Probabilistic Refinement of Focused Ultrasound Thalamotomy Targeting for Parkinson's Disease Tremor.

BACKGROUND: There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD). OBJECTIVE: Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET. METHODS: We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients. RESULTS: The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute < 0.05), with peak TDPD improvement (87%) at x = -13.5; y = -15.0; z = 1.5, ~3.5 mm anterior and 3 mm dorsal to the ET target. Discriminative connectivity projections were to the motor and premotor regions in TDPD, and to the motor and somatosensory regions in ET. The disorder-specific voxel-wise efficacy map could be used to estimate outcome in TDPD patients with high accuracy (R = 0.8; R2 = 0.64; P < 0.0001). The model was validated using the independent cohort of nine TDPD patients (R = 0.73; R2 = 0.53; P = 0.025-voxel analysis). CONCLUSION: We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Essential Tremor.

This JAMA Insights discusses the diagnostic evaluation and treatment, including pharmacological, nonpharmacological, and surgical options, of essential tremor.

Bilateral focused ultrasound medial thalamotomies for trigeminal neuropathic pain: a randomized controlled study.

OBJECTIVE: Medial thalamotomy has been shown to benefit patients with neuropathic pain, but widespread adoption of this procedure has been limited by reporting of clinical outcomes in studies without a control group. This study aimed to minimize confounders associated with medial thalamotomy for treating chronic pain by using modern MRI-guided stereotactic lesioning and a rigorous clinical design. METHODS: This prospective, double-blinded, randomized controlled trial in 10 patients with trigeminal neuropathic pain used sham procedures as controls. Participants underwent assessments by a pain psychologist and pain management clinician, including use of the following measures: the Numeric Pain Rating Scale (NPRS); patient-reported outcome measures; and patient's impression of improvement at baseline, 1 day, 1 week, 1 month, and 3 months postprocedure. Patients in the treated group underwent bilateral focused ultrasound (FUS) medial thalamotomy targeting the central lateral nucleus. Patients in the control group underwent sham procedures with energy output disabled. The primary efficacy outcome measure was between-group differences in pain intensity (using the NPRS) at baseline and at 3 months postprocedure. Adverse events were measured for safety and included MRI analysis. Exploratory measures of connectivity and metabolism were analyzed using diffusion tensor imaging, functional MRI, and PET, respectively. RESULTS: There were no serious complications from the FUS procedures. MRI confirmed bilateral medial thalamic ablations. There was no significant improvement in pain intensity from baseline to 3 months, either for patients undergoing FUS medial thalamotomy or for sham controls; and the between-group change in NPRS score as the primary efficacy outcome measure was not significantly different. Patient-reported outcome assessments demonstrated improvement (i.e., a decrease) only in pain interference with enjoyment of life at 3 months. There was a perception of benefit at 1 week, but only for patients treated with FUS and not for the sham cohort. Advanced neuroimaging showed that these medial thalamic lesions altered structural connectivity with the postcentral gyrus and demonstrated a trend toward hypometabolism in the insula and amygdala. CONCLUSIONS: This randomized controlled trial of bilateral FUS medial thalamotomy did not reduce the intensity of trigeminal neuropathic pain, although it should be noted that the ability to estimate the magnitude of treatment effects is limited by the small cohort.

Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor: An Open-Label Clinical Trial.

Importance: Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option. Objective: To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy. Design, Setting, and Participants: This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category). Intervention: A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation. Main Outcomes and Measures: Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months. Results: The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient. Conclusions and Relevance: Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient. Trial Registration: ClinicalTrials.gov Identifier NCT04112381.