting prespecified criteria proceeded to contralateral PTT a minimum of 6 months later. A radiographic skull density ratio below 0.40 was an exclusion (the bone gate common to all transcranial focused ultrasound). Recruitment ran July 12, 2021 to November 1, 2023; the trial was funded by the device manufacturer (Insightec).

Numbers. 54 patients received unilateral treatment; 40 proceeded to bilateral treatment; 36 completed 12-month follow-up after the second procedure.
Primary endpoint. Percent change from baseline to 3 months after the second procedure in the summed off-medication MDS-UPDRS part III upper- and lower-extremity (ULE) motor score.
Confirmatory/secondary endpoints. Percent change in the MDS-UPDRS part III off-medication total score and in the part IV (motor-complications) total score, plus item-level analyses of dyskinesia and fluctuation time.
A built-in safety feature. Because the lesion is made under live MR thermometry, the target is first tested at sub-ablative temperature (thermal neuromodulation below ~48°C), giving a reversible preview before anything is destroyed.

Part II

What They Found

3.Efficacy: a real benefit, mostly from the first side

On the primary endpoint, the summed bilateral off-medication ULE motor score fell from a median of 33.0 (IQR 28.0–40.5) at baseline to 21.0 (15.0–25.5) at 3 months after the second procedure: a median within-patient improvement of 32% (IQR 18–52; P<0.0001). Benefit appeared within one month of the first procedure and was sustained through 12 months after the second. Crucially, much of the total benefit was captured by the first side : the second side moved patients only a small increment beyond this unilateral plateau. Motor-complication measures (part IV) and off-medication total scores improved as well.

4.Safety: the heart of the paper

The safety signal is candid and is the reason to read the trial closely:

After unilateral treatment: treatment-related adverse events in 21 of 54 (39%), with 1 of 54 patients (2%) having a persistent moderate event at 6 months.
After bilateral treatment: treatment-related adverse events in 22 of 40 (55%), and, the key number, 10 of 40 (25%) had persistent moderate or severe events at 12 months, predominantly affecting speech, gait, and balance.
Worst case: one of 40 patients (reported as 3%) developed severe persistent anarthria.

Interpretation: 1/54 (2%) refers to persistent moderate adverse events at 6 months after unilateral treatment; 10/40 (25%) refers to persistent moderate or severe events at 12 months after bilateral treatment. These are different follow-up windows and selected, overlapping cohorts. A simple fold-increase would misrepresent this comparison.

Part III

Appraisal

5.The results at a glance

Measure	Unilateral	Bilateral (staged)
Off-medication motor improvement	Improvement reported; different measure from the bilateral endpoint	32% (summed ULE, primary endpoint; P<0.0001)
Treatment-related adverse events	39% (21/54)	55% (22/40)
Persistent adverse events (definitions and follow-up differ)	Moderate: 1/54 (2%) at 6 months	Moderate or severe: 10/40 (25%) at 12 months; predominantly speech, gait, balance
Onset / durability	Benefit within 1 month; sustained to 12 months
Eligibility	Levodopa-responsive PD with motor complications; skull density ratio ≥ 0.40

6.Strengths and limitations

Strengths The first systematic, prospective, multicentre evaluation of staged bilateral PTT, with independent adverse-event monitoring and 12-month follow-up. Incisionless and hardware-free, with a reversible sub-ablative test phase. Reporting is refreshingly honest about the unfavourable bilateral risk–benefit ratio rather than emphasising the headline efficacy.

Limitations Single-arm and unblinded, no randomised comparator (notably no head-to-head against bilateral DBS, the obvious alternative), so motor gains and the placebo-sensitive endpoints must be read with caution. The lesion is irreversible and non-adjustable. The sample is modest (40 bilateral) and enriched by per-protocol selection of who advanced to the second side. Manufacturer-funded. Follow-up is 12 months: durability and late speech/gait effects beyond a year are unknown.

Questions For The Table

How should the additional motor benefit be weighed against the moderate or severe treatment-related adverse events persisting at 12 months in 10 of 40 bilaterally treated participants (25%)? How might patient selection affect whether those results apply to an individual patient?
How should staged bilateral PTT be positioned against bilateral DBS, which has adjustable stimulation but carries surgical and hardware risks, and was not directly compared in this trial?
Who is the right candidate for a second side, and who should stop at one?
How do we counsel honestly about an irreversible bilateral lesion while clearly explaining the observed persistent adverse events and the limits of the unilateral–bilateral comparison?
Does the low skull density ratio exclusion (< 0.40), and the deeper PTT target, change who can be offered this at all?

This is the pivotal trial behind the FDA approval of staged bilateral MRgFUS pallidothalamic tractotomy for Parkinson disease: multicentre and prospective, but single-arm and manufacturer-funded.
Unilateral treatment was associated with motor improvement. Persistent moderate adverse events were reported in 1/54 patients (2%) at 6 months; this does not establish comparative safety or eliminate procedural risk.
The primary bilateral result was a 32% summed motor improvement (P<0.0001), but most benefit came from the first side; the second added only a small increment beyond the unilateral plateau.
After bilateral treatment, 10/40 patients (25%) had persistent moderate or severe adverse events at 12 months, predominantly affecting speech, gait, and balance; one patient had severe persistent anarthria.
Use the trial to support careful selection and counselling within the approved indication. Discuss alternatives, including DBS, without inferring superiority from this uncontrolled study.

Selected References

Dalvi A, Eisenberg HM, Wu P, 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. The trial discussed here; behind the July 2025 FDA approval (NCT04728295).
Krishna V, Fishman PS, Eisenberg HM, et al. Trial of globus pallidus focused ultrasound ablation in Parkinson's disease. N Engl J Med. 2023;388(8):683–693. Pivotal unilateral pallidotomy trial.
Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease. JAMA Neurol. 2017;74(12):1412–1418. Basis for the 2018 tremor-dominant PD approval.
Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R, et al. Randomized trial of focused ultrasound subthalamotomy for Parkinson's disease. N Engl J Med. 2020;383(26):2501–2513. The randomised STN comparator: still investigational in the US.

Editorial review: September 18, 2026. The safety numerators, denominators, categories, follow-up times, and citation were checked against the published abstract. The inaccurate “roughly tripling” statement and other direct fold comparisons were removed. This review did not include access to the full article or full correction text. A publisher correction is indexed; consult the corrected publication before using detailed results in clinical teaching. FDA context: July 2025 approval. This is educational commentary, not a treatment directive.