Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results.

OBJECTIVE: The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS: Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported. RESULTS: Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported. CONCLUSIONS: Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov).

American Society for Stereotactic and Functional Neurosurgery Position Statement on Magnetic Resonance-Guided Focused Ultrasound for the Management of Essential Tremor.

Magnetic resonance-guided focused ultrasound thalamotomy is a novel tool in the neurosurgical armamentarium for management of essential tremor (ET). Given the recent introduction of this technology, the American Society of Stereotactic and Functional Neurosurgery (ASSFN), which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, provides here the expert consensus opinion on evidence-based best practices for the use and implementation of this treatment modality. Indications for treatment are outlined, including confirmed diagnosis of ET, failure to respond to first-line therapies, disabling appendicular tremor, and unilateral treatment are detailed, based on current evidence. Contraindications to therapy are also detailed. Finally, the evidence and authority on which the ASSFN bases this consensus position statement is detailed.

Three-year follow-up of prospective trial of focused ultrasound thalamotomy for essential tremor.

OBJECTIVE: To test the hypothesis that transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy is effective, durable, and safe for patients with medication-refractory essential tremor (ET), we assessed clinical outcomes at 3-year follow-up of a controlled multicenter prospective trial. METHODS: Outcomes were based on the Clinical Rating Scale for Tremor, including hand combined tremor-motor (scale of 0-32), functional disability (scale of 0-32), and postural tremor (scale of 0-4) scores, and total scores from the Quality of Life in Essential Tremor Questionnaire (scale of 0-100). Scores at 36 months were compared with baseline and at 6 months after treatment to assess for efficacy and durability. Adverse events were also reported. RESULTS: Measured scores remained improved from baseline to 36 months (all p < 0.0001). Range of improvement from baseline was 38%-50% in hand tremor, 43%-56% in disability, 50%-75% in postural tremor, and 27%-42% in quality of life. When compared to scores at 6 months, median scores increased for hand tremor (95% confidence interval [CI] 0-2, p = 0.0098) and disability (95% CI 1-4, p = 0.0001). During the third follow-up year, all previously noted adverse events remained mild or moderate, none worsened, 2 resolved, and no new adverse events occurred. CONCLUSIONS: Results at 3 years after unilateral tcMRgFUS thalamotomy for ET show continued benefit, and no progressive or delayed complications. Patients may experience mild degradation in some treatment metrics by 3 years, though improvement from baseline remains significant. CLINICALTRIALSGOV IDENTIFIER: NCT01827904. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with severe ET, unilateral tcMRgFUS thalamotomy provides durable benefit after 3 years.

The potential value of probabilistic tractography-based for MR-guided focused ultrasound thalamotomy for essential tremor.

Magnetic Resonance-guided Focused UltraSound (MRgFUS) offers an incisionless approach to treat essential tremor (ET). Due to lack of evident internal anatomy on traditional structural imaging, indirect targeting must still be used to localize the lesion. Here, we investigate the potential predictive value of probabilistic tractography guided thalamic targeting by defining how tractography-defined targets, lesion size and location, and clinical outcomes interrelate. MR imaging and clinical outcomes from 12 ET patients that underwent MRgFUS thalamotomy in a pilot study at the University of Virginia were evaluated in this analysis. FSL was used to evaluate each patient's voxel-wise thalamic connectivity with FreeSurfer generated pre- and post-central gyrus targets, to generate thalamic target maps. Using Receiver Operating Characteristic curves, the overlap between these thalamic target maps and the MRgFUS lesion was systematically evaluated relative to clinical outcome. To further define the connectivity characteristics of effective MRgFUS thalamotomy lesions, we evaluated whole brain probabilistic tractography of lesions (using post-treatment imaging to define the lesion pre-treatment diffusion tensor MRI). The structural connectivity difference was explored between subjects with the best clinical outcome relative to all others. Ten of twelve patients presented high percentage of overlapping between connectivity-based thalamic segmentation maps and lesion area. The improvement of clinical score was predicted (AUC: 0.80) using the volume of intersection between the thalamic target (precentral gyrus) map and MRgFUS induced lesion as feature. The main structural differences between those with different magnitudes of response were observed in connectivity to the pre- and post-central gyri and brainstem/cerebellum. MRgFUS thalamotomy lesions characterized by strong structural connectivity to precentral gyrus demonstrated better responses in a cohort of patients treated with MRgFUS for ET. The intersection between lesion and thalamic-connectivity maps to motor - sensory targets proved to be effective in predicting the response to the therapy. These imaging techniques can be used to increase the efficacy and consistency of outcomes with MRgFUS and potentially shorten treatment times by identifying optimal targets in advance of treatment.

Functional assessment and quality of life in essential tremor with bilateral or unilateral DBS and focused ultrasound thalamotomy.

BACKGROUND: Thalamic deep brain stimulation (DBS) has largely replaced radiofrequency thalamotomy as the treatment of choice for disabling, medication-refractory essential tremor. Recently, the development of transcranial, high-intensity focused ultrasound has renewed interest in thalamic lesioning. The purpose of this study is to compare functional outcomes and quality of life in essential tremor patients treated with either bilateral Vim DBS or unilateral procedures (focused ultrasound or DBS). We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire. METHODS: This is a retrospective study of medication-refractory essential tremor patients treated at the University of Virginia with bilateral Vim DBS (n = 57), unilateral Vim DBS (n = 13), or unilateral focused ultrasound Vim thalamotomy (n = 15). Tremor was rated for all patients before and after treatment, using the Clinical Rating Scale for Tremor and Quality of Life in Essential Tremor Questionnaire. RESULTS: Patients undergoing bilateral DBS treatment had more baseline tremor and worse quality of life scores. Patients had significant improvements in tremor symptoms and quality of life with all three treatments. Both DBS procedures improved axial tremor. No difference was seen in the degree of improvement in upper extremity tremor score, disability, or overall quality of life between bilateral and either unilateral procedure. CONCLUSIONS: Bilateral thalamic DBS improves overall tremor more than unilateral DBS or focused ultrasound treatment; however, unilateral treatments are equally effective in treating contralateral hand tremor. Despite the greater overall tremor reduction with bilateral DBS, there is no difference in disability or quality of life comparing bilateral versus unilateral treatments.

Human thalamus regulates cortical activity via spatially specific and structurally constrained phase-amplitude coupling.

Although the thalamus is believed to regulate and coordinate cortical activity both within and across functional regions, such as motor and visual cortices, direct evidence for such regulation and the mechanism of regulation remains poorly described. Using simultaneous invasive recordings of cortical and thalamic electrophysiological activity in 2 awake and spontaneously behaving human subjects, we provide direct evidence of thalamic regulation of cortical activity through a mechanism of phase-amplitude coupling (PAC), in which the phase of low frequency oscillations regulates the amplitude of higher frequency oscillations. Specifically, we show that cortical PAC between the theta phase and beta amplitude is spatially dependent on and time variant with the magnitude of thalamocortical theta coherence. Moreover, using causality analysis and MR diffusion tractography, we provide evidence that thalamic theta activity drives cortical theta oscillations and PAC across structures and that these thalamocortical relationships are structurally constrained by anatomic pathways. This relationship allows for new evidence of thalamocortical PAC. Given the diffuse connectivity of the thalamus with the cerebral cortex, thalamocortical PAC may play an important role in addressing the binding problem, including both integration and segregation of information within and across cortical areas.

Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.

PURPOSE: To use diffusion-tensor (DT) magnetic resonance (MR) imaging in patients with essential tremor who were treated with transcranial MR imaging-guided focused ultrasound lesion inducement to identify the structural connectivity of the ventralis intermedius nucleus of the thalamus and determine how DT imaging changes correlated with tremor changes after lesion inducement. MATERIALS AND METHODS: With institutional review board approval, and with prospective informed consent, 15 patients with medication-refractory essential tremor were enrolled in a HIPAA-compliant pilot study and were treated with transcranial MR imaging-guided focused ultrasound surgery targeting the ventralis intermedius nucleus of the thalamus contralateral to their dominant hand. Fourteen patients were ultimately included. DT MR imaging studies at 3.0 T were performed preoperatively and 24 hours, 1 week, 1 month, and 3 months after the procedure. Fractional anisotropy (FA) maps were calculated from the DT imaging data sets for all time points in all patients. Voxels where FA consistently decreased over time were identified, and FA change in these voxels was correlated with clinical changes in tremor over the same period by using Pearson correlation. RESULTS: Ipsilateral brain structures that showed prespecified negative correlation values of FA over time of -0.5 or less included the pre- and postcentral subcortical white matter in the hand knob area; the region of the corticospinal tract in the centrum semiovale, in the posterior limb of the internal capsule, and in the cerebral peduncle; the thalamus; the region of the red nucleus; the location of the central tegmental tract; and the region of the inferior olive. The contralateral middle cerebellar peduncle and bilateral portions of the superior vermis also showed persistent decrease in FA over time. There was strong correlation between decrease in FA and clinical improvement in hand tremor 3 months after lesion inducement (P < .001). CONCLUSION: DT MR imaging after MR imaging-guided focused ultrasound thalamotomy depicts changes in specific brain structures. The magnitude of the DT imaging changes after thalamic lesion inducement correlates with the degree of clinical improvement in essential tremor.

A magnetic resonance imaging, histological, and dose modeling comparison of focused ultrasound, radiofrequency, and Gamma Knife radiosurgery lesions in swine thalamus.

OBJECT: The purpose of this study was to use MRI and histology to compare stereotactic lesioning modalities in a large brain model of thalamotomy. METHODS: A unilateral thalamotomy was performed in piglets utilizing one of 3 stereotactic lesioning modalities: focused ultrasound (FUS), radiofrequency, and radiosurgery. Standard clinical lesioning parameters were used for each treatment; and clinical, MRI, and histological assessments were made at early (< 72 hours), subacute (1 week), and later (1-3 months) time intervals. RESULTS: Histological and MRI assessment showed similar development for FUS and radiofrequency lesions. T2-weighted MRI revealed 3 concentric lesional zones at 48 hours with resolution of perilesional edema by 1 week. Acute ischemic infarction with macrophage infiltration was most prominent at 72 hours, with subsequent resolution of the inflammatory reaction and coalescence of the necrotic zone. There was no apparent difference in ischemic penumbra or "sharpness" between FUS or radiofrequency lesions. The radiosurgery lesions presented differently, with latent effects, less circumscribed lesions at 3 months, and apparent histological changes seen in white matter beyond the thalamic target. Additionally, thermal and radiation lesioning gradients were compared with modeling by dose to examine the theoretical penumbra. CONCLUSIONS: In swine thalamus, FUS and radiosurgery lesions evolve similarly as determined by MRI, histological examination, and theoretical modeling. Radiosurgery produces lesions with more delayed effects and seemed to result in changes in the white matter beyond the thalamic target.

Multi-institutional evaluation of deep brain stimulation targeting using probabilistic connectivity-based thalamic segmentation.

OBJECT: Due to the lack of internal anatomical detail with traditional MR imaging, preoperative stereotactic planning for the treatment of tremor usually relies on indirect targeting based on atlas-derived coordinates. The object of this study was to preliminarily investigate the role of probabilistic tractography-based thalamic segmentation for deep brain stimulation (DBS) targeting for the treatment of tremor. METHODS: Six patients undergoing bilateral implantation of DBS electrodes in the thalamus for the treatment of upper-extremity tremor were studied. All patients underwent stereotactic surgical implantation using traditional methods (based on indirect targeting methodologies and intraoperative macrostimulation findings) that were programmed for optimal efficacy, independent of tractography-based segmentations described in this report. Connectivity-based thalamic segmentations were derived by identifying with which of 7 cortical target regions each thalamic voxel had the highest probability of connectivity. The authors retrospectively analyzed the location of the optimal contact for treatment of tremor with connectivity-based thalamic segmentations. Findings from one institution (David Geffen School of Medicine at UCLA) were validated with results from 4 patients at another institution (University of Virginia Health System). RESULTS: Of 12 electrodes implanted using traditional methodologies, all but one resulted in efficacious tremor control. Connectivity-based thalamic segmentation consistently revealed discrete thalamic regions having unique connectivity patterns with distinct cortical regions. Although the authors initially hypothesized that the most efficacious DBS contact for controlling tremor would colocalize with the thalamic region most highly connected with the primary motor cortex, they instead found it to highly colocalize with those thalamic voxels demonstrating a high probability of connectivity with premotor cortex (center-to-center distance: 0.36 ± 0.55 mm). In contrast to the high degree of colocalization with optimal stimulation site, the precise localization of the premotor cortex-defined thalamic region relative to the anterior and posterior commissures was highly variable. Having defined a connectivity-based target for thalamic stimulation in a cohort of patients at David Geffen School of Medicine at UCLA, the authors validated findings in 4 patients (5 electrodes) who underwent surgery at a different institution (University of Virginia Health System) by a different surgeon. CONCLUSIONS: This report identifies and provides preliminary external validation of a novel means of targeting a patient-specific therapeutic thalamic target for the treatment of tremor based on individualized analysis of thalamic connectivity patterns. This novel thalamic targeting approach is based on identifying the thalamic region with the highest probability of connectivity with premotor and supplementary motor cortices. This approach may prove to be advantageous over traditional preoperative methods of indirect targeting, providing patient-specific targets that could improve the precision, efficacy, and efficiency of deep brain stimulation surgery. Prospective evaluation and development of methodologies to make these analyses more widely available to neurosurgeons are likely warranted.