Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

Neuromodulation in the Treatment of Alzheimer's Disease: Current and Emerging Approaches.

Neuromodulation as a treatment strategy for psychiatric and neurological diseases has grown in popularity in recent years, with the approval of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression being one such example. These approaches offer new hope in the treatment of diseases that have proven largely intractable to traditional pharmacological approaches. For this reason, neuromodulation is increasingly being explored for the treatment of Alzheimer's disease. However, such approaches have variable, and, in many cases, very limited evidence for safety and efficacy, with most human evidence obtained in small clinical trials. Here we review work in animal models and humans with Alzheimer's disease exploring emerging neuromodulation modalities. Approaches reviewed include deep brain stimulation, transcranial magnetic stimulation, transcranial electrical stimulation, ultrasound stimulation, photobiomodulation, and visual or auditory stimulation. In doing so, we clarify the current evidence for these approaches in treating Alzheimer's disease and identify specific areas where additional work is needed to facilitate their clinical translation.

Cost-effectiveness analysis of MR-guided focused ultrasound thalamotomy for tremor-dominant Parkinson's disease.

OBJECTIVE: The development of transcranial MR-guided focused ultrasound (MRgFUS) has revitalized the practice of lesioning procedures in functional neurosurgery. Previous health economic analysis found MRgFUS thalamotomy to be a cost-effective treatment for patients with essential tremor, supporting its reimbursement. With the publication of level I evidence in support of MRgFUS thalamotomy for patients with tremor-dominant Parkinson's disease (TDPD), the authors performed a health economic comparison between MRgFUS, deep brain stimulation (DBS), and medical therapy. METHODS: The authors used a decision tree model with rollback analysis and one-factor sensitivity analysis. Literature searches of MRgFUS thalamotomy and unilateral DBS of the ventrointermediate nucleus of the thalamus for TDPD were performed to determine the utility and probabilities for the model. Costs in Canadian dollars (CAD) were derived from the Schedule of Benefits and Fees in Ontario, Canada, and expert opinion on usage. RESULTS: MRgFUS was associated with an expected cost of $14,831 CAD. Adding MRgFUS to continued medical therapy resulted in an incremental cost-effectiveness ratio of $30,078 per quality-adjusted life year (QALY), which remained cost-effective under various scenarios in the sensitivity analysis. Comparing DBS to MRgFUS, while DBS did not achieve the willingness-to-pay threshold ($56,503 per QALY) in the base case scenario, it did so under several scenarios in the sensitivity analysis. CONCLUSIONS: MRgFUS thalamotomy is a cost-effective treatment for patients with TDPD, particularly over continued medical therapy. While MRgFUS remains competitive with DBS, the cost-effectiveness advantage is less substantial. These results will help inform the integration of this technology in the healthcare system.

Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases.

Low-intensity MR-guided focused ultrasound in combination with intravenously injected microbubbles is a promising platform for drug delivery to the central nervous system past the blood-brain barrier. The blood-brain barrier is a key bottleneck for cancer therapeutics via limited inter- and intracellular transport. Further, drugs that cross the blood-brain barrier when delivered in a spatially nonspecific way, result in adverse effects on normal brain tissue, or at high concentrations, result in increasing risks to peripheral organs. As such, various anti-cancer drugs that have been developed or to be developed in the future would benefit from a noninvasive, temporary, and repeatable method of targeted opening of the blood-brain barrier to treat metastatic brain diseases. MR-guided focused ultrasound is a potential solution to these design requirements. The safety, feasibility and preliminary efficacy of MRgFUS aided delivery have been demonstrated in various animal models. In this review, we discuss this preclinical evidence, mechanisms of focused ultrasound mediated blood-brain barrier opening, and translational efforts to neuro-oncology patients.