Competing interestsJ. K. K. is a consultant for Medtronic and Boston Scientific. P. B. is a consultant for Medtronic. W. M. G. is the Director, Chief Scientific Officer and share owner of Deep Brain Innovations, LLC. He also receives royalty payments for licensed patents on temporal patterns of deep brain stimulation. M. I. H. has received travel expenses and honoraria from Boston Scientific for speaking at meetings. A. H. was supported by the German Research Council (DFG grant 410169619) and reports lecture fees from Medtronic and Boston Scientific unrelated to the present work. P. A. T. works as a consultant for Boston Scientific Neuromodulation. J. V. works as a consultant to Boston Scientific, Medtronic, and Newronika and has received honoraria for lectures from Boston Scientific and Medtronic as well as research grants from Boston Scientific and Medtronic. A. M. L. has served as a consultant for Boston Scientific, Medtronic, Aleva, and Abbott and is a co-founder of Functional Neuromodulation. All other authors declare no competing interests. Peer review informationNature Reviews Neurology thanks V. Visser-Vandewalle and Y. Temel for their contribution to the peer review of this work. Publisher's noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

OBJECTIVETranscranial 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.METHODSA 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.RESULTSIn 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.CONCLUSIONSAlthough 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.

MRgFUS is a safe, noninvasive method to deliver spatially targeted monoclonal antibody across the BBB in patients with brain tumors.

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OBJECTIVE A surgical series of 201 benign and malignant peripheral nerve sheath tumors (PNSTs) was assessed to characterize the anatomical and clinical presentation of tumors and identify predictors of neurological outcome, recurrence, and extent of resection. METHODS All surgically treated PNSTs from the Division of Neurosurgery at Toronto Western Hospital from 1993 to 2010 were reviewed retrospectively. Data were collected on patient demographics, clinical presentation, surgical technique, extent of resection, postoperative neurological outcomes, and recurrence. RESULTS One hundred seventy-five patients with 201 tumors had adequate follow-up for analysis. There were 182 benign and 19 malignant PNSTs. Of the benign lesions, 133 were schwannomas, 21 of which were associated with a diagnosis of schwannomatosis. There were 49 neurofibromas, and 26 were associated with neurofibromatosis Type 1 (NF1). Patients presenting with schwannomas were significantly older than those with neurofibromas. Schwannomas were more readily resected than neurofibromas, with the extent of resection of the former influenced by tumor location. Patients with benign PNSTs typically presented with a painful mass and less frequently with motor deficits. The likelihood of worsened postoperative motor function was decreased in patients with fully resected tumors or preoperative deficits. Recurrence of schwannomas and neurofibromas were seen more frequently in patients diagnosed with NF3 and NF1, respectively. Subtotal resection was associated with the increased recurrence of all benign lesions. CONCLUSIONS Outcomes following resection of benign PNSTs depend on tumor histopathology, tumor location, and genetic predisposition syndrome. Gross-total resection should be attempted for benign lesions where possible. The management of malignant PNSTs remains challenging, requiring a multimodal approach.

This study examined the effects of strength, aerobic fitness, and activity profile on the incidence of overuse injuries, particularly stress fractures, during military training. A total of 136 military recruits were followed during 9 weeks of basic training. Maximal strength and aerobic fitness were determined by a one-repetition maximum leg press and a 2,000-m run, respectively. An activity profile was determined by the recruit's activity history. Twelve recruits (8.8%) were diagnosed with stress fractures. Recruits who were 1 SD below the population mean in both absolute (98.4 ± 36.6 kg) and relative strength (1.72 ± 0.61 kglkg of body weight) had a five times greater risk for stress fracture (p < 0.05) than stronger recruits. Poor aerobic fitness did not appear to be related to any increased incidence of stress fracture. It appears that recruits with lower body strength levels, within 1 SD of the population mean, have a reduced incidence of stress fractures during military training.

Background Liquid biopsy is promising for early detection, monitoring of response and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. Methods Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening alone (NCT03739905). Results Brain regions averaging 7.8±6.0 cm 3 (range 0.8–23.1 cm 3) were successful treated within 111±39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6±1.2 fold, p&lt;0.01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2±1.9 fold, p&lt;0.01), and brain specific protein S100b (1.4±0.2 fold, p&lt;0.01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease and post-BBB opening specific, in keeping with our hypothesis. We also found cfDNA mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbour the tumor mutation. Conclusions This first-in-human proof-of concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.