Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease.

Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aß) load in patients with Alzheimer's disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood-brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aß was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment. (Funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.).

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.

Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.

The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

Restoring cortical control of functional movement in a human with quadriplegia.

Millions of people worldwide suffer from diseases that lead to paralysis through disruption of signal pathways between the brain and the muscles. Neuroprosthetic devices are designed to restore lost function and could be used to form an electronic 'neural bypass' to circumvent disconnected pathways in the nervous system. It has previously been shown that intracortically recorded signals can be decoded to extract information related to motion, allowing non-human primates and paralysed humans to control computers and robotic arms through imagined movements. In non-human primates, these types of signal have also been used to drive activation of chemically paralysed arm muscles. Here we show that intracortically recorded signals can be linked in real-time to muscle activation to restore movement in a paralysed human. We used a chronically implanted intracortical microelectrode array to record multiunit activity from the motor cortex in a study participant with quadriplegia from cervical spinal cord injury. We applied machine-learning algorithms to decode the neuronal activity and control activation of the participant's forearm muscles through a custom-built high-resolution neuromuscular electrical stimulation system. The system provided isolated finger movements and the participant achieved continuous cortical control of six different wrist and hand motions. Furthermore, he was able to use the system to complete functional tasks relevant to daily living. Clinical assessment showed that, when using the system, his motor impairment improved from the fifth to the sixth cervical (C5-C6) to the seventh cervical to first thoracic (C7-T1) level unilaterally, conferring on him the critical abilities to grasp, manipulate, and release objects. This is the first demonstration to our knowledge of successful control of muscle activation using intracortically recorded signals in a paralysed human. These results have significant implications in advancing neuroprosthetic technology for people worldwide living with the effects of paralysis.

Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease.

Background Opening of the blood-brain barrier (BBB) induced with MRI-guided focused ultrasound has been shown in experimental animal models to reduce amyloid-ß plaque burden, improve memory performance, and facilitate delivery of therapeutic agents to the brain. However, physiologic effects of this procedure in humans with Alzheimer disease (AD) require further investigation. Purpose To assess imaging effects of focused ultrasound-induced BBB opening in the hippocampus of human participants with early AD and to evaluate fluid flow patterns after BBB opening by using serial contrast-enhanced MRI. Materials and Methods Study participants with early AD recruited to a Health Insurance Portability and Accountability Act-compliant, prospective, ongoing phase II clinical trial (ClinicalTrials.gov identifier, NCT03671889) underwent three separate focused ultrasound-induced BBB opening procedures that used a 220-kHz transducer with a concomitant intravenous microbubble contrast agent administered at 2-week intervals targeting the hippocampus and entorhinal cortex between October 2018 and May 2019. Posttreatment effects and gadolinium-based contrast agent enhancement patterns were evaluated by using 3.0-T MRI. Results Three women (aged 61, 72, and 73 years) consecutively enrolled in the trial successfully completed repeated focused ultrasound-induced BBB opening of the hippocampus and entorhinal cortex. Postprocedure contrast enhancement was clearly identified within the targeted brain volumes, indicating immediate spatially precise BBB opening. Parenchymal enhancement resolved within 24 hours after all treatments, confirming BBB closure. Transient perivenous enhancement was consistently observed during the acute phase after BBB opening. Notably, contrast enhancement reappeared in the perivenular regions after BBB closure. This imaging marker is consistent with blood-meningeal barrier permeability and persisted for 24-48 hours before spontaneous resolution. No evidence of intracranial hemorrhage or other adverse effect was identified. Conclusion MRI-guided focused ultrasound-induced blood-brain barrier opening was safely performed in the hippocampi of three participants with Alzheimer disease without any adverse effects. Posttreatment MRI reveals a unique spatiotemporal contrast enhancement pattern that suggests a perivenular immunologic healing response downstream from targeted sites. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Klibanov in this issue.

Improving Safety of MRI in Patients with Deep Brain Stimulation Devices.

MRI is a valuable clinical and research tool for patients undergoing deep brain stimulation (DBS). However, risks associated with imaging DBS devices have led to stringent regulations, limiting the clinical and research utility of MRI in these patients. The main risks in patients with DBS devices undergoing MRI are heating at the electrode tips, induced currents, implantable pulse generator dysfunction, and mechanical forces. Phantom model studies indicate that electrode tip heating remains the most serious risk for modern DBS devices. The absence of adverse events in patients imaged under DBS vendor guidelines for MRI demonstrates the general safety of MRI for patients with DBS devices. Moreover, recent work indicates that-given adequate safety data-patients may be imaged outside these guidelines. At present, investigators are primarily focused on improving DBS device and MRI safety through the development of tools, including safety simulation models. Existing guidelines provide a standardized framework for performing safe MRI in patients with DBS devices. It also highlights the possibility of expanding MRI as a tool for research and clinical care in these patients going forward.

Deep Brain Stimulation for Multiple Sclerosis Tremor: A Meta-Analysis.

OBJECTIVES: To examine the effect of deep brain stimulation (DBS) on multiple sclerosis (MS)-tremor, as measured by a normalized scale of tremor severity, with a meta-analysis of the published literature. METHODS: Medline and EBSCO Host (January, 1998 to June, 2018) were systematically reviewed with librarian guidance, using the keywords "Deep brain stimulation" and "multiple sclerosis." Bibliographies and experts in the field were also consulted to identify missed articles. All therapeutic studies on DBS for MS-tremor, reported in the English language, within the study period were included. Papers that reported outcomes without a measure of central tendency and/or distribution were excluded. The papers were read in their entirety and graded for risk of bias according to the American Academy of Neurology (AAN) standards. To maximize statistical power, papers using different stimulation targets were grouped together. Outcomes were reported with the Fahn-Tolosa-Marin scale (FTM), the Bain-Finchley scale (CRS) and 3- and 4-point tremor severity scales and normalized with a Hedges g. RESULTS: The search produced 13 studies suitable for meta-analysis. The random-effects meta-analysis showed that DBS improved the Hedges standardized mean tremor score by 2.86 (95%CI 2.03-3.70, p < .00001). Heterogeneity was high, with an I2 of 84%, suggesting that random effects model is more appropriate. Adverse event rates varied from 8% to 50%. CONCLUSIONS: This meta-analysis provides level III evidence that DBS may improve MS-related tremor as measured by standardized tremor severity scales.

Charting the road forward in psychiatric neurosurgery: proceedings of the 2016 American Society for Stereotactic and Functional Neurosurgery workshop on neuromodulation for psychiatric disorders.

OBJECTIVE: Refractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain stimulation (DBS)-based therapies for depression and obsessive-compulsive disorder (OCD). Results from recent pivotal trials of these therapies, however, did not demonstrate the degree of efficacy expected from previous smaller trials. To discuss next steps, neurosurgeons, neurologists, psychiatrists and representatives from industry convened a workshop sponsored by the American Society for Stereotactic and Functional Neurosurgery in Chicago, Illinois, in June of 2016. DESIGN: Here we summarise the proceedings of the workshop. Participants discussed a number of issues of importance to the community. First, we discussed how to interpret results from the recent pivotal trials of DBS for OCD and depression. We then reviewed what can be learnt from lesions and closed-loop neurostimulation. Subsequently, representatives from the National Institutes of Health, the Food and Drug Administration and industry discussed their views on neuromodulation for psychiatric disorders. In particular, these third parties discussed their criteria for moving forward with new trials. Finally, we discussed the best way of confirming safety and efficacy of these therapies, including registries and clinical trial design. We close by discussing next steps in the journey to new neuromodulatory therapies for these devastating illnesses. CONCLUSION: Interest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.

Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression.

BACKGROUND: We report the neuropsychological outcome of 25 patients with treatment-resistant major depressive disorder (TRD) who participated in an Institutional Review Board (IRB)-approved randomised double-blind trial comparing active to sham deep brain stimulation (DBS) in the anterior limb of the ventral capsule/ventral striatum (VC/VS). METHODS: Participants were randomised to active (n=12) versus sham (n=13) DBS for 16 weeks. Data were analysed at the individual and group levels. Group differences were analysed using repeated measures ANOVAs. Relationships between depression severity and cognition were examined using partial correlations. The false discovery rate method controlled for multiple analyses. RESULTS: No significant interactions comparing active versus sham stimulation over time were evident. Change in depression was unrelated to change in neuropsychological measures. Twenty patients declined by ≥1 SD on at least one measure (41.3% of declines occurred in active group participants; 63.0% in older participants regardless of stimulation status). Twenty-two patients exhibited improvements >1 SD on neuropsychological measures (47.7% in the active group; 63.1% in younger participants). CONCLUSIONS: These data suggest that VC/VS DBS in patients with TRD does not significantly affect neuropsychological function. Age at surgery, regardless of stimulation status, may be related to cognitive outcome at the individual patient level. TRIAL REGISTRATION NUMBER: NCT00837486; Results.

Spinal Cord Stimulation (SCS) and Functional Magnetic Resonance Imaging (fMRI): Modulation of Cortical Connectivity With Therapeutic SCS.

INTRODUCTION: The neurophysiological basis of pain relief due to spinal cord stimulation (SCS) and the related cortical processing of sensory information are not completely understood. The aim of this study was to use resting state functional magnetic resonance imaging (rs-fMRI) to detect changes in cortical networks and cortical processing related to the stimulator-induced pain relief. METHODS: Ten patients with complex regional pain syndrome (CRPS) or neuropathic leg pain underwent thoracic epidural spinal cord stimulator implantation. Stimulation parameters associated with "optimal" pain reduction were evaluated prior to imaging studies. Rs-fMRI was obtained on a 3 Tesla, Philips Achieva MRI. Rs-fMRI was performed with stimulator off (300TRs) and stimulator at optimum (Opt, 300 TRs) pain relief settings. Seed-based analysis of the resting state functional connectivity was conducted using seeds in regions established as participating in pain networks or in the default mode network (DMN) in addition to the network analysis. NCUT (normalized cut) parcellation was used to generate 98 cortical and subcortical regions of interest in order to expand our analysis of changes in functional connections to the entire brain. We corrected for multiple comparisons by limiting the false discovery rate to 5%. RESULTS: Significant differences in resting state connectivity between SCS off and optimal state were seen between several regions related to pain perception, including the left frontal insula, right primary and secondary somatosensory cortices, as well as in regions involved in the DMN, such as the precuneus. In examining changes in connectivity across the entire brain, we found decreased connection strength between somatosensory and limbic areas and increased connection strength between somatosensory and DMN with optimal SCS resulting in pain relief. This suggests that pain relief from SCS may be reducing negative emotional processing associated with pain, allowing somatosensory areas to become more integrated into default mode activity. CONCLUSION: SCS reduces the affective component of pain resulting in optimal pain relief. Study shows a decreased connectivity between somatosensory and limbic areas associated with optimal pain relief due to SCS.

Neurosurgical neuromodulation therapy for psychiatric disorders.

Psychiatric disorders are among the leading contributors to global disease burden and disability. A significant portion of patients with psychiatric disorders remain treatment-refractory to best available therapy. With insights from the neurocircuitry of psychiatric disorders and extensive experience of neuromodulation with deep brain stimulation (DBS) in movement disorders, DBS is increasingly being considered to modulate the neural network in psychiatric disorders. Currently, obsessive-compulsive disorder (OCD) is the only U.S. FDA (United States Food and Drug Administration) approved DBS indication for psychiatric disorders. Medically refractory depression, addiction, and other psychiatric disorders are being explored for DBS neuromodulation. Studies evaluating DBS for psychiatric disorders are promising but lack larger, controlled studies. This paper presents a brief review and the current state of DBS and other neurosurgical neuromodulation therapies for OCD and other psychiatric disorders. We also present a brief review of MR-guided Focused Ultrasound (MRgFUS), a novel form of neurosurgical neuromodulation, which can target deep subcortical structures similar to DBS, but in a noninvasive fashion. Early experiences of neurosurgical neuromodulation therapies, including MRgFUS neuromodulation are encouraging in psychiatric disorders; however, they remain investigational. Currently, DBS and VNS are the only FDA approved neurosurgical neuromodulation options in properly selected cases of OCD and depression, respectively.

Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder.

OBJECTIVE: There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment-refractory OUD. METHODS: A prospective, open-label, single-arm study was conducted among participants with longstanding treatment-refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and 18FDG-PET neuroimaging. RESULTS: Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation-related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One participant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. CONCLUSIONS: DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment-refractory OUD. A randomized, sham-controlled trial in a larger cohort of patients is being initiated.

Posttraumatic stress disorder: neurocircuitry and implications for potential deep brain stimulation.

Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling psychiatric disorder that is notoriously difficult to treat. At some point in their lifetimes, 5-8% of men, 10-14% of women, and up to a quarter of combat veterans carry this diagnosis. Despite pharmacological and behavioral therapies, up to 30% of patients are still symptomatic 10 years after initial diagnosis. Recent advances in imaging have implicated changes in the limbic and autonomic corticostriatopallidothalamocortical (CSPTC) circuitry in the pathogenesis of this disease. Deep brain stimulation modulates CSPTC circuits in movement and other neuropsychiatric disorders. In this review, we discuss the salient clinical features and neurocircuitry of PTSD and propose a neuromodulation strategy for the disorder.

Neuropsychological outcome after deep brain stimulation in the ventral capsule/ventral striatum for highly refractory obsessive-compulsive disorder or major depression.

BACKGROUND: Deep brain stimulation (DBS) has shown promise as a treatment for severe, highly treatment-refractory obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). We describe the neuropsychological outcome in 21 patients (10 OCD and 11 MDD) who received DBS in the anterior limb of the internal capsule/ventral striatum (VC/VS). METHODS: All patients completed a preoperative and postoperative neuropsychological battery. Average duration of DBS stimulation was 8.91 months (SD = 4.63) at the time of follow-up testing. Data were analyzed using practice-effect-corrected change scores. RESULTS: No significant cognitive declines were seen. There were significant improvements in prose passage recall after chronic DBS. The cognitive improvements were not related to change in severity of OCD, depression or global impairment. CONCLUSIONS: This preliminary study suggests that VC/VS DBS does not result in cognitive declines. The observations that verbal memory improved are consistent with current theories on the role of the VS in the memory, but require replication in larger studies.

Deep Brain Stimulation for the Management of AIFM1-Related Disabling Tremor: A Case Series.

The AIFM1 gene encodes a mitochondrial protein that acts as a flavin adenine dinucleotide-dependent nicotinamide adenine dinucleotide oxidase and apoptosis regulator. Monoallelic pathogenic AIFM1 variants result in a spectrum of X-linked neurological disorders, including Cowchock syndrome. Common features in Cowchock syndrome include a slowly progressive movement disorder, cerebellar ataxia, progressive sensorineural hearing loss, and sensory neuropathy. We identified a novel maternally inherited hemizygous missense AIFM1 variant, c.1369C>T p.(His457Tyr), in two brothers with clinical features consistent with Cowchock syndrome using next-generation sequencing. Both individuals had a progressive complex movement disorder phenotype, including disabling tremor poorly responsive to medications. Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus ameliorated contralateral tremor and improved their quality of life; this suggests the beneficial role for DBS in treatment-resistant tremor within AIFM1-related disorders.

Identifying biomarkers of drug use recurrence using wearable device technologies and phone applications.

BACKGROUND: Identifying predictors of drug use recurrence (DUR) is critical to combat the addiction epidemic. Wearable devices and phone-based applications for obtaining self-reported assessments in the patient's natural environment (e.g., ecological momentary assessment; EMA) have been used in various healthcare settings. However, the utility of combining these technologies to predict DUR in substance use disorder (SUD) has not yet been explored. This study investigates the combined use of wearable technologies and EMA as a potential mechanism for identifying physiological/behavioral biomarkers of DUR. METHODS: Participants, recruited from an SUD treatment program, were provided with a commercially available wearable device that continuously monitors biometric signals (e.g., heart rate/variability [HR/HRV], sleep characteristics). They were also prompted daily to complete an EMA via phone-based application (EMA-APP) that included questionnaires regarding mood, pain, and craving. RESULTS: Seventy-seven participants are included in this pilot study (34 participants experienced a DUR during enrollment). Wearable technologies revealed that physiological markers were significantly elevated in the week prior to DUR relative to periods of sustained abstinence (p<0.001). Results from the EMA-APP revealed that those who experienced a DUR reported greater difficulty concentrating, exposure to triggers associated with substance use, and increased isolation the day prior to DUR (p<0.001). Compliance with study procedures during the DUR week was lower than any other period of measurement (p<0.001). CONCLUSIONS: These results suggest that data acquired via wearable technologies and the EMA-APP may serve as a method of predicting near-term DUR, thereby potentially prompting intervention before drug use occurs.

Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease.

BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD). METHODS: At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI. RESULTS: Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant. CONCLUSIONS: FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.

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.

Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial.

Introduction: While current treatments for substance use disorder (SUD) are beneficial, success rates remain low and treatment outcomes are complicated by co-occurring SUDs, many of which are without available medication treatments. Research involving neuromodulation for SUD has recently gained momentum. This study evaluated two doses (60 and 90 W) of Low Intensity Focused Ultrasound (LIFU), targeting the bilateral nucleus accumbens (NAc), in individuals with SUD. Methods: Four participants (three male), who were receiving comprehensive outpatient treatment for opioid use disorder at the time of enrollment and who also had a history of excessive non-opioid substance use, completed this pilot study. After confirming eligibility, these participants received 10 min sham LIFU followed by 20 min active LIFU (10 min to left then right NAc). Outcomes were the safety, tolerability, and feasibility during the LIFU procedure and throughout the 90-day follow-up. Outcomes also included the impact of LIFU on cue-induced substance craving, assessed via Visual Analog Scale (VAS), both acutely (pre-, during and post-procedure) and during the 90-day follow-up. Daily craving ratings (without cues) were also obtained for one-week prior to and one-week following LIFU. Results: Both LIFU doses were safe and well-tolerated based on reported adverse events and MRI scans revealed no structural changes (0 min, 24 h, and 1-week post-procedure). For the two participants receiving "enhanced" (90 W) LIFU, VAS craving ratings revealed active LIFU attenuated craving for participants' primary substances of choice relative to sham sonication. For these participants, reductions were also noted in daily VAS craving ratings (0 = no craving; 10 = most craving ever) across the week following LIFU relative to pre-LIFU; Participant #3 pre- vs. post-LIFU: opioids (3.6 ± 0.6 vs. 1.9 ± 0.4), heroin (4.2 ± 0.8 vs. 1.9 ± 0.4), methamphetamine (3.2 ± 0.4 vs. 0.0 ± 0.0), cocaine (2.4 ± 0.6 vs. 0.0 ± 0.0), benzodiazepines (2.8 ± 0.5 vs. 0.0 ± 0.0), alcohol (6.0 ± 0.7 vs. 2.7 ± 0.8), and nicotine (5.6 ± 1.5 vs. 3.1 ± 0.7); Participant #4: alcohol (3.5 ± 1.3 vs. 0.0 ± 0.0) and nicotine (5.0 ± 1.8 vs. 1.2 ± 0.8) (all p's < 0.05). Furthermore, relative to screening, longitudinal reductions in cue-induced craving for several substances persisted during the 90-day post-LIFU follow-up evaluation for all participants. Discussion: In conclusion, LIFU targeting the NAc was safe and acutely reduced substance craving during the LIFU procedure, and potentially had longer-term impact on craving reductions. While early observations are promising, NAc LIFU requires further investigation in a controlled trial to assess the impact on substance craving and ultimately substance use and relapse.

Axonal pathways linked to therapeutic and nontherapeutic outcomes during psychiatric deep brain stimulation.

OBJECTIVE: The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS. EXPERIMENTAL DESIGN: Our approach combined clinical data, diffusion tensor tractography, and computer models of patient-specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment-resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS). PRINCIPAL OBSERVATIONS: Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders. CONCLUSIONS: Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices.