Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review.

The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.

Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

Disease applications of spinal cord stimulation: Chronic nonmalignant pain.

Neuropathic pain is a chronic condition representing a significant burden for society. It is estimated 1 out of 10 people over the age of 30 that in the US have been diagnosed with neuropathic pain. Most of the available treatments for neuropathic pain have moderate efficacy over time which limit their use; therefore, other therapeutic approaches are needed for patients. Spinal cord stimulation is an established and cost-effective modality for treating severe chronic pain. In this article we will review the current approved indications for the use of spinal cord stimulation in the US and the novel therapeutic options which are now available using this therapy.

A phase 1 open-label trial evaluating focused ultrasound unilateral anterior thalamotomy for focal onset epilepsy.

OBJECTIVE: Focused ultrasound ablation (FUSA) is an emerging treatment for neurological and psychiatric diseases. We describe the initial experience from a pilot, open-label, single-center clinical trial of unilateral anterior nucleus of the thalamus (ANT) FUSA in patients with treatment-refractory epilepsy. METHODS: Two adult subjects with treatment-refractory, focal onset epilepsy were recruited. The subjects received ANT FUSA using the Exablate Neuro (Insightec) system. We determined the safety and feasibility (primary outcomes), and changes in seizure frequency (secondary outcome) at 3, 6, and 12 months. Safety was assessed by the absence of side effects, that is, new onset neurological deficits or performance deterioration on neuropsychological testing. Feasibility was defined as the ability to create a lesion within the anterior nucleus. The monthly seizure frequency was compared between baseline and postthalamotomy. RESULTS: The patients tolerated the procedure well, without neurological deficits or serious adverse events. One patient experienced a decline in verbal fluency, attention/working memory, and immediate verbal memory. Seizure frequency reduced significantly in both patients; one patient was seizure-free at 12 months, and in the second patient, the frequency reduced from 90-100 seizures per month to 3-6 seizures per month. SIGNIFICANCE: This is the first known clinical trial to assess the safety, feasibility, and preliminary efficacy of ANT FUSA in adult patients with treatment-refractory focal onset epilepsy.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes.

OBJECTIVE: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6-12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe. METHODS: In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in ß-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben ß-amyloid PET. RESULTS: Ten participants (range 55-76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6-12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24-48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer's Disease Assessment Scale-cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer's Disease Neuroimaging Initiative. PET scans demonstrated an average ß-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions. CONCLUSIONS: This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of ß-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.

Vagus nerve stimulation paired with rehabilitation for stroke: Implantation experience from the VNS-REHAB trial.

OBJECTIVE: Vagus Nerve Stimulation (VNS) paired with rehabilitation delivered by the Vivistim® Paired VNS™ System was approved by the FDA in 2021 to improve motor deficits in chronic ischemic stroke survivors with moderate to severe arm and hand impairment. Vagus nerve stimulators have previously been implanted in over 125,000 patients for treatment-resistant epilepsy and the surgical procedure is generally well-tolerated and safe. In this report, we describe the Vivistim implantation procedure, perioperative management, and complications for chronic stroke survivors enrolled in the pivotal trial. METHODS: The pivotal, multisite, randomized, triple-blind, sham-controlled trial (VNS-REHAB) enrolled 108 participants. All participants were implanted with the VNS device in an outpatient procedure. Thrombolytic agents were temporarily discontinued during the perioperative period. Participants were discharged within 48 hrs and started rehabilitation therapy approximately 10 days after the Procedure. RESULTS: The rate of surgery-related adverse events was lower than previously reported for VNS implantation for epilepsy and depression. One participant had vocal cord paresis that eventually resolved. There were no serious adverse events related to device stimulation. Over 90% of participants were taking antiplatelet drugs (APD) or anticoagulants and no adverse events or serious adverse events were reported as a result of withholding these medications during the perioperative period. CONCLUSIONS: This study is the largest, randomized, controlled trial in which a VNS device was implanted in chronic stroke survivors. Results support the use of the Vivistim System in chronic stroke survivors, with a safety profile similar to VNS implantations for epilepsy and depression.

A scientometric analysis of the 100 most cited articles on magnetic resonance guided focused ultrasound.

Background: Diagnostic ultrasound has long been a part of a physician's armamentarium, but transcranial focused ultrasound (FUS) is an emerging treatment of neurological disorders. Consequently, the literature in this field is increasing at a rapid pace. Objective: This analysis was aimed to identify the top-cited articles on FUS to discern their origin, spread, current trends highlighting future impact of this novel neurosurgical intervention. Methods: We searched the Web of Science database on 28th May 2021 and identified the top 100 cited articles. These articles were analyzed with various scientometric parameters like the authors, corresponding authors, country of corresponding author, journal of publication, year of publication. Citation based parameters including total citations, mean citations per article and mean citations, citation count, and the citation per year, citations per year and co-authors per document were studied as well in addition to Hirsch h-index, g-index, m-index, Bradford's Law, Lotka's law and Collaboration index. Results: The 100 top-cited articles were published between 1998 and 2019 in 45 different journals. The average citations per document and citations per document per year were 97.78 and 12.47, respectively. The most prolific authors were Hynynen K (Medical Biophysics-Toronto), Elias WJ (Neurosurgery-Virginia), Zadicario (InSightec). The Journal of Neurosurgery published the most top-cited articles (n = 11), and most articles originated from the United States, followed by Canada. Among individual institutions, the University of Toronto was the most productive. Conclusion: FUS is an emerging treatment of neurological disorders. With its increasing application, the FUS literature is increasing rapidly. Eleven countries contributed to the top 100 cited articles, with the top 2 countries (the United States and Canada) contributing to more than half of these articles.

Reliable cognitive change following unilateral deep brain stimulation in essential tremor.

Objective: This retrospective analysis assessed regression-based reliable change (RC) of cognition in a sample of essential tremor (ET) patients who underwent unilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM-DBS).Method: Thirty patients (mean age at pre-evaluation = 70.4 ± 6.3 years) underwent neuropsychological evaluation pre- and post-unilateral VIM-DBS placement (mean time between pre and post-evaluation = 13.1 ± 4.0 months). Paired samples t-tests and RC analyses were employed.Results: No significant within-group differences were observed when cognitive scores were compared between evaluations. The vast majority of patients demonstrated stability across pre-and post-surgical evaluations (i.e. 29 out of 30); however, those with high-risk co-morbid medical conditions may be vulnerable to post-surgical cognitive decline as indicated by RC measures.Conclusions: The use of regression-based RC indices to assess individual cognitive changes between pre and post-surgical evaluations control for systematic and measurement errors that can occur over repeated evaluations, and may be able to identify cognitive changes that evade detection in traditional within-group comparisons.

Non-motor effects of subthalamic nucleus stimulation in Parkinson patients.

The current white matter connectivity analyses of the subthalamic region have focused on the motor effects of deep brain stimulation. We investigate white matter connectivity associated with the stimulation-induced non-motor acute clinical effects in three domains: mood changes, dizziness, and sweating. We performed whole-brain probabilistic tractography seeded from the domain-specific stimulation volumes. The resultant connectivity maps were statistically compared across patients. The cortical voxels associated with each non-motor domain were compared with stimulation-induced motor improvements in a multivariate model. The resulting voxel maps were thresholded for false discovery (FDR q < 0.05) and clustered using a multimodal atlas. We also performed a group-level parcellation of stimulation volumes to identify the local pathways associated with each non-motor domain. The non-motor effects were rarely observed during stimulation titration: from 1100 acute clinical effects, mood change was observed in 14, dizziness in 23, and sweating in 20. Distinct cortical clusters were associated with each domain; notably, mood change was associated with voxels in the salience network and dizziness with voxels in the visual association cortex. The subthalamic parcellation yielded a mediolateral gradient, with the motor parcel being lateral and the non-motor parcels medial. We also observed an anteroposterior organization in the medial non-motor clusters with mood changes being anterior, followed posteriorly by dizziness, and sweating. We interpret these findings based on the literature and foresee these to be useful in guiding DBS programming.

Continual cerebrospinal fluid sampling in the neonatal domestic piglet for biomarker and discovery studies.

BACKGROUND: Longitudinal access to cerebrospinal fluid (CSF) is useful for biomarker discovery in neurological disorders or diseases affecting CSF composition. Here, we aim to test a new method for insertion of a permanent intrathecal catheter, facilitating longitudinal collection of CSF. NEW METHOD: We surgically placed a permanent intrathecal catheter into the cisterna magna of anesthetized neonatal piglets. The thecal sac was accessed at the L5-S1 spinal level and a radiopaque catheter was inserted under fluoroscopic x-ray guidance to position the tip at the cisterna magna. A titanium access port was connected to the catheter and anchored subcutaneously. Immediately after surgery, we confirmed CSF flow through the catheter and port via needle aspiration. Catheter patency over a two-month study period was determined through periodic CSF collection from the port. RESULTS: Frequent (up to 3 times weekly), longitudinal sampling of CSF was achievable in neonatal piglets up to 60 days after implantation. CSF was readily accessible through the port without major adverse events. Catheterized piglets demonstrated slower, but normal, weight gain compared to control piglets. Post-operative complications were managed with standard access precautions and medications. There were no complications involving the implanted hardware. COMPARISON WITH EXISTING METHOD(S): This method fills a critical gap in the existing methods for longitudinal CSF sampling through an implanted intrathecal catheter system in neonatal piglets. CONCLUSIONS: This novel method is both safe and effective for longitudinal CSF access in the domestic piglet. Catheter patency and access to CSF is maintained over multiple months without major adverse events.

Intraoperative lesion characterization after focused ultrasound thalamotomy.

OBJECTIVE: Outcomes after focused ultrasound ablation (FUSA) for essential tremor remain heterogeneous, despite therapeutic promise. Clinical outcomes are directly related to the volume and location of the therapeutic lesions, consistent with CNS ablative therapies. Recent data demonstrate that postoperative diffusion MRI, specifically the quantification of intracellular diffusion by restricted diffusion imaging (RDI), can accurately characterize focused ultrasound lesions. However, it is unclear whether RDI can reliably detect focused ultrasound lesions intraoperatively (i.e., within a few minutes of lesioning) and whether the intraoperative lesions predict delayed clinical outcomes. METHODS: An intraoperative imaging protocol was implemented that included RDI and T2-weighted imaging in addition to intraoperative MR thermography. Lesion characteristics were defined with each sequence and then compared. An imaging-outcomes analysis was performed to determine lesion characteristics associated with delayed clinical outcomes. RESULTS: Intraoperative RDI accurately identified the volume and location of focused ultrasound lesions. Intraoperative T2-weighted imaging underestimated the lesion volume but accurately identified the location. Intraoperative RDI revealed that lesions of the ventral border of the ventral intermediate nucleus were significantly associated with postoperative tremor improvement. In contrast, the lesions extending into the inferolateral white matter were associated with postoperative ataxia. CONCLUSIONS: These data support the acquisition of intraoperative RDI to characterize focused ultrasound lesions. Future research should test the histological correlates of intraoperative RDI and test whether it can be developed as feedback to optimize the current technique of FUSA.

Radiological identification of the globus pallidus motor subregion in Parkinson's disease.

OBJECTIVE: Globus pallidus (GP) lesioning improves motor symptoms of Parkinson's disease (PD) and is occasionally associated with nonmotor side effects. Although these variable clinical effects were shown to be site-specific within the GP, the motor and nonmotor subregions have not been distinguished radiologically in patients with PD. The GP was recently found to have a distinct radiological signature on diffusion MRI (dMRI), potentially related to its unique cellular content and organization (or tissue architecture). In this study, the authors hypothesize that the magnitude of water diffusivity, a surrogate for tissue architecture, will radiologically distinguish motor from nonmotor GP subregions in patients with PD. They also hypothesize that the therapeutic focused ultrasound pallidotomy lesions will preferentially overlap the motor subregion. METHODS: Diffusion MRI from healthy subjects (n = 45, test-retest S1200 cohort) and PD patients (n = 33) was parcellated based on the magnitude of water diffusivity in the GP, as measured orientation distribution function (ODF). A clustering algorithm was used to identify GP parcels with distinct ODF magnitude. The individual parcels were used as seeds for tractography to distinguish motor from nonmotor subregions. The locations of focused ultrasound lesions relative to the GP parcels were also analyzed in 11 patients with PD. RESULTS: Radiologically, three distinct parcels were identified within the GP in healthy controls and PD patients: posterior, central, and anterior. The posterior and central parcels comprised the motor subregion and the anterior parcel was classified as a nonmotor subregion based on their tractography connections. The focused ultrasound lesions preferentially overlapped with the motor subregion (posterior more than central). The hotspots for motor improvement were localized in the posterior GP parcel. CONCLUSIONS: Using a data-driven approach of ODF-based parcellation, the authors radiologically distinguished GP motor subregions in patients with PD. This method can aid stereotactic targeting in patients with PD undergoing surgical treatments, especially focused ultrasound ablation.

New Frontiers for Deep Brain Stimulation: Directionality, Sensing Technologies, Remote Programming, Robotic Stereotactic Assistance, Asleep Procedures, and Connectomics.

Over the last few years, while expanding its clinical indications from movement disorders to epilepsy and psychiatry, the field of deep brain stimulation (DBS) has seen significant innovations. Hardware developments have introduced directional leads to stimulate specific brain targets and sensing electrodes to determine optimal settings via feedback from local field potentials. In addition, variable-frequency stimulation and asynchronous high-frequency pulse trains have introduced new programming paradigms to efficiently desynchronize pathological neural circuitry and regulate dysfunctional brain networks not responsive to conventional settings. Overall, these innovations have provided clinicians with more anatomically accurate programming and closed-looped feedback to identify optimal strategies for neuromodulation. Simultaneously, software developments have simplified programming algorithms, introduced platforms for DBS remote management via telemedicine, and tools for estimating the volume of tissue activated within and outside the DBS targets. Finally, the surgical accuracy has improved thanks to intraoperative magnetic resonance or computerized tomography guidance, network-based imaging for DBS planning and targeting, and robotic-assisted surgery for ultra-accurate, millimetric lead placement. These technological and imaging advances have collectively optimized DBS outcomes and allowed "asleep" DBS procedures. Still, the short- and long-term outcomes of different implantable devices, surgical techniques, and asleep vs. awake procedures remain to be clarified. This expert review summarizes and critically discusses these recent innovations and their potential impact on the DBS field.

Functional Neuroimaging During Asleep DBS Surgery: A Proof of Concept Study.

Object: A real-time functional magnetic resonance imaging (fMRI) feedback during ventral intermediate nucleus (VIM) deep brain stimulation (DBS) under general anesthesia (or "asleep" DBS) does not exist. We hypothesized that it was feasible to acquire a reliable and responsive fMRI during asleep VIM DBS surgery. Methods: We prospectively enrolled 10 consecutive patients who underwent asleep DBS for the treatment of medication-refractory essential tremor. Under general anesthesia, we acquired resting-state functional MRI immediately before and after the cannula insertion. Reliability was determined by a temporal signal-to-noise-ratio >100. Responsiveness was determined based on the fMRI signal change upon insertion of the cannula to the VIM. Results: It was feasible to acquire reliable fMRI during asleep DBS surgery. The fMRI signal was responsive to the brain cannula insertion, revealing a reduction in the tremor network's functional connectivity, which did not reach statistical significance in the group analysis. Conclusions: It is feasible to acquire a reliable and responsive fMRI signal during asleep DBS. The acquisition steps and the preprocessing pipeline developed in these experiments will be useful for future investigations to develop fMRI-based feedback for asleep DBS surgery.

Thermal Neuromodulation With Focused Ultrasound: Implications for the Technique of Subthreshold Testing.

BACKGROUND: During focused ultrasound ablation (FUSA), the presumed stereotactic target is tested with subthreshold sonications before permanent ablation. This testing relies on ultrasound-induced reversible clinical effects (thermal neuromodulation, TN). However, the thermal dose and spot size thresholds to induce TN are not yet defined. OBJECTIVE: To define the thermal dose and spot size thresholds associated with TN. METHODS: We performed a retrospective analysis of intraoperative FUSA data of essential tremor patients. Sonications with a thermal dose of less than 25 cumulative equivalent minutes (CEM) were classified as subthreshold. The intraoperative writing samples were independently rated by 2 raters using the clinical rating scale for tremor. The association between thermal dose and tremor scores was statistically analyzed, and the thermal dose and spot size thresholds for TN were computed using leave-one-out cross-validation analysis. RESULTS: A total of 331 pairs of sonications and writing samples were analyzed; 97 were classified as subthreshold sonications. TN was observed in 23 (24%) subthreshold sonications. The median tremor improvement during TN was 20% (interquartile range = 41.6). The thermal dose threshold for TN was 0.67 CEM (equivalent to 30 s thermal exposure at 43°C). The spot size threshold for TN was 2.46 mm. Ventral intermediate medial nucleus was exposed to TN thermal dose during subablative and ablative sonications. CONCLUSION: The TN thermal dose and spot size thresholds are significantly higher than the current FUSA standard of care. We recommend long duration (>30 s), subthreshold sonications for intraoperative testing during FUSA. Future investigations should test whether the thermal dose threshold is tissue-specific and determine the mechanisms underlying focused ultrasound TN.

VNS Stopping Anti-NMDA Receptor Encephalitis-Triggered Nonconvulsive Status Epilepticus.

BACKGROUND: Anti-NMDA receptor encephalitis (ANRE) is a rare autoimmune neurologic disorder characterized by encephalitis and a constellational of symptoms, including seizures, psychiatric disturbances, autonomic instability, and respiratory insufficiency. It is caused by the anti-NMDA receptor antibody. The most common etiologies for ANRE include malignancy and infection. Ovarian teratoma is the most commonly associated malignancy. CASE DESCRIPTION: We describe the first reported case to our knowledge of ovarian teratoma causing ANRE resulting in nonconvulsive status epilepticus (NCSE), which was terminated with vagus nerve stimulation (VNS). CONCLUSIONS: This case report provides a temporal correlation suggesting that VNS significantly altered the natural history of this patient's NCSE-ANRE. As more data are collected, and the VNS treatment modality more liberally used to treat NCSE, especially in the situation of ANRE, stronger layers of evidence will emerge to fill the gaps of understanding beyond this case report.