Impact of skull density ratio on efficacy and safety of magnetic resonance–guided focused ultrasound treatment of essential tremor

Marissa D’Souza Departments of Neurosurgery and

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Kevin S. Chen Departments of Neurosurgery and

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Jarrett Rosenberg Radiology, Stanford University School of Medicine, Stanford, California;

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W. Jeffrey Elias Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia;

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Howard M. Eisenberg University of Maryland School of Medicine, Baltimore, Maryland;

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Ryder Gwinn Swedish Neuroscience Institute, Seattle, Washington;

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Takaomi Taira Tokyo Women’s Medical University, Tokyo, Japan;

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Jin Woo Chang Yonsei University College of Medicine, Seoul, Korea;

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Nir Lipsman Sunnybrook Health Sciences Center, Toronto, Ontario, Canada;

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Vibhor Krishna The Ohio State University Medical Center, Columbus, Ohio;

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Keiji Igase Washoukai Sadamoto Hospital, Matsuyama City, Japan;

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Kazumichi Yamada Kumamoto University Hospital, Obihiro City, Japan;

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Haruhiko Kishima Osaka University Hospital, Osaka, Japan;

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Rees Cosgrove Brigham and Women’s Hospital, Boston, Massachusetts;

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Jordi Rumià ResoFUS Alomar, Barcelona, Spain;

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Michael G. Kaplitt Weill Cornell School of Medicine, New York, New York;

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Hidehiro Hirabayashi Nara Medical University, Kashihara, Japan;

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Dipankar Nandi St. Mary’s Hospital, London, United Kingdom; and

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Jaimie M. Henderson Departments of Neurosurgery and

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Kim Butts Pauly Radiology, Stanford University School of Medicine, Stanford, California;

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Mor Dayan InSightec, Ltd., Dallas, Texas

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Casey H. Halpern Departments of Neurosurgery and

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Pejman Ghanouni Radiology, Stanford University School of Medicine, Stanford, California;

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OBJECTIVE

Skull density ratio (SDR) assesses the transparency of the skull to ultrasound. Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy in essential tremor (ET) patients with a lower SDR may be less effective, and the risk for complications may be increased. To address these questions, the authors analyzed clinical outcomes of MRgFUS thalamotomy based on SDRs.

METHODS

In 189 patients, 3 outcomes were correlated with SDRs. Efficacy was based on improvement in Clinical Rating Scale for Tremor (CRST) scores 1 year after MRgFUS. Procedural efficiency was determined by the ease of achieving a peak voxel temperature of 54°C. Safety was based on the rate of the most severe procedure-related adverse event. SDRs were categorized at thresholds of 0.45 and 0.40, selected based on published criteria.

RESULTS

Of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. There was no significant difference in improvement in CRST scores between those with an SDR ≥ 0.45 (58% ± 24%), 0.40 ≤ SDR < 0.45 (i.e., SDR ≥ 0.40 but < 0.45) (63% ± 27%), and SDR < 0.40 (49% ± 28%; p = 0.0744). Target temperature was achieved more often in those with an SDR ≥ 0.45 (p < 0.001). Rates of adverse events were lower in the groups with an SDR < 0.45 (p = 0.013), with no severe adverse events in these groups.

CONCLUSIONS

MRgFUS treatment of ET can be effectively and safely performed in patients with an SDR < 0.45 and an SDR < 0.40, although the procedure is more efficient when SDR ≥ 0.45.

ABBREVIATIONS

CRST = Clinical Rating Scale for Tremor; ET = essential tremor; FUS = focused ultrasound; MRgFUS = magnetic resonance–guided focused ultrasound; SDR = skull density ratio.

OBJECTIVE

Skull density ratio (SDR) assesses the transparency of the skull to ultrasound. Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy in essential tremor (ET) patients with a lower SDR may be less effective, and the risk for complications may be increased. To address these questions, the authors analyzed clinical outcomes of MRgFUS thalamotomy based on SDRs.

METHODS

In 189 patients, 3 outcomes were correlated with SDRs. Efficacy was based on improvement in Clinical Rating Scale for Tremor (CRST) scores 1 year after MRgFUS. Procedural efficiency was determined by the ease of achieving a peak voxel temperature of 54°C. Safety was based on the rate of the most severe procedure-related adverse event. SDRs were categorized at thresholds of 0.45 and 0.40, selected based on published criteria.

RESULTS

Of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. There was no significant difference in improvement in CRST scores between those with an SDR ≥ 0.45 (58% ± 24%), 0.40 ≤ SDR < 0.45 (i.e., SDR ≥ 0.40 but < 0.45) (63% ± 27%), and SDR < 0.40 (49% ± 28%; p = 0.0744). Target temperature was achieved more often in those with an SDR ≥ 0.45 (p < 0.001). Rates of adverse events were lower in the groups with an SDR < 0.45 (p = 0.013), with no severe adverse events in these groups.

CONCLUSIONS

MRgFUS treatment of ET can be effectively and safely performed in patients with an SDR < 0.45 and an SDR < 0.40, although the procedure is more efficient when SDR ≥ 0.45.

In Brief

Magnetic resonance–guided focused ultrasound (MRgFUS) is shown to be both a safe and effective treatment of essential tremor (ET) for patients previously excluded from treatment due to presumed unsuitable skull density ratios (SDRs). Because an SDR cutoff of 0.45 ± 0.05 served as exclusion criterion from past clinical trials evaluating MRgFUS for ET, these findings represent an immediate opportunity for more patients to access this modality as an alternative to current therapy.

Essential tremor (ET) is one of the most common neurological disorders in the world, affecting approximately 4% of adults aged 40 and over.18 For medically refractory ET cases, 4 surgical treatments are currently available: radiofrequency ablation, deep brain stimulation, stereotactic radiosurgery, and focused ultrasound (FUS) ablation.11,12

Transcranial magnetic resonance–guided focused ultrasound (MRgFUS) represents the newest of these surgical approaches. Compared to radiofrequency ablation and deep brain stimulation, MRgFUS is a less invasive, incisionless procedure by which high-intensity ultrasound beams are targeted to a preplanned coordinate so that the desired tissue may be heated and ablated. The ultrasound is generated from a helmet-shaped transducer, using between 750 and 1000 individual elements to distribute the ultrasound energy over a large skull surface area. In order for the ultrasound to propagate through the skull and be focused at the target, individual transducer elements have their phase corrected to account for the heterogeneity of the skull through which the beams travel.

However, skulls are not equally penetrable by this method. In order to evaluate the suitability of a patient skull for treatment, CT scans taken prior to MRgFUS treatment are used to calculate a skull density ratio (SDR). The SDR is calculated as the global average of the ratio between the radiodensity in CT Hounsfield units of cancellous to cortical bone within the skull.6 The range of SDR is from 0 to 1, with SDR values greater than 0.4 typically considered more efficacious for FUS lesioning.1,16 Lower values of the SDR reflect greater heterogeneity between cancellous and cortical bone and typically thicker skulls.16 This, in turn, impacts the transmission of ultrasonic energy through the skull, with low-SDR skulls resulting in greater attenuation and reflection of ultrasound waves, thereby requiring increased energy or lesioning time to achieve target temperatures. In some cases, a low SDR may result in a failure to reach a sufficient tissue temperature required to achieve a permanent ablation.6

Because of an analysis suggesting that patients with skulls with a low SDR are at risk for less effective treatment,6 and presumably also for greater side effects, a large prospective clinical trial evaluating FUS for ET used an SDR of less than 0.45 ± 0.05 as an exclusion criterion for MRgFUS treatment eligibility (https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150038B.pdf).5,7 Since these initial studies, patients with SDRs at the lower range and below this criterion have been treated based on medical need. Here, we address this assumption about the efficacy and safety of MRgFUS by comparing technical results and clinical outcomes at 1-year post-ablation for 189 ET patients, divided into three groups based on SDR thresholds of < 0.40, 0.40 to < 0.45 , and ≥ 0.45.

Methods

Patient Population

All 189 subjects were part of FDA pre–market approval submission (P150038), comprising efficacy, safety, and technical data from 5 clinical trials conducted in the United States, Canada, South Korea, Japan, the United Kingdom, and Spain.8

Skull Density Ratio

Typical CT scan acquisition parameters were as follows: axial, helical acquisition, 1-mm slice thickness with no slice spacing, 512 × 512 matrix, and bone kernel. The SDR was calculated via a model in which, for each of the 1024 transducer elements, parallel rays were created traversing the skull from the ultrasound transducer to the target; the CT Hounsfield values along each ray were then used to calculate a ratio of density of trabecular (minimum Hounsfield value in ray) to cortical bone (maximum Hounsfield value in ray) density. The resulting ratio for each ray was averaged to produce the reported overall skull SDR.6 Patients in this cohort were divided into 3 groups based on SDR < 0.40, 0.40 ≤ SDR < 0.45 (i.e., an SDR ≥ 0.40 but < 0.45), and SDR ≥ 0.45.

Focused Ultrasound Sonication Procedure

Studies utilized the ExAblate Model 4000 Type 1.0 system (InSightec) for unilateral MRgFUS thalamotomy to treat medically refractory, disabling ET. Targeting of the ventral intermediate nucleus of the thalamus utilized stereotactic anatomical landmarks as previously reported, although some centers used MRI tractography–based localization.10 Acoustic energy (sonication) was titrated while continuously monitoring the intensity and location of the ultrasound focus with MR thermometry and repeatedly assessing the clinical response. It is generally agreed that permanent ablation is achieved when tissue temperature reaches at least 54°C.2 Thalamic sonication was performed until peak voxel temperatures, averaged in a 3 × 3 box at the target, reached 54°C–60°C; sonications were repeated if tremor persisted.

Efficacy and Safety Analysis

Efficacy was based on improvement from baseline scores from the Clinical Rating Scale for Tremor (CRST) parts A and B for the treated hand at 1 year after MRgFUS treatment.7 Safety was based on the rate of the most severe procedure- or thalamotomy-related adverse event that did not resolve within the first 3 days after the procedure. Consistent with published criteria, the severity of adverse events was defined as mild (minor inconvenience: not affecting daily routine activities), moderate (bothersome: interferes with daily routine activities), or severe (incapacitating: cannot perform activities of daily living).8 Statistical analyses were performed using GraphPad Prism 7 or STATA Release 15.1 (StataCorp LP). Values reported represent mean ± SD. Differences in frequency of events were tested using the Fisher’s exact test. Correlation between SDR values and improvement in CRST scores was assessed by computing the coefficient of determination (r2) from a linear least-squares regression. Differences in improvement in CRST scores were compared between the three SDR groups using the Kruskal-Wallis test. To assess if differences in results were present after regrouping patients, CRST scores and rates of adverse events between both an SDR ≥ 0.45 versus an SDR < 0.45 and an SDR ≥ 0.40 versus an SDR < 0.40 were separately compared using the Mann-Whitney U-test. A significance level of p < 0.05 was used.

Results

Clinical Efficacy

There was no correlation between the SDR and percentage change in CRST score at 12 months (r2 = 0.0098; Fig. 1). We then assessed the relationship between SDR and CRST score after categorizing patients based on SDR thresholds. The majority of patients (72%) with ET treated with MRgFUS in this cohort had an SDR greater than 0.45; the average SDR was 0.52 ± 0.11. Fifty-three patients (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40 (Fig. 2). In patients with an SDR ≥ 0.45, the average improvement in CRST scores 1 year after MRgFUS was 58% ± 24%. In the group with an SDR 0.40 ≤ SDR < 0.45, we observed a tremor improvement of 63% ± 27%. The group with an SDR < 0.40 had the lowest average improvement in tremor scores (49% ± 28%; Table 1), but the difference in tremor improvement among the three SDR categories was not statistically significant (p = 0.0744). When regrouped, 36 (68%) of 53 of patients with an SDR < 0.45 and 92 (68%) of 136 of those with an SDR ≥ 0.45 obtained at least a 50% improvement in tremor scores at 1 year (p = 0.838). There was also no significant difference in tremor scores when comparing the group with an SDR ≥ 0.40 (59% ± 25%) to those with an SDR < 0.40 (p = 0.0749). At least a 50% improvement in tremor scores was demonstrated in 92 (68%) of the 136 patients with SDR ≥ 0.45, in 26 patients (79%) with 0.40 ≤ SDR < 0.45, and in 10 patients (50%) with SDR < 0.40 (Fig. 3). A threshold value of 50% improvement in CRST scores was chosen based on previous publications reporting the average results of MRgFUS treatment in patients with ET.5,7

FIG. 1.
FIG. 1.

SDR compared to change in CRST score. The percentage change in CRST score at 12 months after MRgFUS did not correlate with the SDR (blue line, r2 = 0.0098; < 1% of the variance in CRST score can be explained by variance in the SDR). Improvement of 50% in CRST scores is marked on the graph (dotted line). Figure is available in color online only.

FIG. 2.
FIG. 2.

SDR distribution of 189 patients with ET treated with MRgFUS. Each bar represents the percentage of patients of the cohort within each SDR interval, with each interval representing SDRs less than the higher number in the range. The mean SDR value was 0.52 ± 0.11 (± SD). SDRs ranged from 0.27 to 0.82. Out of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. Figure is available in color online only.

TABLE 1.

Clinical and technical results compared to SDR categories in 189 patients who underwent MRgFUS

SDRImprovement in CRST at 1 Yr After MRgFUS (mean ± SD)Probability of Target Reaching 54°C (%) (95% CI)
SDR < 0.4049% ± 28%11 (55%) of 20 (32%–77%)
0.40 ≤ SDR < 0.4563% ± 27%21 (64%) of 33 (45%–80%)
SDR ≥ 0.4558% ± 24%124 (91%) of 136 (85%–95%)

The percentage improvement in CRST scores at 1 year after MRgFUS was not significantly different across SDR categories (p = 0.0744). The percentage of patients in whom a peak temperature of 54°C was reached differed among the SDR groups (p < 0.001); the likelihood was higher as the SDR increased, although the majority of treatments in the patients with lower SDRs still reached the target temperature. The probability of reaching 54°C in patients with an SDR < 0.45 (60%; 95% CI 46%–74%) was significantly lower compared to those with an SDR ≥ 0.45 (p < 0.001).

FIG. 3.
FIG. 3.

Cumulative percent improvement in CRST scores at 1 year after MRgFUS for patients based on SDR categories. For patients with an SDR ≥ 0.45 (green line), 68% demonstrated at least a 50% improvement in CRST score at the 1-year follow-up (n = 136; the mean percentage improvement in CRST score was 58% ± 24%). For patients with 0.40 ≤ SDR < 0.45 (red line), 79% demonstrated at least a 50% improvement in CRST score at the 1-year follow-up (n = 33; the mean percentage improvement in CRST was 63% ± 27%). For patients with an SDR < 0.40 (blue line), 50% demonstrated at least a 50% improvement in CRST score at the 1-year follow-up (n = 20; the mean percentage improvement in CRST score was 49% ± 28%). The dashed line intersects each curve at the point where patients have at least a 50% improvement in CRST scores 1 year after MRgFUS. The threshold value of 50% improvement was chosen based on previous publications reporting the average results of MRgFUS treatment in patients with ET.5,7 Figure is available in color online only.

Procedural Efficiency

The likelihood of reaching a peak average temperature (Tmax) at the focal spot of at least 54°C differed based on the SDR (p < 0.001). The target temperature was achieved in 124 (91%) of those with SDR ≥ 0.45, in 21 (64%) of those with 0.40 ≤ SDR < 0.45, and in 11 (55%) of those with SDR < 0.40. The probability of reaching 54°C in patients with an SDR < 0.45 (60%) was significantly lower than in those with an SDR ≥ 0.45 (p < 0.001; Table 1).

Safety

The majority of adverse events across the entire cohort were mild (81 [74%] of 109). The probability of an adverse event differed significantly among the SDR categories (p = 0.040), with adverse events reported in 86 (63%) of those with an SDR ≥ 0.45, 15 (45%) of those with 0.40 ≤ SDR < 0.45, and in 8 (40%) of those with an SDR < 0.40. The frequency of adverse events in patients with an SDR < 0.45 (43%) was significantly lower than in those with an SDR ≥ 0.45 (p = 0.013). There was no significant difference in the rate of moderate and severe adverse events between those with an SDR < 0.45 (9%) and those with an SDR ≥ 0.45 (17%; p = 0.256). The rate of moderate and severe adverse events was lower in the group with an SDR < 0.40 (0%) than it was in the group with an SDR ≥ 0.45 (17%; p = 0.0457), although this observation was limited by the small sample size of the former group (Table 2).

TABLE 2.

Rates of adverse events

No. of Patients w/ AEs
SDRNo. of PatientsNoneMildModerateSevereProbability of AE (95% CI)
SDR < 0.402012 (60%)8 (40%)0 (0%)0 (0%)40% (19%–64%)
0.40 ≤ SDR < 0.453318 (55%)10 (30%)5 (15%)0 (0%)45% (28%–64%)
SDR ≥ 0.4513650 (38%)63 (46%)20 (15%)3 (2%)63% (55%–71%)

AE = adverse event.

ET patients were divided based on SDR range and most severe adverse event related to the MRgFUS procedure. The different SDR types differed in the probability of having an adverse event (p = 0.040). The frequency of adverse events was significantly lower in patients with an SDR < 0.45 (43%; 95% CI 30%–58%) than it was in those with an SDR ≥ 0.45 (p = 0.013).

Discussion

An SDR between 0.40 and 0.45 was initially used as a lower limit range to determine candidacy for MRgFUS.6 Recognizing that the SDR is an imperfect parameter and that patients with low SDRs can still be treated with MRgFUS, we compared the clinical and technical results of treatment based on patient SDR. Our study demonstrates that MRgFUS thalamotomy for treatment of ET remains both safe and efficacious for patients with an SDR of < 0.45 and < 0.40. Chang et al. reported failure to achieve sufficient temperature for ablation in 3 of 28 patients and correlated this not only to low SDR but also increased skull volume.6 In our study of this larger cohort, however, we found that 79% of patients with an SDR between 0.40 and 0.45 and 50% of patients with an SDR of < 0.40 had at least 50% improvement in CRST scores at the 1-year follow-up. Overall, the percentage of patients with at least a 50% improvement in CRST scores at 1 year after MRgFUS (68%) was the same when comparing patients with an SDR greater versus less than 0.45. While procedural efficiency, as measured by reaching the target temperature in the thalamus, is better in the group with an SDR ≥ 0.45, the procedure can still be safely performed in the groups in which the SDR is < 0.45.

Skulls vary within and between patients in terms of size and shape, as well as the thickness and proportion of cortical to trabecular bone. As ultrasound propagates through the skull, the bone heterogeneously reflects, refracts, and attenuates the ultrasound waves. The SDR is calculated from CT scan as a ratio of the densities of cancellous to cortical bone. The SDR represents an estimate of how readily the ultrasound beam can penetrate the skull with sufficient intensity to ablate the targeted tissue. Because previous studies have shown a correlation between the SDR and acoustic energy transmitted through the skull, patients with low SDR scores have typically been excluded from undergoing MRgFUS treatment.5,7,14 However, the SDR remains a single, simple parameter, and its reliability at predicting treatment results is limited. For example, some skulls with lower SDRs are more easily treated than others with similar SDR values. Indeed, new simulation techniques have been introduced to better model and understand the delivery of ultrasound energy across the skull and improve patient-specific calibration before treatment.13,15

The initially predicted ease of treatability provided by the SDR becomes less valid as the procedure progresses and more sonications are performed, mainly because the efficiency with which the skull is penetrated generally decreases with additional sonications. It has been hypothesized that changes in the cranium occur with repeated transcranial sonication, making subsequent acoustic transmission more difficult.4,9 Thus, in prolonged treatments, such as when the initial target needs to be adjusted for optimal symptom relief, it can become more difficult to reach the desired temperature. As surgeons have become more experienced with this technology, treatment protocols have emphasized more rapid ramping of energies and temperatures in an effort to reach the desired ablative temperature of at least 54°C at the target before the skull properties change. If none of the sonications reach the desired temperature, multiple sonications are performed to accumulate sufficient thermal dose to result in adequate ablation.

Study Limitations and Future Work

MRgFUS is currently being investigated as a potential therapy for brain tumors, Parkinson disease, obsessive-compulsive disorder, major depressive disorder, neuropathic pain, and epilepsy. Considering the number of new indications under investigation, it must be noted that the treatment efficiency and ability to reach therapeutic temperatures vary depending on the specific sonication target within the brain. For example, focused ultrasound pallidotomy may require higher energy to reach therapeutic temperatures compared to thalamotomy procedures, despite similar SDRs. Future metrics to predict temperature rise should include incident angle and skull thickness in addition to skull heterogeneity and could also incorporate a rigorous model of the impact of additional CT parameters across vendors on SDR.13,17

Because MRgFUS is a relatively new procedure, the experience gained from treating patients with an SDR ≥ 0.45 may be a potential bias for the safety and efficacy results noted in the group with an SDR < 0.45. For example, greater experience and/or a lower SDR may result in smaller lesion size after thalamotomy, which could correlate with the increased safety seen at a lower SDR. While studies are underway to assess the impact of experience on tremor outcomes, and insight into the role of lesion size and location on safety and efficacy has been recently published,3 the relationship between SDR and experience or lesion size remains to be elucidated. Whereas the current analysis is limited by its retrospective nature and the limited sample size of the group with an SDR < 0.40, the finding that MRgFUS in patients with SDRs < 0.45 is similarly safe and effective presents an opportunity for more patients to access this modality as a feasible noninvasive therapy.

Conclusions

SDR is an indicator of the acoustic transparency of the skull to the ultrasound beam and serves as an eligibility criterion for transcranial MRgFUS. Our analysis shows that MRgFUS treatment of ET is safe and beneficial for patients with SDR of < 0.45 and < 0.40.

Disclosures

InSightec provided research funding for clinical trials related to MRgFUS treatment of essential tremor. Drs. Ghanouni, Halpern, Henderson, Elias, Eisenberg, Gwinn, Taira, Chang, Lipsman, Krishna, Igase, Yamada, Kishima, Cosgrove, Rumià, Kaplitt, Hirabayashi, Eisenberg, and Nandi receive research funding from InSightec.

Conduct of the study, data analysis and interpretation, and preparation and approval of the manuscript were done independently of InSightec. Initial design of the study was performed by Drs. Ghanouni, Halpern, and Dayan, who is an employee of InSightec. Data collection was performed by Dr. Dayan, who also reviewed the manuscript.

Dr. Elias reports receiving support of non–study-related clinical or research efforts that he oversees from InSightec. Dr. Taira reports being a consultant for InSightec Japan. Dr. Lipsman reports having served as chair on the Expert Steering Committee of the Focused Ultrasound Foundation. Dr. Krishna reports receiving funding for a clinical trial from InSightec. Dr. Yamada reports receiving support for the study described from Hokuto Hospital. Dr. Cosgrove reports receiving research funding for clinical trials from InSightec. Dr. Halpern reports receiving speaking honoraria from Mazor Robotics and being a consultant for Medtronic. Dr. Ghanouni reports receiving support of non–study-related clinical or research efforts that he oversees from InSightec. Dr. Dayan is an employee of InSightec.

Author Contributions

Conception and design: Ghanouni, Dayan, Halpern. Acquisition of data: Ghanouni, Elias, Eisenberg, Gwinn, Taira, Chang, Lipsman, Krishna, Igase, Yamada, Kishima, Cosgrove, Rumià, Kaplitt, Hirabayashi, Nandi, Henderson, Butts Pauly, Halpern. Analysis and interpretation of data: Ghanouni, D’Souza, Chen, Rosenberg. Drafting the article: D’Souza, Chen. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ghanouni. Statistical analysis: Ghanouni, D’Souza, Rosenberg. Administrative/technical/material support: D’Souza. Study supervision: Ghanouni, Halpern.

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    Ravikumar VK, Parker JJ, Hornbeck TS, Santini VE, Pauly KB, Wintermark M, et al.: Cost-effectiveness of focused ultrasound, radiosurgery, and DBS for essential tremor. Mov Disord 32:11651173, 2017

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  • 13

    Sammartino F, Beam DW, Snell J, Krishna V: Kranion, an open-source environment for planning transcranial focused ultrasound surgery: technical note. J Neurosurg [epub ahead of print March 1, 2019. DOI: 10.3171/2018.11.JNS181995]

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  • 14

    Schwartz ML, Yeung R, Huang Y, Lipsman N, Krishna V, Jain JD, et al.: Skull bone marrow injury caused by MR-guided focused ultrasound for cerebral functional procedures. J Neurosurg 130:758762, 2019

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    • Export Citation
  • 15

    Vyas U, Ghanouni P, Halpern CH, Elias J, Pauly KB: Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: comparison in seventeen subject datasets. Med Phys 43:51705180, 2016

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    • Export Citation
  • 16

    Wang TR, Bond AE, Dallapiazza RF, Blanke A, Tilden D, Huerta TE, et al.: Transcranial magnetic resonance imaging-guided focused ultrasound thalamotomy for tremor: technical note. Neurosurg Focus 44(2):E3, 2018

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    • Search Google Scholar
    • Export Citation
  • 17

    Webb TD, Leung SA, Rosenberg J, Ghanouni P, Dahl JJ, Pelc NJ, et al.: Measurements of the relationship between CT Hounsfield units and acoustic velocity and how it changes with photon energy and reconstruction method. IEEE Trans Ultrason Ferroelectr Freq Control 65:11111124, 2018

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  • 18

    Zesiewicz TA, Chari A, Jahan I, Miller AM, Sullivan KL: Overview of essential tremor. Neuropsychiatr Dis Treat 6:401408, 2010

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Illustration from Ivan et al. (pp 1517–1528). Copyright Kenneth Probst. Published with permission.

  • FIG. 1.

    SDR compared to change in CRST score. The percentage change in CRST score at 12 months after MRgFUS did not correlate with the SDR (blue line, r2 = 0.0098; < 1% of the variance in CRST score can be explained by variance in the SDR). Improvement of 50% in CRST scores is marked on the graph (dotted line). Figure is available in color online only.

  • FIG. 2.

    SDR distribution of 189 patients with ET treated with MRgFUS. Each bar represents the percentage of patients of the cohort within each SDR interval, with each interval representing SDRs less than the higher number in the range. The mean SDR value was 0.52 ± 0.11 (± SD). SDRs ranged from 0.27 to 0.82. Out of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. Figure is available in color online only.

  • FIG. 3.

    Cumulative percent improvement in CRST scores at 1 year after MRgFUS for patients based on SDR categories. For patients with an SDR ≥ 0.45 (green line), 68% demonstrated at least a 50% improvement in CRST score at the 1-year follow-up (n = 136; the mean percentage improvement in CRST score was 58% ± 24%). For patients with 0.40 ≤ SDR < 0.45 (red line), 79% demonstrated at least a 50% improvement in CRST score at the 1-year follow-up (n = 33; the mean percentage improvement in CRST was 63% ± 27%). For patients with an SDR < 0.40 (blue line), 50% demonstrated at least a 50% improvement in CRST score at the 1-year follow-up (n = 20; the mean percentage improvement in CRST score was 49% ± 28%). The dashed line intersects each curve at the point where patients have at least a 50% improvement in CRST scores 1 year after MRgFUS. The threshold value of 50% improvement was chosen based on previous publications reporting the average results of MRgFUS treatment in patients with ET.5,7 Figure is available in color online only.

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    Abe K, Taira T: Focused ultrasound treatment, present and future. Neurol Med Chir (Tokyo) 57:386391, 2017

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    Bond AE, Elias WJ: Predicting lesion size during focused ultrasound thalamotomy: a review of 63 lesions over 3 clinical trials. Neurosurg Focus 44(2):E5, 2018

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    Boutet A, Ranjan M, Zhong J, Germann J, Xu D, Schwartz ML, et al.: Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor. Brain 141:34053414, 2018

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    Butts Pauly K, Federau C, Werner B, Halpern C, Ghanouni P: Inflection of temperature vs. power curve in tcMRgFUS: correlation with lesion location. J Therapeutic Ultrasound 4 (Suppl 1):A19, 2016 (Abstract A19)

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    Chang JW, Park CK, Lipsman N, Schwartz ML, Ghanouni P, Henderson JM, et al.: A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: results at the 2-year follow-up. Ann Neurol 83:107114, 2018

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    Chang WS, Jung HH, Zadicario E, Rachmilevitch I, Tlusty T, Vitek S, et al.: Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull. J Neurosurg 124:411416, 2016

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    Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, et al.: a randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 375:730739, 2016

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  • 8

    Fishman PS, Elias WJ, Ghanouni P, Gwinn R, Lipsman N, Schwartz M, et al.: Neurological adverse event profile of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor. Mov Disord 33:843847, 2018

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  • 9

    Hughes A, Huang Y, Schwartz ML, Hynynen K: The reduction in treatment efficiency at high acoustic powers during MR-guided transcranial focused ultrasound thalamotomy for essential tremor. Med Phys 45:29252936, 2018

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  • 10

    Krishna V, Sammartino F, Agrawal P, Changizi BK, Bourekas E, Knopp MV, et al.: Prospective tractography-based targeting for improved safety of focused ultrasound thalamotomy. Neurosurgery 84:160168, 2019

    • Crossref
    • PubMed
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    • Export Citation
  • 11

    Laitinen LV: Brain targets in surgery for Parkinson’s disease. Results of a survey of neurosurgeons. J Neurosurg 62:349351, 1985

  • 12

    Ravikumar VK, Parker JJ, Hornbeck TS, Santini VE, Pauly KB, Wintermark M, et al.: Cost-effectiveness of focused ultrasound, radiosurgery, and DBS for essential tremor. Mov Disord 32:11651173, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Sammartino F, Beam DW, Snell J, Krishna V: Kranion, an open-source environment for planning transcranial focused ultrasound surgery: technical note. J Neurosurg [epub ahead of print March 1, 2019. DOI: 10.3171/2018.11.JNS181995]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Schwartz ML, Yeung R, Huang Y, Lipsman N, Krishna V, Jain JD, et al.: Skull bone marrow injury caused by MR-guided focused ultrasound for cerebral functional procedures. J Neurosurg 130:758762, 2019

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Vyas U, Ghanouni P, Halpern CH, Elias J, Pauly KB: Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: comparison in seventeen subject datasets. Med Phys 43:51705180, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wang TR, Bond AE, Dallapiazza RF, Blanke A, Tilden D, Huerta TE, et al.: Transcranial magnetic resonance imaging-guided focused ultrasound thalamotomy for tremor: technical note. Neurosurg Focus 44(2):E3, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Webb TD, Leung SA, Rosenberg J, Ghanouni P, Dahl JJ, Pelc NJ, et al.: Measurements of the relationship between CT Hounsfield units and acoustic velocity and how it changes with photon energy and reconstruction method. IEEE Trans Ultrason Ferroelectr Freq Control 65:11111124, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Zesiewicz TA, Chari A, Jahan I, Miller AM, Sullivan KL: Overview of essential tremor. Neuropsychiatr Dis Treat 6:401408, 2010

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