The relevance of skull density ratio in selecting candidates for transcranial MR-guided focused ultrasound

Alexandre Boutet University Health Network, Toronto;
Joint Department of Medical Imaging, University of Toronto;

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Dave Gwun University Health Network, Toronto;

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Robert Gramer University Health Network, Toronto;

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Manish Ranjan Krembil Research Institute, Toronto;

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Gavin J. B. Elias University Health Network, Toronto;

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David Tilden Insightec, Ltd., Dallas, Texas

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Yuexi Huang Physical Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto;

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Stanley Xiangyu Li University Health Network, Toronto;

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Benjamin Davidson University Health Network, Toronto;

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Hua Lu Joint Department of Medical Imaging, University of Toronto;

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Pascal Tyrrell Department of Statistical Sciences, University of Toronto;
Joint Department of Medical Imaging, University of Toronto;

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Ryan M. Jones Physical Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto;

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Alfonso Fasano Krembil Research Institute, Toronto;
Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto;

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Kullervo Hynynen Physical Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto;
Department of Medical Biophysics, University of Toronto;
Institute of Biomaterials and Biomedical Engineering, University of Toronto;

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Walter Kucharczyk University Health Network, Toronto;
Joint Department of Medical Imaging, University of Toronto;

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Michael L. Schwartz Division of Neurosurgery, Sunnybrook Health Sciences Center, University of Toronto, Ontario, Canada; and

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Andres M. Lozano University Health Network, Toronto;

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OBJECTIVE

Transcranial MR-guided focused ultrasound (MRgFUS) is a minimally invasive treatment for movement disorders. Considerable interpatient variability in skull transmission efficiency exists with the current clinical devices, which is thought to be dependent on each patient’s specific skull morphology. Lower skull density ratio (SDR) values are thought to impede acoustic energy transmission across the skull, attenuating or preventing the therapeutic benefits of MRgFUS. Patients with SDR values below 0.4 have traditionally been deemed poor candidates for MRgFUS. Although considerable anecdotal evidence has suggested that SDR is a reliable determinant of procedural and clinical success, relationships between SDR and clinical outcomes have yet to be formally investigated. Moreover, as transcranial MRgFUS is becoming an increasingly widespread procedure, knowledge of SDR distribution in the general population may enable improved preoperative counseling and preparedness.

METHODS

A total of 98 patients who underwent MRgFUS thalamotomy at the authors’ institutions between 2012 and 2018 were analyzed (cohort 1). The authors retrospectively assessed the relationships between SDR and various clinical outcomes, including tremor improvement and adverse effects, as well as procedural factors such as sonication parameters. An SDR was also prospectively obtained in 163 random emergency department patients who required a head CT scan for various clinical indications (cohort 2). Patients’ age and sex were used to explore relationships with SDR.

RESULTS

In the MRgFUS treatment group, 17 patients with a thalamotomy lesion had an SDR below 0.4. Patients with lower SDRs required more sonication energy; however, their low SDR did not influence their clinical outcomes. In the emergency department patient group, about one-third of the patients had a low SDR (< 0.4). SDR did not correlate with age or sex.

CONCLUSIONS

Although lower SDR values correlated with higher energy requirements during MRgFUS thalamotomy, within the range of this study population, the SDR did not appreciably impact or provide the ability to predict the resulting clinical outcomes. Sampling of the general population suggests that age and sex have no relationship with SDR. Other variables, such as local variances in bone density, should also be carefully reviewed to build a comprehensive appraisal of a patient’s suitability for MRgFUS treatment.

ABBREVIATIONS

ET = essential tremor; MRgFUS = MR-guided focused ultrasound; SDR = skull density ratio; VIM = ventral intermediate nucleus.

OBJECTIVE

Transcranial MR-guided focused ultrasound (MRgFUS) is a minimally invasive treatment for movement disorders. Considerable interpatient variability in skull transmission efficiency exists with the current clinical devices, which is thought to be dependent on each patient’s specific skull morphology. Lower skull density ratio (SDR) values are thought to impede acoustic energy transmission across the skull, attenuating or preventing the therapeutic benefits of MRgFUS. Patients with SDR values below 0.4 have traditionally been deemed poor candidates for MRgFUS. Although considerable anecdotal evidence has suggested that SDR is a reliable determinant of procedural and clinical success, relationships between SDR and clinical outcomes have yet to be formally investigated. Moreover, as transcranial MRgFUS is becoming an increasingly widespread procedure, knowledge of SDR distribution in the general population may enable improved preoperative counseling and preparedness.

METHODS

A total of 98 patients who underwent MRgFUS thalamotomy at the authors’ institutions between 2012 and 2018 were analyzed (cohort 1). The authors retrospectively assessed the relationships between SDR and various clinical outcomes, including tremor improvement and adverse effects, as well as procedural factors such as sonication parameters. An SDR was also prospectively obtained in 163 random emergency department patients who required a head CT scan for various clinical indications (cohort 2). Patients’ age and sex were used to explore relationships with SDR.

RESULTS

In the MRgFUS treatment group, 17 patients with a thalamotomy lesion had an SDR below 0.4. Patients with lower SDRs required more sonication energy; however, their low SDR did not influence their clinical outcomes. In the emergency department patient group, about one-third of the patients had a low SDR (< 0.4). SDR did not correlate with age or sex.

CONCLUSIONS

Although lower SDR values correlated with higher energy requirements during MRgFUS thalamotomy, within the range of this study population, the SDR did not appreciably impact or provide the ability to predict the resulting clinical outcomes. Sampling of the general population suggests that age and sex have no relationship with SDR. Other variables, such as local variances in bone density, should also be carefully reviewed to build a comprehensive appraisal of a patient’s suitability for MRgFUS treatment.

In Brief

The authors investigated relationships between SDR and clinical outcomes after MRgFUS thalamotomy. They found that SDR does not seem to govern clinical outcomes, and, for the vast majority of patients with low SDR, a thalamotomy lesion could be successfully made.

Magnetic resonance–guided focused ultrasound (MRgFUS) is a minimally invasive treatment approach with established and emerging intracranial applications.8,11,14 Depending on the treatment paradigm employed, MRgFUS can induce thermal effects (e.g., tissue ablation, hyperthermia), mechanical effects (e.g., blood-brain barrier permeabilization, clot dissolution, tissue homogenization), and physiological effects (e.g., neuromodulation).8,14 Currently, transcranial MRgFUS is predominantly used to perform thalamotomies in patients with essential tremor (ET) and other movement disorders. Transcranial MRgFUS has received FDA5 and Health Canada15 approvals for the treatment of ET in North America and the European CE marking for ET, Parkinson’s disease, and neuropathic pain applications.12 MRgFUS produces striking clinical results; for example, a randomized controlled trial described a 47% tremor reduction in the treated hand at 3 months postprocedure.5

Several preoperative criteria are considered when selecting patients for MRgFUS, one of which is the skull density ratio (SDR) metric. Such a metric is necessary, as previous ex vivo7,16 and clinical studies15,18 have demonstrated wide variation in skull transmission efficiency. Obtained from pretreatment head CT scans, SDR represents the global averaged ratio between the mean Hounsfield unit values of the skull’s cancellous and cortical bones.4 It has been proposed that a greater density difference between cancellous and cortical bones (i.e., low SDR) impedes ultrasound energy transmission across the skull by reflecting and attenuating energy at interfaces. Indeed, low SDR has been shown to hinder temperature rise at the treatment site,4 potentially precluding or leading to a suboptimal therapeutic lesion. In that study, SDR was also shown to correlate inversely with the energy required during treatment, and patients with low SDRs are thought to be less favorable candidates for MRgFUS. The maximum applied energy during MRgFUS has been positively correlated with bone marrow necrosis.18 To optimize procedural parameters and minimize the potential for suboptimal lesioning, an SDR threshold of 0.45 ± 0.05 was approved by the FDA.6 Similar to other groups,19 our clinical practice suggests that a threshold of 0.4 is generally sufficient for successful lesioning. While SDR has been shown to impact sonication parameters, the relationship between SDR and clinical outcomes has not yet been formally investigated.

In addition to movement disorders, the utility of MRgFUS in treating neuropsychiatric disorders, including depression and pain syndromes, is currently being explored.14 Given the expanding cohort of patients who may benefit from MRgFUS, it is important to understand how SDR influences therapeutic efficacy and develop an appreciation of the variability and distribution of SDRs across the general population.

In this study, we aimed to 1) explore the relationship between SDR and both procedural parameters and clinical outcomes after MRgFUS thalamotomy in patients with refractory tremor, and 2) estimate the SDR distribution in the general population from a random cohort of patients presenting to the emergency department who received CT scanning for various clinical indications.

Methods

Cohort 1: MRgFUS Patients

On obtaining institutional research ethics board approval, the charts of 136 consecutive tremor patients screened for MRgFUS thalamotomy at Sunnybrook Health Sciences Centre and Toronto Western Hospital between May 2012 and July 2018 were reviewed (Fig. 1; prior to regulatory agency approvals, patients were enrolled in clinical trial registration no. NCT02252380, clinicaltrials.gov; principal investigators: Dr. Andres M. Lozano and Dr. Michael Schwartz). Our practice largely followed previously published MRgFUS trials.5,15 While there was not a definite SDR threshold, SDR less than 0.4 was considered unfavorable. However, over the 6-year period, we changed our practice to 1) include patients outside the initial age range criteria (18–80 years), 2) treat patients with an SDR below 0.4, and 3) give more importance to local versus global skull variations, hyperostosis frontalis. Additional procedural changes included 1) limiting the maximum energy per sonication to 40 kJ (per updated company guidelines), 2) increasing the rate at which the sonication power is raised over the course of treatment,10 and 3) centering the lesion 1–2 mm superior to the anterior commissure–posterior commissure plane.2 The subset of patients who were screened but not offered the procedure due to unamenable skulls were tracked. Seven patients were not offered the procedure due to low SDR (n = 2, SDR 0.34 and 0.37), severe hyperostosis frontalis (n = 4) preventing reliable SDR calculation, and presence of intracranial tumor (n = 1). Patients for whom no lesion could be made (n = 4) were tracked but not included in the outcome analysis. Patients with a clinical follow-up less than 3 months or sham procedures (e.g., see Elias et al.5) were also excluded from the outcome analysis. Of 125 patients with thalamotomy, 98 had 3-month follow-up and were included in the outcome analysis (Table 1 and Fig. 1). Of these patients, 48 patients had 12-month follow-ups. SDR was calculated using their preoperative head CT scan (Toshiba Aquilion 64 V3.35 and Aquilion ONE V6.0; voxel size 0.5 × 0.5 × 1 mm; convolution kernel [filter] FC30). For all patients in this study, a single rater (D.T.) performed the SDR calculations using a proprietary algorithm (Insightec Inc.) similar to that initially described by Jung et al.13 SDR values are dependent on the target location within the brain and the orientation of the transducer with respect to the patient’s skull. For this study, SDR was calculated with the ventral intermediate nucleus (VIM) as the intended target. Similar to previous studies,4,5,15 this algorithm calculates the Hounsfield units of the cortical and trabecular bones over the entire skull surface. More specifically, it calculates an element-wise SDR sampling over the skull surface (i.e., across active transducer elements, up to 1024) and provides the mean value as the global SDR. Inactive transducers are usually due to the large angle of incidence. In other words, the hemispherical transducer is positioned such that the geometrical focus is aligned with the intended target, with an angular tilt of the array similar to that which would be expected during a clinical treatment. As previously reported, hand tremor contralateral to the MRgFUS target was assessed using subscores of the Clinical Rating Scale for Tremor.3 Tremor improvement in the treated hand was then calculated [(baseline score − follow-up)/baseline score × 100] for each of the follow-up time points (i.e., 3 and 12 months). Adverse effects (sensory, motor, speech, and ataxia) were recorded at each follow-up visit from clinical history and physical examination. Since most early adverse effects from MRgFUS are transient, only those symptoms persisting 3 months postoperatively were included. Procedural data were obtained from the sonication console (ExAblate 4000, Insightec Inc.). Since lesion volume has been shown to be related to maximal temperature achieved at the treatment site, we also investigated whether SDR was a determinant of lesion volume. Lesion volumes were obtained by manual segmentation using the 1-day postprocedure T1-weighted MRI scan (Sunnybrook Health Sciences Centre, 3T MR650 Discovery [GE Healthcare]: TR 8 msec, TE 3 msec, flip angle 12°, isotropic voxel 1 mm; and Toronto Western Hospital, Signa HDx 3T scanner [GE Healthcare]: TR 8 msec; TE 3 msec; flip angle 12°; isotropic voxel 1 mm).

FIG. 1.
FIG. 1.

Summary of MRgFUS thalamotomy patients.

TABLE 1.

Summary of patient demographics and procedural data included in the analysis for both cohorts.

Value
MRgFUS thalamotomy (n = 98)
 SDR
  Mean ± SD0.48 ± 0.10
  Range0.25–0.82
 Male sex69
 Age, yrs
  Mean71 ± 8
  Range42–93
 Disease
  ET87
  PD11
 Mean disease duration, yrs30 ± 19
 Mean % improvement in treated hand tremor score compared w/ baseline
   3 mos53 ± 33%
   12 mos45 ± 30%
 % patients experiencing adverse effects persistent at 3 mos51%
 Categorization of adverse effects persistent at 3 mos
  Sensory21%
  Motor15%
  Ataxia57%
  Speech7%
 Mean lesion vol, mm3188 ± 11
 Mean maximum temperature, °C*60 ± 4
 Mean maximum energy, kJ27 ± 31
 Mean duration, mins85 ± 38
 Mean no. of sonications13 ± 4
Emergency department patients (n = 163)
 Mean SDR0.46 ± 0.13
 Male sex70
 Age, yrs
  Mean63 ± 20
  Range14–100

PD = Parkinson’s disease.

Mean age (2-sample t-test, p < 0.001) and sex (chi-square test, p < 0.001) were significantly different between the MRgFUS and emergency department patient cohorts. Mean values are presented as mean ± SD.

Defined as the highest temperature recorded during the sonications.

Total procedure time, from the first to the last sonication.

Cohort 2: Emergency Department Patients

On obtaining institutional research ethics board approval, 189 consecutive emergency department patients who required a head CT scan as part of their clinical care from September 2017 to October 2017 were screened (Aquilion 64 V3.35 and Aquilion ONE V6.0, both Toshiba; voxel size: 0.5 × 0.5 × 1 mm; convolution kernel [filter]: FC30). Indications for the CT scans used in the analysis included clinical suspicion for intracranial hemorrhage, brain ischemia, and increased intracranial pressure. Patients whose scans showed bony abnormalities (e.g., osteogenic tumor, previous craniotomies) or intracranial lesions distorting the midline (e.g., intracranial hemorrhage, tumors, aberrant neuroanatomy) were excluded on the grounds that these findings prevented reliable SDR calculation. Patients with incomplete skull coverage were also excluded. In total, 163 patients were included in the analysis (Table 1). SDR was calculated with the VIM as the intended target.

Statistical Analysis

For the MRgFUS-treated patients (cohort 1), linear (or logistic) regressions were used to investigate the relationships between SDR and clinical outcomes and sonication parameters. The maximal energy and lesion size were transformed using a logarithmic function. Tremor improvement scores were exponentially transformed. Since lesion sizes and baseline tremor scores may have a relationship with clinical outcomes, they were used as covariates when assessing the relationship between SDR and clinical outcomes (tremor improvement and adverse effects).

To explore the SDR distribution and its relationship with age and sex in the emergency patient cohort (cohort 2), linear regression and independent t-tests were used. Statistical analysis was performed using IBM SPSS (version 24, IBM Corp.).

Results

Cohort 1: Role of SDR in MRgFUS Thalamotomy

Of the 129 MRgFUS procedures performed at our institutions from 2012 to 2018, it was not possible to make a satisfactory lesion in 4 patients (Fig. 1). In one case (SDR = 0.55), technical difficulties with the device precluded sonication. In another case (SDR = 0.4), the patient demonstrated severe hyperostosis frontalis (Fig. 2). Two patients had very low SDR values of 0.17 and 0.27. The mean SDR of MRgFUS patients in which a thalamotomy lesion was possible was 0.48 ± 0.10 (n = 98). Of those, 17 had an SDR less than 0.4 (Table 2). SDR was inversely correlated with maximal energy required to make a therapeutic brain lesion (r2 = 0.054, p = 0.021) (Tables 3 and 4).

FIG. 2.
FIG. 2.

Head CT scan (bone window) obtained in a patient with an SDR = 0.4 in whom no lesions could be made. Hyperostosis frontalis is demonstrated (red shading). Figure is available in color online only.

TABLE 2.

Patients with unfavorable SDR (< 0.04)

Case No. (treated patients)SDR% Improvement in Treated Hand Tremor Score at 3 Mos Compared w/ Baseline% Improvement in Treated Hand Tremor Score at 12 Mos Compared w/ BaselineMax Temp (°C)Lesion Vol (mm3)
10.3750.0%64.3%61.0240
20.3658.3%41.7%59.684
30.2866.7%NA58.3204
40.2983.3%25.0%60.9143
50.37−78.6%−85.7%64.0178
60.3773.7%52.6%62.9212
70.3325.0%12.5%54.090
80.3576.2%76.2%60.3323
90.3675.0%NA65.5332
100.3963.0%NA61.1160
110.2520.0%20.0%53.86
120.3852.0%28.0%57.385
130.3840.6%34.4%60.5132
140.3456.5%60.9%58.4170
150.3558.3%NA59.397
160.3886.4%NA62.9330
170.3428.6%NA58.957

NA = not available.

Of the patients treated with MRgFUS thalamotomy, 17 had an SDR < 0.4. The number of patients with SDR < 0.4 in whom the procedure screening failed and had unsuccessful thalamotomy were 2 and 2, respectively. Thus, 21 of 136 patients screened had an SDR < 0.4 (15%).

TABLE 3.

Relationships between SDR and clinical outcomes (cohort 1)

Clinical OutcomeValue*p Value
% improvement in treated hand tremor score compared w/ baseline
 3 mosr2 < 0.001, SE = 0.0790.952
 12 mosr2 = 0.009, SE = 0.1240.489
Lesion volr2 = 0.035, y = −0.7143 + 8.6x0.067
Adverse effectsOR 32.259, 95% CI 0.433–2405.9530.114

SE = standard error.

Partial linear regressions were used for tremor improvement and lesion volume. Logistic regression was used for adverse effects. Since lesion sizes and baseline tremor scores may have a relationship with clinical outcomes, they were used as covariates when assessing the relationship between SDR and clinical outcomes (tremor improvement and adverse effects). The tremor improvement scores at 3 months and 12 months were exponentially transformed to fit a normal distribution. The lesion size was transformed using natural log.

TABLE 4.

Relationships between SDR and sonication parameters (cohort 1)

Sonication ParameterLinear Regressionp Value
Maximum temperature (°C)r2 = 0.002, y = 42.8 + 35.7x0.639
Maximum energy (kJ)r2 = 0.054, y = 10.6 − 1.5x0.021
Duration time (mins)r2 = 0.010, y = 104.0 − 39.2x0.315
No. of sonicationsr2 < 0.001, y = 13.1 + 0.5x0.913

Linear regressions were used. Maximum energy was transformed using a natural log function to fit a normal distribution. Maximum temperature was defined as the highest temperature recorded during the sonications. Boldface type indicates statistical significance (p < 0.05).

Cohort 2: SDR Demographics in Emergency Department Patients

SDR values were calculated for 163 patients (mean age 63 ± 20 years [SD], 43% males) presenting to the emergency department who required head CT scans for various clinical indications. In this group, the SDR values approximated a normal distribution (Fig. 3). The mean SDR for the emergency department patients was 0.48 ± 0.13, 37% of whom had an SDR < 0.4. While a larger proportion of females seem to have unfavorable SDRs (Fig. 4), sex was not a significant determinant of SDR (p = 0.208). Age did not significantly correlate with SDR (r2 = 0.013, y = 0.2 + 0.007x; p = 0.147).

FIG. 3.
FIG. 3.

Distribution of SDR in the treated patients (cohort 1) and the emergency department patients (cohort 2). The SDR threshold of 0.4 is highlighted. Mean (x̄) and standard deviations (σ) are also shown. Figure is available in color online only.

FIG. 4.
FIG. 4.

Proportion of unfavorable skulls (SDR < 0.4) in males and females in the emergency department patients (cohort 2).

Discussion

This study investigated how SDR affects procedural parameters of MRgFUS thalamotomy for refractory tremor and its effect on clinical outcomes. While SDR was inversely correlated with the maximal energy required to create a lesion, it did not influence other sonication parameters or clinical outcomes (including tremor improvement). We also examined the SDR distribution in a cohort of consecutive patients receiving head CT scans as standard of care as part of their emergency department visit. In this population, SDR appears to be normally distributed, and slightly more than one-third had an SDR < 0.4.

The issue of an SDR cutoff for MRgFUS treatment has been controversial. The FDA has approved the procedure in patients with refractory tremor with an SDR > 0.45 (± 0.05),6 and, in our experience, an SDR > 0.4 allows more efficient lesioning. The practice at our institutions was to have a “soft” cutoff of SDR greater than 0.4 to be considered a good candidate for MRgFUS. However, we were able to make a thalamotomy in 17 patients with an SDR < 0.4 (range 0.25–0.39) and were unsuccessful in only 2 patients with very low SDRs of 0.17 and 0.27 (Table 2). If patients with low SDR can be successfully treated, this measure should not be used as a firm preoperative prognostic indicator. In addition to SDR, it is also possible that focal bony irregularities, often not appreciated by the global average of SDR, may influence treatment success.18 For example, we failed to produce a lesion in a patient with an SDR of 0.4, likely due to significant hyperostosis frontalis (Fig. 2). Focal areas of increased bone density could hinder energy penetrance and should be considered before performing MRgFUS thalamotomy. Numerical simulations of transcranial ultrasound propagation could also be used to improve the SDR metric.17 In the future, integrating SDR values with local skull density measurements may provide more clinically appropriate assessments.

SDR has been previously reported to influence procedural parameters and the maximal achievable lesioning temperature.1,4 Maximal temperature and accumulated thermal dose have been demonstrated to influence lesion size which has been shown to correlate with the incidence of adverse effects.9 Contrary to Chang et al.,4 we did not find SDR to correlate with the temperature at the lesion site in this larger cohort of patients. However, low SDR values were associated with higher intraprocedural maximal energy requirements, which may increase the risk of bone marrow necrosis and pain during the procedure.18

Understanding the distribution of SDR values in the general population is becoming increasingly important as the applications for transcranial MRgFUS expand. This is the first study to assess the distribution of SDR in a larger cohort (i.e., cohort 2). Using the same SDR calculation algorithm for both cohorts, we found that a greater proportion of the emergency patient cohort had low SDR (< 0.4; 37%) compared with the MRgFUS cohort (15%). This difference may be attributed in part to the inherent procedure selection bias against patients with low SDR (< 0.4). However, differences in demographics such as age, sex, and ethnic data may also explain this difference. Among the general population, age and sex did not influence SDR. Understanding that a sizeable proportion of the general population may be poor MRgFUS candidates (37% in cohort 2) provides an impetus for further technological improvement to overcome this limitation and/or exploration of other secondary surrogate markers to stratify patients for the suitability of MRgFUS treatment.

There were some limitations to this study. For one, it was underpowered to assess the effect of SDR < 0.4 on clinical outcomes. This limitation is likely to persist in future studies since standard practice entails preferential selection of patients with a favorable SDR, which will lead to disproportionately low numbers of patients treated with SDR < 0.4. Additionally, SDR in pediatric patients could not be assessed as our cohort of emergency department patients (cohort 2) consisted mostly of adults. Although cohort 2 may not be perfectly reflective of the average population, granted the cohort characteristics—patients randomly presenting for emergency care for disparate indications—we feel that this random sample of SDR data is largely generalizable to the population in which transcranial MRgFUS is currently utilized. Also, SDR calculations may vary according to the acquisition parameters and intended MRgFUS target.

Conclusions

SDR does not seem to govern clinical outcomes. For the vast majority of patients with low SDR, a thalamotomy lesion can be successfully made. SDR was normally distributed in the general population, with a mean value of approximately 0.46. More than one-third of the general population has a traditionally unfavorable SDR value (< 0.4). While SDR provides a global measure of SDR, focal areas of hyperdense bone may deserve closer attention when recommending MRgFUS to patients. Together, these findings suggest that SDR, at least within a reasonable range, should not be used as an exclusion criterion from MRgFUS candidacy. Still, extremely low SDR values may be preclusive to achieving adequate clinical benefit. As such, SDR should be complementary, not deterministic, in selecting who receives MRgFUS, as further study is still required to expound the implications of extremely low SDR values on clinical efficacy.

Acknowledgments

This work was supported by the R.R. Tasker Chair in Functional Neurosurgery at University Health Network and a Tier 1 Canada Research Chair in Neuroscience.

Disclosures

The study was partially supported by Insightec. Insightec assisted by calculating the SDR, but otherwise, had no role in data acquisition, analysis, or interpretation. The corresponding author confirms that they had full access to all the data in the study and had final responsibility for the decision to submit for publication.

David Tilden: clinical or research support for this study from and employee of Insightec. Dr. Hynynen: inventor/patent holder of intellectual property owned by Brigham and Women’s Hospital (BWH), which BWH has licensed to Insightec; receives royalties from BWH. Dr. Lozano: consultant to Medtronic, St. Jude, Boston Scientific, and Insightec.

Author Contributions

Conception and design: Lozano, Boutet, Ranjan. Acquisition of data: Boutet, Gwun, Gramer, Ranjan, Elias, Tilden, Huang, Li, Kucharczyk, Schwartz. Analysis and interpretation of data: Boutet, Gwun, Gramer, Elias, Tilden, Huang, Davidson, Lu, Tyrrell, Jones, Fasano, Hynynen, Schwartz. Drafting the article: Boutet, Gwun, Gramer, Elias, Davidson, Hynynen. Critically revising the article: all authors. Reviewed submitted version of manuscript: Lozano, Boutet, Gwun, Gramer, Ranjan, Elias, Tilden, Huang, Li, Davidson, Lu, Jones, Fasano, Hynynen, Kucharczyk, Schwartz. Approved the final version of the manuscript on behalf of all authors: Lozano. Statistical analysis: Boutet, Gwun, Huang, Lu, Tyrrell, Jones, Fasano. Administrative/technical/material support: Lozano, Tilden, Kucharczyk, Schwartz. Study supervision: Lozano, Boutet.

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    Fry FJ, Barger JE: Acoustical properties of the human skull. J Acoust Soc Am 63:15761590, 1978

  • 8

    Ghanouni P, Pauly KB, Elias WJ, Henderson J, Sheehan J, Monteith S, et al.: Transcranial MRI-guided focused ultrasound: A review of the technologic and neurologic applications. AJR Am J Roentgenol 205:150159, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Huang Y, Lipsman N, Schwartz ML, Krishna V, Sammartino F, Lozano AM, et al.: Predicting lesion size by accumulated thermal dose in MR-guided focused ultrasound for essential tremor. Med Phys 45:47044710, 2018

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    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Hynynen K, Clement G: Clinical applications of focused ultrasound-the brain. Int J Hyperthermia 23:193202, 2007

  • 12

    Insightec: INSIGHTEC’s ExAblate Neuro System Awarded European CE Mark for non-invasive treatment of neurological disorders in the brain. Insightec News & Events. December 4, 2012 (https://www.insightec.com/news-events/press-releases/insightecs-exablate-neuro-system-awarded-european-ce-mark) [Accessed March 7, 2019]

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    • Search Google Scholar
    • Export Citation
  • 13

    Jung HH, Chang WS, Rachmilevitch I, Tlusty T, Zadicario E, Chang JW: Different magnetic resonance imaging patterns after transcranial magnetic resonance-guided focused ultrasound of the ventral intermediate nucleus of the thalamus and anterior limb of the internal capsule in patients with essential tremor or obsessive-compulsive disorder. J Neurosurg 122:162168, 2015

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Lipsman N, Mainprize TG, Schwartz ML, Hynynen K, Lozano AM: Intracranial applications of magnetic resonance-guided focused ultrasound. Neurotherapeutics 11:593605, 2014

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

    Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, et al.: MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol 12:462468, 2013

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

    Pichardo S, Sin VW, Hynynen K: Multi-frequency characterization of the speed of sound and attenuation coefficient for longitudinal transmission of freshly excised human skulls. Phys Med Biol 56:219250, 2011

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

    Pulkkinen A, Werner B, Martin E, Hynynen K: Numerical simulations of clinical focused ultrasound functional neurosurgery. Phys Med Biol 59:16791700, 2014

  • 18

    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, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    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
  • Collapse
  • Expand

Cortical visual prostheses offer the potential to translate video into patterned visual cortex stimulation to produce predictable and consistent visual percepts. Artist and copyright Kenneth Probst. Published with permission. See the article by Niketeghad et al. (pp 2000–2007).

  • FIG. 1.

    Summary of MRgFUS thalamotomy patients.

  • FIG. 2.

    Head CT scan (bone window) obtained in a patient with an SDR = 0.4 in whom no lesions could be made. Hyperostosis frontalis is demonstrated (red shading). Figure is available in color online only.

  • FIG. 3.

    Distribution of SDR in the treated patients (cohort 1) and the emergency department patients (cohort 2). The SDR threshold of 0.4 is highlighted. Mean (x̄) and standard deviations (σ) are also shown. Figure is available in color online only.

  • FIG. 4.

    Proportion of unfavorable skulls (SDR < 0.4) in males and females in the emergency department patients (cohort 2).

  • 1

    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

    • Crossref
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    • Search Google Scholar
    • Export Citation
  • 2

    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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    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    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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    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Food and Drug Administration: Summary of Safety and Effectiveness Data (SSED). Magnetic Resonance Guided Focused Ultrasound Surgery System (MRgFUS). Silver Spring, MD: Food and Drug Adminsistration, 2016 (https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150038B.pdf) [Accessed March 7, 2019]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Fry FJ, Barger JE: Acoustical properties of the human skull. J Acoust Soc Am 63:15761590, 1978

  • 8

    Ghanouni P, Pauly KB, Elias WJ, Henderson J, Sheehan J, Monteith S, et al.: Transcranial MRI-guided focused ultrasound: A review of the technologic and neurologic applications. AJR Am J Roentgenol 205:150159, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Huang Y, Lipsman N, Schwartz ML, Krishna V, Sammartino F, Lozano AM, et al.: Predicting lesion size by accumulated thermal dose in MR-guided focused ultrasound for essential tremor. Med Phys 45:47044710, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Hynynen K, Clement G: Clinical applications of focused ultrasound-the brain. Int J Hyperthermia 23:193202, 2007

  • 12

    Insightec: INSIGHTEC’s ExAblate Neuro System Awarded European CE Mark for non-invasive treatment of neurological disorders in the brain. Insightec News & Events. December 4, 2012 (https://www.insightec.com/news-events/press-releases/insightecs-exablate-neuro-system-awarded-european-ce-mark) [Accessed March 7, 2019]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Jung HH, Chang WS, Rachmilevitch I, Tlusty T, Zadicario E, Chang JW: Different magnetic resonance imaging patterns after transcranial magnetic resonance-guided focused ultrasound of the ventral intermediate nucleus of the thalamus and anterior limb of the internal capsule in patients with essential tremor or obsessive-compulsive disorder. J Neurosurg 122:162168, 2015

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Lipsman N, Mainprize TG, Schwartz ML, Hynynen K, Lozano AM: Intracranial applications of magnetic resonance-guided focused ultrasound. Neurotherapeutics 11:593605, 2014

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

    Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, et al.: MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol 12:462468, 2013

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

    Pichardo S, Sin VW, Hynynen K: Multi-frequency characterization of the speed of sound and attenuation coefficient for longitudinal transmission of freshly excised human skulls. Phys Med Biol 56:219250, 2011

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

    Pulkkinen A, Werner B, Martin E, Hynynen K: Numerical simulations of clinical focused ultrasound functional neurosurgery. Phys Med Biol 59:16791700, 2014

  • 18

    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, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    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

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