Current Progress in Magnetic Resonance-Guided Focused Ultrasound to Facilitate Drug Delivery across the Blood-Brain Barrier.

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer's disease, Parkinson's disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions.

Insertional effect following electrode implantation: an underreported but important phenomenon.

Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as 'insertional effect', can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation as an active part of the deep brain stimulation therapy.

Deep brain stimulation for Alzheimer's disease - current status and next steps.

INTRODUCTION: Alzheimer's disease (AD) requires novel therapeutic approaches due to limited efficacy of current treatments. AREAS COVERED: This article explores AD as a manifestation of neurocircuit dysfunction and evaluates deep brain stimulation (DBS) as a potential intervention. Focusing on fornix-targeted stimulation (DBS-f), the article summarizes safety, feasibility, and outcomes observed in phase 1/2 trials, highlighting findings such as cognitive improvement, increased metabolism, and hippocampal growth. Topics for further study include optimization of electrode placement, and the role of stimulation-induced autobiographical-recall. Nucleus basalis of Meynert (DBS-NBM) DBS is also discussed and compared with DBS-f. Challenges with both DBS-f and DBS-NBM are identified, emphasizing the need for further research on optimal stimulation parameters. The article also reviews alternative DBS targets, including medial temporal lobe structures and the ventral capsule/ventral striatum. EXPERT OPINION: Looking ahead, a phase-3 DBS-f trial, and the prospect of closed-loop stimulation using EEG-derived biomarkers or hippocampal theta activity are highlighted. Recent FDA-approved therapies and other neuromodulation techniques like temporal interference and low-intensity ultrasound are considered. The article concludes by underscoring the importance of imaging-based diagnosis and staging to allow for circuit-targeted therapies, given the heterogeneity of AD and varied stages of neurocircuit dysfunction.

Neuroscience fundamentals relevant to neuromodulation: Neurobiology of deep brain stimulation in Parkinson's disease.

Deep Brain Stimulation (DBS) has become a pivotal therapeutic approach for Parkinson's Disease (PD) and various neuropsychiatric conditions, impacting over 200,000 patients. Despite its widespread application, the intricate mechanisms behind DBS remain a subject of ongoing investigation. This article provides an overview of the current knowledge surrounding the local, circuit, and neurobiochemical effects of DBS, focusing on the subthalamic nucleus (STN) as a key target in PD management. The local effects of DBS, once thought to mimic a reversible lesion, now reveal a more nuanced interplay with myelinated axons, neurotransmitter release, and the surrounding microenvironment. Circuit effects illuminate the modulation of oscillatory activities within the basal ganglia and emphasize communication between the STN and the primary motor cortex. Neurobiochemical effects, encompassing changes in dopamine levels and epigenetic modifications, add further complexity to the DBS landscape. Finally, within the context of understanding the mechanisms of DBS in PD, the article highlights the controversial question of whether DBS exerts disease-modifying effects in PD. While preclinical evidence suggests neuroprotective potential, clinical trials such as EARLYSTIM face challenges in assessing long-term disease modification due to enrollment timing and methodology limitations. The discussion underscores the need for robust biomarkers and large-scale prospective trials to conclusively determine DBS's potential as a disease-modifying therapy in PD.

Adverse Effects of Deep Brain Stimulation for Treatment-Resistant Depression: A Scoping Review.

Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD). Although adverse effects have been reported in early-phase and a few randomized clinical trials, little is known about its overall safety profile, which has been assumed to be similar to that of DBS for movement disorders. The objective of this study was to pool existing safety data on DBS for TRD. Following PRISMA guidelines, PubMed was searched for English articles describing adverse outcomes after DBS for TRD. Studies were included if they reported at least 5 patients with a minimal follow-up of 6 months. After abstract (n = 607) and full-article review (n = 127), 28 articles reporting on 353 patients met criteria for final inclusion. Follow-up of the studies retrieved ranged from 12 to 96 months. Hemorrhages occurred in 0.8% of patients and infections in 10.2%. The rate of completed suicide was 2.5%. Development or worsening of depressive symptoms, anxiety, and mania occurred in 18.4%, 9.1%, and 5.1%, respectively. There were some differences between targets, but between-study heterogeneity precluded statistical comparisons. In conclusion, DBS for TRD is associated with surgical and psychiatric adverse events. Hemorrhage and infection occur at rates within an accepted range for other DBS applications. The risk of suicide after DBS for TRD is 2.5% but may not represent a significant deviation from the natural history of TRD. Finally, risks of worsening depression, anxiety, and the incidence of mania should be acknowledged when considering DBS for TRD.

Neuromodulation techniques - From non-invasive brain stimulation to deep brain stimulation.

Over the past 30 years, the field of neuromodulation has witnessed remarkable advancements. These developments encompass a spectrum of techniques, both non-invasive and invasive, that possess the ability to both probe and influence the central nervous system. In many cases neuromodulation therapies have been adopted into standard care treatments. Transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial ultrasound stimulation (TUS) are the most common non-invasive methods in use today. Deep brain stimulation (DBS), spinal cord stimulation (SCS), and vagus nerve stimulation (VNS), are leading surgical methods for neuromodulation. Ongoing active clinical trials using are uncovering novel applications and paradigms for these interventions.

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

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 (NCT04118764) 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-ß42/40 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.

Deep brain stimulation of the subgenual cingulum and uncinate fasciculus for the treatment of posttraumatic stress disorder.

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.

Cognitive effects of unilateral thalamotomy for tremor: a meta-analysis.

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.

Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance-Guided Focused Ultrasound in Parkinson's Disease: A Phase I Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial.

Alcohol use disorder (AUD) is a highly prevalent, often refractory, medical illness. The symptoms of AUD are driven by dysfunction in several neurocircuits centered on the nucleus accumbens (NAc). Case reports and animal studies suggest NAc-DBS may be an effective harm-reduction treatment in severe AUD. Six patients with severe, refractory AUD underwent NAc-DBS. Safety metrics and clinical outcomes were recorded. Positron emission tomography (FDG-PET) was used to measure glucose metabolism in the NAc at baseline and 6 months. Functional magnetic resonance imaging (fMRI) was used to characterize postoperative changes in NAc functional connectivity to the rest of the brain, as well as NAc and dorsal striatal reactivity to alcoholic visual cues. This study was registered with ClinicalTrials.gov, NCT03660124. All patients experienced a reduction in craving. There was a significant reduction in alcohol consumption, alcohol-related compulsivity, and anxiety at 12 months. There was no significant change in depression. FDG-PET analysis demonstrated reduced NAc metabolism by 6 months, which correlated with improvements in compulsive drinking behaviors. Clinical improvement correlated with reduced functional connectivity between the NAc and the visual association cortex. Active DBS was associated with reduced activation of the dorsal striatum during passive viewing of alcohol-containing pictures. NAc-DBS is feasible and safe in patients with severe, otherwise refractory AUD. It is associated with a reduction in cravings and addictive behavior. A potential mechanism underlying this process is a down-regulation of the NAc, a disruption of its functional connectivity to the visual association cortex, and interference of cue-elicited dorsal striatum reactivity. Trial Registration NCT03660124 ( www.clinicaltrials.gov ).

Lesional psychiatric neurosurgery: meta-analysis of clinical outcomes using a transdiagnostic approach.

BACKGROUND: Four 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. METHODS: A 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. RESULTS: Of 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; p<0.0001), obsessive-compulsive symptoms (g=2.25; p<0.0001) and anxiety (g=1.76; p<0.0001). The pooled clinical global impression improvement score was 2.36 (p<0.0001). On subgroup analysis, there was only a significant degree of heterogeneity in effect sizes between procedure types for anxiety symptoms, with capsulotomy resulting in a greater reduction in anxiety than cingulotomy. CONCLUSIONS: Contemporary ablative neurosurgical procedures were significantly associated with improvements in depression, obsessive-compulsive symptoms, anxiety and clinical global impression. PROSPERO REGISTRATION NUMBER: CRD42020164784.

MR-guided focused ultrasound enhances delivery of trastuzumab to Her2-positive brain metastases.

The blood-brain barrier (BBB) is an important factor limiting the effectiveness of central nervous system (CNS) therapeutics. MR-guided focused ultrasound (MRgFUS) is a noninvasive, spatially precise technology that enhances drug delivery across a temporarily permeable BBB. However, despite promising preclinical data, successful drug delivery has yet to be proven in human patients. In this study, we provide primary evidence of enhanced brain penetration of trastuzumab with MRgFUS in patients with Her2-positive breast cancer and brain metastases (NCT03714243). Four patients with progressive intracranial disease and stable systemic disease were enrolled in a single-arm open-labeled study. Twenty treatments combining transcranial MRgFUS with concomitant standard-of-care intravenous trastuzumab-based therapies were administered as outpatient procedures. The primary outcome was safety, and there were no treatment-related serious adverse events. The efficacy of trastuzumab delivery was demonstrated using 111In-BzDTPA-NLS-trastuzumab SPECT imaging. The standardized uptake value ratio (SUVR) of MRgFUS-treated lesions increased, on average, by 101 ± 71%, compared to −18 ± 26% in control lesions. MRgFUS enhanced drug uptake in 87 ± 17% of sonicated voxels (>20% increase in SUVR), with up to a 450% voxel-wise increase detected. Control lesions had 8 ± 8% voxels with >20% increase in SUVR. With treatment, unidimensional tumor measurements decreased by 19 ± 12%. This study provides first-in-human evidence of noninvasive, spatially targeted monoclonal antibody delivery across the BBB using MRgFUS, demonstrating the promise of this technology for a broad range of CNS diseases.

A systematic review on neuromodulation therapies for reducing body weight in patients with obesity.

The global prevalence of obesity increases yearly along with a rising demand for efficacious, safe, and accessible treatments. Neuromodulation interventions (i.e., deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES]) have been proposed as novel therapies. This systematic review sought to examine the safety and efficacy of neuromodulation therapies in reducing body weight in patients with obesity. Using PRISMA guidelines, we performed a systematic review for studies on neuromodulation for the treatment of obesity, resulting in 60 trials included (7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES; a total of 3,042 participants). While promising results have been reported in open label studies, double-blinded randomized clinical trials often did not reach their primary endpoints, with no technique inducing a striking reduction in body weight. Bearing in mind the complexity and multifactorial nature of obesity, it is possible that a single treatment may not be enough for patients to lose or maintain the weight lost at long term.

The Crucial Role of Eosinophils in the Life Cycle, Radiographical Architecture, and Risk of Recurrence of Chronic Subdural Hematomas.

Chronic subdural hematomas (CSDHs) are a common neurological condition, whose incidence is expected to increase with an aging population. Although surgical evacuation is the mainstay of treatment, it results in a recurrence requiring reoperation (RrR) in 3-30% of cases. Recurrence is thought to be driven by a combination of inflammatory and angiogenic processes occurring within the CSDH outer membrane. Pathological specimens of 72 primary CSDHs were examined for eosinophilic infiltrate. For each case, the pre-operative computed tomography (CT) scan was graded according to the Nakaguchi grading scheme as homogeneous, laminar, separated, or trabecular. Rate of RrR was compared based on eosinophilic infiltrate and CT grade. A dense eosinophilic infiltrate was observed in 22% of specimens. The rate of RrR among specimens with a dense eosinophilic infiltrate was 0%, whereas it was 14.3% among specimens without a dense eosinophilic infiltrate. Incidence among homogeneous, laminar, separated, and trabecular CT subtypes was 4%, 27%, 58%, and 24%, respectively. A dense eosinophilic infiltrate found within the outer membrane of a CSDH may be a marker of hematoma maturation, signaling a transition toward healing and fibrosis, and a lower risk of RrR.

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors.

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 from brain tumors, 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 that 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 (BBBO) alone (NCT03739905). RESULTS: Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-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 harbor 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.