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OBJECTIVE With the incorporation of real-time image guidance on the Gamma Knife system allowing for mask-based immobilization (Gamma Knife Icon [GKI]), conventionally fully fractionated (1.8–3.0 Gy/day) GKI radiation can now be delivered to take advantage of an inherently minimal margin for delivery uncertainty, sharp dose falloff, and inhomogeneous dose distribution. This case series details the authors’ preliminary experience in re-irradiating 7 complex primary intracranial tumors, which were considered to have been previously maximally radiated and situated adjacent to critical organs at risk. METHODS The authors retrospectively reviewed all patients who received fractionated re-irradiation using GKI at the Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada, between 2016 and 2021. Patients with brain metastases, and those who received radiotherapy courses in 5 or fewer fractions, were excluded. All radiotherapy doses were converted to the equivalent total dose in 2-Gy fractions (EQD2), with the assumption of an α/β ratio of 2 for late normal tissue toxicity and 10 for the tumor. RESULTS A total of 7 patients were included in this case series. Three patients had recurrent meningiomas, as well as 1 patient each with ependymoma, intracranial sarcoma, pituitary macroadenoma, and papillary pineal tumor. Six patients had undergone prior linear accelerator–based conventional fractionated radiotherapy and 1 patient had undergone prior proton therapy. Patients were re-irradiated with a median (range) total dose of 50.4 (30–63.4) Gy delivered in a median (range) of 28 (10–38) fractions with GKI. The median (range) target volume was 6.58 (0.2–46.3) cm3. The median (range) cumulative mean EQD2 administered to the tumor was 121.1 (107.9–181.3) Gy, and the median (range) maximum point EQD2 administered to the brainstem, optic nerves, and optic chiasm were 91.6 (74.0–111.5) Gy, 58.9 (6.3–102.9) Gy, and 59.9 (36.7–127.3) Gy, respectively. At a median (range) follow-up of 15 (6–42) months, 6 of 7 patients were alive with 4 having locally controlled disease. Only 3 patients experienced treatment-related toxicities, which were self-limited. CONCLUSIONS Fractionated radiotherapy using GKI may be a safe and effective method for the re-irradiation of complex progressive primary intracranial tumors, where the aim is to minimize the potential for serious late effects.

The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

History of adverse childhood experiences (ACEs) is associated with poorer treatment outcomes in depression. How ACEs affect outcomes from repetitive transcranial magnetic stimulation (rTMS) is not well-defined. The primary aim was to investigate whether ACEs affect depression outcomes in patients receiving high frequency rTMS, either deep TMS (dTMS) or intermittent theta burst stimulation (iTBS), to the left dorsolateral prefrontal cortex.The Hamilton Depression Rating Scale (HAMD-17) was collected at baseline and every 2 weeks for 4-6 weeks. Outcomes included improvement in HAMD-17 and remission. The ACE-10 questionnaire was used to quantify categories of ACEs. Data from 99 patients with MDD receiving an acute rTMS course were analyzed.Patients had a mean of 2.4 ACEs (SD 2.5). No significant differences in outcomes were found between dTMS or iTBS so these data were pooled. Using a continuous ACE variable showed no significant impact on outcomes. Using a categorical ACE variable (0, 1, 2, 3, 4 or more) did not reveal significant effects of ACEs on outcomes. Higher ACE was associated with steeper decrease in HAMD-17 only from baseline to week 2 but not at other times.This was an open-label study. The well-validated ACE questionnaire does not measure severity or frequency of adversities.Patients with depression receiving rTMS reported on average 2.4 ACEs. ACE scores may lead to a steeper early decline in HAMD-17 but did not otherwise impact depression outcomes. Presence of high levels of ACEs should not preclude consideration of rTMS for depression.

GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery.This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations.BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08.Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gamma Knife Icon-based hypofractionated stereotactic radiosurgery (GKI-HSRS) is a novel technical paradigm in the treatment of brain metastases that allows for both the dosimetric benefits of the GKI stereotactic radiosurgery (SRS) platform as well as the biologic benefits of fractionation. We report mature local control and adverse radiation effect (ARE) outcomes following 5 fraction GKI-HSRS for intact brain metastases.Patients with intact brain metastases treated with 5-fraction GKI-HSRS were retrospectively reviewed. Survival, local control, and adverse radiation effect rates were determined. Univariable and multivariable regression (MVA) were performed on potential predictive factors.Two hundred and ninety-nine metastases in 146 patients were identified. The median clinical follow-up was 10.7 months (range 0.5-47.6). The median total dose and prescription isodose was 27.5 Gy (range, 20-27.5) in 5 daily fractions and 52% (range, 45-93), respectively. The median overall survival (OS) was 12.7 months, and the 1-year local failure rate was 15.2%. MVA identified a total dose of 27.5 Gy vs. ≤ 25 Gy (hazard ratio [HR] 0.59, p = 0.042), and prior chemotherapy exposure (HR 1.99, p = 0.015), as significant predictors of LC. The 1-year ARE rate was 10.8% and the symptomatic ARE rate was 1.8%. MVA identified a gross tumor volume of ≥ 4.5 cc (HR 7.29, p 0.001) as a significant predictor of symptomatic ARE.Moderate total doses in 5 daily fractions of GKI-HSRS were associated with high rates of LC and a low incidence of symptomatic ARE.

With a high prevalence of posttraumatic stress disorder (PTSD) in females, studying sex differences in preclinical models is of substantial importance. We have previously employed behavioural criteria to identify and characterize a subpopulation of rats that presented impaired fear extinction and long-term fear and anxiety responses following fear conditioning. We now exposed male and female rats to fear conditioning and extinction and segregated the animals into weak- (WE) and strong-extinction (SE) groups based on behavioural scores during extinction. Animals were subsequently tested for tone and context recall, as well as anxiety-like responses in the marble burying and novelty suppression of feeding (NSF) tests. Vaginal lavages were collected to characterize the phase of the estrous cycle during fear extinction. We found that females had reduced freezing during tone recall and a lower latency to feed in the NSF test. No differences were found in females undergoing extinction during high and low estrogen phases of the cycle in any of the performed tests. Overall, the percentage of animals that presented WE and SE phenotypes was similar in males and females. Both, WE males and females had increased freezing during tone and context recall. Along with our previous reports, WE males presented anxiety-like responses, particularly in the NSF compared to SE animals. In contrast, WE females buried less marbles than their SE mates. Future investigation including a larger number of behavioural tests are certainly required to corroborate our findings and ascertain potential mechanisms to explain the differences observed in our study.

Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation have led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations, and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion.

BackgroundAggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB.ObjectivesTo test whether pHyp-DBS reduces aggressive behavior in mice through mechanisms involving testosterone and 5-HT.MethodsMale mice were housed with females for two weeks. These resident animals tend to become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5h/day for 8 consecutive days prior to daily encounters with the intruder. After testing, blood and brain were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1Aantagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 days.ResultsDBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1Areceptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS.ConclusionsThis study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1Amechanisms.HIGHLIGHTS-Posterior hypothalamus DBS reduces aggressive behavior in mice-Aggressive behavior was correlated with plasma testosterone levels-DBS increased 5-HT1A receptor density in the orbitofrontal cortex and amygdala-Pre-treatment with 5-HT1A antagonist (WAY) blocked the anti-aggressive effect of DBS

Functional neurological disorder and somatic symptom disorder are complex neuropsychiatric conditions that have been linked to circuit-based dysfunction of brain networks. Neuromodulation is a novel therapeutic strategy capable of modulating relevant brain networks, making it a promising potential candidate for the treatment of these patient populations. We conducted a systematic review of Medline, Embase and PsycINFO up to 4 March 2021. Trials investigating neuromodulation devices for the treatment of functional neurological disorder or somatic symptom disorder were selected. Extracted variables included study design, demographic and clinical characteristics, psychiatric comorbidity, neurostimulation protocols, clinical outcome measures and results. 404 studies were identified with 12 meeting inclusion criteria. 221 patients were treated in the included studies with mean study sample size of 18 (4–70). Five studies were randomised clinical trials. Functional motor symptoms (six weakness, four movement disorders) were the most studied subpopulations. Transcranial magnetic stimulation (TMS) was the most frequently used device (10 studies), followed by electroconvulsive therapy (one study) and direct-current stimulation (one study). Treatment protocols varied in intended therapeutic mechanism(s): eight studies aimed to modulate underlying network dysfunction, five aimed to demonstrate movement (one also leveraged the former) and three boosted their primary mechanism with enhanced suggestion/expectation. All but one study reported positive results; however, methodological/outcome heterogeneity, mixed study quality and small sample sizes precluded quantitative meta-analysis. Neuromodulation, particularly TMS for the treatment of functional motor symptoms, shows preliminary promise in a growing line of research. Larger, sham-controlled studies are needed to further establish efficacy and better understand therapeutic mechanisms.

Deep brain stimulation (DBS) has been investigated for neuropsychiatric disorders. In this phase 1 trial, we treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus. In addition to validated clinical scales, patients underwent neuroimaging studies and psychophysiological assessments of fear conditioning, extinction, and recall. We show that the procedure is safe and potentially effective (55% reduction in Clinical Administered PTSD Scale scores). Posttreatment imaging data revealed metabolic activity changes in PTSD neurocircuits. During psychophysiological assessments, patients with PTSD had higher skin conductance responses when tested for recall compared to healthy controls. After DBS, this objectively measured variable was significantly reduced. Last, we found that a ratio between recall of extinguished and nonextinguished conditioned responses had a strong correlation with clinical outcome. As this variable was recorded at baseline, it may comprise a potential biomarker of treatment response.

Tremor is a debilitating symptom that can lead to functional impairment. Pharmacotherapy is often successful, but up to 50% of patients are resistant to medications or cannot tolerate side effects. Thalamotomy to the ventral intermediate nucleus of the thalamus is a surgical intervention for refractory tremor. Thalamotomy surgeries include radiofrequency and incisionless procedures, such as Gamma Knife radiosurgery and magnetic resonance-guided focused ultrasound. Cognitive changes following thalamotomy have been inconsistently reported across studies. We performed a meta-analysis to summarize the impact of unilateral thalamotomy to the ventral intermediate nucleus of the thalamus across multiple cognitive domains. We searched MEDLINE, Embase Classic, Embase and EBM Reviews for relevant studies. Neuropsychological tests were categorized into seven cognitive domains: global cognition, verbal memory, non-verbal memory, executive function, phonemic fluency, semantic fluency and visuospatial processing. We calculated standardized mean differences as Hedges’ g and 95% confidence intervals of the change between pre- and postoperative cognitive scores. Pooling of standardized mean differences across studies was performed using random-effects models. Risk of bias across studies and quality of evidence for each cognitive domain were assessed with the National Institute of Health quality assessment tool and the GRADEpro Guideline Development Tool, respectively. Of the 1251 records reviewed, eight studies met inclusion criteria. We included 193 patients with essential tremor, Parkinson’s disease, or multiple sclerosis in the meta-analysis. There was a small significant decline in phonemic fluency [standardized mean difference = −0.29, 95% confidence interval: (−0.52, −0.05), P = 0.017] and a trend towards a decline in semantic fluency [standardized mean difference = −0.19, 95% confidence interval: (−0.40, 0.01), P = 0.056]. No postoperative changes were observed in the other cognitive domains (P values >0.14). In secondary analyses, we restricted the analyses to studies using magnetic resonance-guided focused ultrasound given its growing popularity and more precise targeting. In those analyses, there was no evidence of cognitive decline across any domain (P values >0.37). In terms of risk of bias, five studies were rated as ‘good’ and three studies were rated as ‘fair’. According to GRADEpro guidelines, the certainty of the effect for all cognitive domains was low. This study provides evidence that unilateral thalamotomy to the ventral intermediate nucleus of the thalamus is relatively safe from a cognitive standpoint, however, there may be a small decline in verbal fluency. Magnetic resonance-guided focused ultrasound might have a more favourable postoperative cognitive profile compared with other thalamotomy techniques.

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as treatment for refractory aggressive behaviour, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. 91% of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral posterior hypothalamic area and normative connectomic analyses identified fiber tracts and interconnected brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and the amygdala – together with patient age – was highly predictive of treatment outcome. Finally, transcriptomic analysis showed that genes involved in mechanisms of aggressive behaviour, neuronal communication, plasticity and neuroinflammation may underlie this functional network.SIGNIFICANCE STATEMENTThis study investigated the brain mechanisms associated with symptom improvement following deep brain stimulation of the posterior hypothalamus for severe and refractory aggressive behavior. Conducting an integrated imaging analysis of a large international multi-center dataset of patients treated with hypothalamic deep brain stimulation, we were able to show for the first time that treatment is highly efficacious across various patients with an average improvement greater than 70%. Leveraging this unique dataset allowed us to demonstrate that some patient characteristics are important for treatment success, describe the optimal target zone for maximal benefit, that engagement of distinct fiber tracts and networks within the emotional neurocircuitry are key for positive outcome, and - using imaging transcriptomics - elucidate some potential molecular underpinnings. The provided optimal stimulation site allows for direct clinical application.

Despite manifold advances in oncology, cancers of the central nervous system remain among the most lethal. Unique features of the brain, including distinct cellular composition, immunological privilege, and physical barriers to therapeutic delivery, likely contribute to the poor prognosis of patients with neuro-oncological disease. Focused ultrasound is an emerging technology that allows transcranial delivery of ultrasound energy to focal brain targets with great precision. A review of the clinical and preclinical focused ultrasound literature was performed to obtain data regarding the current state of the focused ultrasound in context of neuro-oncology. A narrative review was then constructed to provide an overview of current and future applications of this technology. Focused ultrasound can facilitate direct control of tumors by thermal or mechanical ablation, as well as enhance delivery of diverse therapeutics by disruption of the blood–brain barrier without local tissue damage. Indeed, ultrasound-sensitive drug formulations or sonosensitizers may be combined with ultrasound blood–brain barrier disruption to achieve high local drug concentration while limiting systemic exposure to therapeutics. Furthermore, focused ultrasound can induce radiosensitization, immunomodulation, and neuromodulation. Here we review applications of focused ultrasound with a focus on approaches currently under clinical investigation for the treatment of neuro-oncological disease, such as blood–brain barrier disruption for drug delivery and thermal ablation. We also discuss design of clinical trials, selection of patient cohorts, and emerging approaches to improve the efficacy of transcranial ultrasound, such as histotripsy, as well as combinatorial strategies to exploit synergistic biological effects of existing cancer therapies and ultrasound. Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.

Body dysmorphic disorder (BDD), hoarding disorder (HD), skin-picking disorder (SPD), and hair-pulling disorder (HPD) are characterized by compulsive behaviours leading to distress and impairment. Current treatments attain only partial or non-response. Interventional psychiatric approaches may target specific regions of the brain for treatment. This scoping review maps the current literature and synthesizes key findings. Databases were searched up to June 27, 2022 for studies examining interventional psychiatric treatments for BDD, HD, SPD, and HPD, producing 910 results. Twenty were included; 16 were case reports, two were case series, and two were randomized controlled trials. Studies reported on electroconvulsive therapy (ECT) (n=7), deep brain stimulation (DBS) (n=1), and intermittent theta-burst stimulation repetitive transcranial magnetic stimulation (rTMS) (n=1) for BDD; rTMS (n=1) and transcranial direct current stimulation (n=1) for HD; gamma knife capsulotomy (n=1) and rTMS (n=1) for SPD; and rTMS (n=2) and ECT (n=1) for HPD. Four studies reported on DBS for other indications complicated by SPD or HPD. The current literature consists mainly of case reports. Future studies should be randomized, controlled, adequately powered and blinded, examining rTMS localized to the anatomical targets for each disorder. Presently, the mainstay of treatment remains disorder-specific psychotherapy with limited evidence for medications.

Traumatic brain injury (TBI) has been associated with several lasting impairments that affect quality of life. Pre-clinical models of TBI have been studied to further our understanding of the underlying short-term and long-term symptomatology. Neuromodulation techniques have become of great interest in recent years as potential rehabilitative therapies after injury because of their capacity to alter neuronal activity and neural circuits in targeted brain regions. This systematic review aims to provide an overlook of the behavioral and neurochemical effects of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) in pre-clinical TBI models. After screening 629 abstracts, 30 articles were pooled for review. These studies showed that tDCS, TMS, DBS, or VNS delivered to rodents restored TBI-induced deficits in coordination, balance, locomotor activity and improved cognitive impairments in memory, learning, and impulsivity. Potential mechanisms for these effects included neuroprotection, a decrease in apoptosis, neuroplasticity, and the restoration of neural circuit abnormalities. The translational value, potential applicability, and the interpretation of these findings in light of outcome data from clinical trials in patients with TBI are discussed.

ObjectiveTo describe a case of functional tremor occurring after a successful MR-guided focused ultrasound thalamotomy (MRgFUS) for essential tremor.MethodsA 71-year-old right-handed man with essential tremor was referred to us for consideration of deep brain stimulation surgery for worsening bilateral upper limb tremor after a successful left MRgFUS for essential tremor.ResultsOn clinical exam, signs compatible with a functional tremor were noted, including entertainability and suppressibility. Electrophysiological studies were consistent with essential tremor and superimposed tremor fulfilling the laboratory-supported criteria for functional tremor.DiscussionWe describe the first reported case of a functional movement disorder occurring after successful MRgFUS procedure for essential tremor. Recognising this entity and its development after such therapeutic interventions is essential to avoid further unnecessary invasive therapies.

BackgroundFour ablative neurosurgical procedures are used in the treatment of refractory psychiatric illness. The long-term effects of these procedures on psychiatric symptoms across disorders has never been synthesised and meta-analysed.MethodsA preregistered systematic review was performed on studies reporting clinical results following ablative psychiatric neurosurgery. Four possible outcome measures were extracted for each study: depression, obsessive–compulsive symptoms, anxiety and clinical global impression. Effect sizes were calculated using Hedge’s g. Equipercentile linking was used to convert symptom scores to a common metric. The main outcome measures were the magnitude of improvement in depression, obsessive compulsive symptoms, anxiety and clinical global impression. The secondary outcome was a subgroup analysis comparing the magnitude of symptom changes between the four procedures.ResultsOf 943 articles, 43 studies reporting data from 1414 unique patients, were included for pooled effects estimates with a random-effects meta-analysis. Results showed that there was a large effect size for improvements in depression (g=1.27; pConclusionsContemporary ablative neurosurgical procedures were significantly associated with improvements in depression, obsessive–compulsive symptoms, anxiety and clinical global impression.PROSPERO registration numberCRD42020164784.