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Introduction: Disorders of consciousness (DoC) represent a range of clinical states, affect hundreds of thousands of people in the United States, and have relatively poor outcomes. With few effective pharmacotherapies, neuromodulation has been investigated as an alternative for treating DoC. To summarize the available evidence, a systematic review of studies using various forms of neuromodulation to treat DoC was conducted., Materials and Methods: Adhering to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic literature review, the PubMed, Scopus, and Web of Science databases were queried to identify articles published between 1990 and 2023 in which neuromodulation was used, usually in conjunction with pharmacologic intervention, to treat or reverse DoC in humans and animals. Records were excluded if DoC (eg, unresponsive wakefulness syndrome, minimally conscious state, etc) were not the primary clinical target., Results: A total of 69 studies (58 human, 11 animal) met the inclusion criteria for the systematic review, resulting in over 1000 patients and 150 animals studied in total. Most human studies investigated deep brain stimulation (n = 15), usually of the central thalamus, and transcranial magnetic stimulation (n = 18). Transcranial direct-current stimulation (n = 15) and spinal cord stimulation (n = 6) of the dorsal column also were represented. A few studies investigated low-intensity focused ultrasound (n = 2) and median nerve stimulation (n = 2). Animal studies included primate and murine models, with nine studies involving deep brain stimulation, one using ultrasound, and one using transcranial magnetic stimulation., Discussion: While clinical outcomes were mixed and possibly confounded by natural recovery or pharmacologic interventions, deep brain stimulation appeared to facilitate greater improvements in DoC than other modalities. However, repetitive transcranial magnetic stimulation also demonstrated clinical potential with much lower invasiveness., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (

Introduction: Despite centuries of joint investigation of philosophy and neurological interventions, a founding account for the philosophy of neurosurgery has yet to be rigorously constructed or defended. This paper reviews recent work on the philosophy of neurosurgery, spanning metaphysics, epistemology, and value theory, to establish a framework and clinical relevance for study in the philosophy of neurosurgery., Methods: A systematic review of an online database was conducted using the broad search terms, "Philosophy AND (Neurosurgery OR Neurological Surgery)." Records were included if they demonstrated relevance to the philosophy of neurosurgery and analytical rigor, but were excluded if solely legal, clinical, or ethical principles were considered without substantive discussion of underlying ethical frameworks and philosophical principles., Results: Of 8025 candidates from online and print records, 16 records (14 from online sources and 2 from an edited volume) met inclusion criteria for the systematic review. Three dealt with metaphysics, 3 dealt with epistemology, 4 dealt with value theory, 5 dealt with metaphysics/epistemology, and 1 dealt with value theory/metaphysics. Questions of free will, consciousness, personal identity, neurosurgical knowledge, ascription of other minds, deontology, and minimalism, among others, were considered., Discussion: Based on identified studies, the philosophy of neurosurgery is defined as the discipline of rigorously and methodically addressing metaphysical, epistemological, and value-theoretic questions arising from physically intervening in the nervous system. We discuss future directions for questions within the philosophy of neurosurgery and consider their relevance for patient care and the practice of neurosurgery., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection., Methods: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log 10 IU/ml reduction from baseline) rate, safety and pharmacokinetics., Results: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log 10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours., Conclusions: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified., Clinical Trial Number: NCT03020745., Lay Summary: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections., Competing Interests: Conflict of interest MFY has been an advisor for and received consulting fees from AbbVie, Arbutus, Bristol-Myers Squibb (BMS), Dicerna, GSK, Gilead, Janssen, Merck Sharp & Dohme (MSD), Clear B Therapeutics, Springbank and Roche; and received grants from Assembly biosciences, Arrowhead, BMS, Fujirebio, Gilead, MSD, Springbank and Sysmex. JHeo, YS, QX, JJ, YK, JLT, WX, ZD, S-JP, RK, Y-OK and HJY report no conflicts of interest. HK has received teaching fees from MSD, Gilead, AbbVie, Eisei and Dainippon Sumitomo. FS has received teaching fees from AbbVie and Gilead. JLHou has received consulting fees from Aligos, Assembly, Gilead Sciences, Johnson & Johnson, Roche; lecturer fees from Gilead, Johnson & Johnson, Roche and grants from BMS. KC has received grants from AbbVie and Dainippon Sumitomo; and has received teaching fees from MSD, BMS and Gilead. MI received grants and teaching fees from BMS. S-GL has been an advisor for and received grants from Abbott Diagnostics, Gilead, Roche and MSD; and has been an advisor for Kaleido Bioscience, Arbutus, Assembly Grifols, Janssen, Fibronostics and GSK. YTanaka received grants from Gilead, Janssen and Chugai; and teaching fees from Gilead and Fujirebio, Inc. J-HY received grants from GSK, Dicerna Pharmaceuticals, Roche, AstraZeneca, Daewoong and Hanmi. MK was an advisor for Gilead and GSK; and received speaking fees from Gilead, AbbVie, MSD, Eisai, Chugai and Bayer. MEL has been an advisor for and received speaking fees for Abbott Diagnostics, Hi-Eisai, Menarini, Mylan and Roche. YTao, JC, RE, MD, SB-B, KH, FMC, MP and DT are employees of GSK and hold GSK stocks/options. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Numerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions., Objective/hypothesis: We sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field., Methods: ClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source., Results: From 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased., Conclusion(s): These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field., Competing Interests: Declaration of competing interest This study was financially supported by the Canadian Institutes of Health Research (CIHR reference #164235: GJBE), the RR Tasker Chair in Functional Neurosurgery at University Health Network (AML), and an Academic Scholar Award from the University of Toronto Department of Psychiatry (VB). ES is supported by the Beth Israel Deaconess Medical Center (BIDMC), the Defense Advanced Research Projects Agency (DARPA), the National Institute of Health (NIH), the Alzheimer's Drug Discovery Foundation (ADDF), and the Association for Frontotemporal Dementia (AFTD). AML is the co-founder of Functional Neuromodulation, is a consultant for Boston Scientific, Medtronic, and Abbott, and holds intellectual property in the field of DBS. AF is a consultant for Medtronic, Boston Scientific, and Abbott. DMB has received research support from CIHR, NIH, Brain Canada, and the Temerty Family through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and is the principal site investigator for three sponsor-initiated studies for Brainsway Ltd. DMB also received in-kind equipment support from Magventure for investigator-initiated research and received medication supplies for an investigator-initiated trial from Indivior. SHK has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, CIHR, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, and Sun Pharmaceuticals. He also holds stock in Field Trip Health. VB has received research support from the University of Toronto, CIHR, Brain & Behavior Foundation, MOH Innovation Funds, RCPSC, and DND Canada. He receives support for an investigator-initiated trial from Roche Canada. The other authors report no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Single neuron or unit recording enables researchers to measure the electrophysiologic responses of single neurons using a microelectrode system. This approach is widely used in cognitive science and has become more widespread in humans with the use of hybrid (micro-within-macrowire) depth electrodes that enable the implantation of microwires into the brain parenchyma., Methods: The authors describe their surgical technique in a total of 7 patients with intractable epilepsy who underwent robot-enhanced stereoencephalography in which both standard (nonhybrid) and hybrid depth electrodes were used for invasive chronic monitoring., Results: The technique and accuracy of the procedure were evaluated with a total of 84 depth electrodes (46 hybrid, 38 standard) in 7 patients. No major complications, such as intracranial hemorrhage, infection or cerebrospinal fluid leakage, occurred regardless of the type of electrode used., Conclusions: The addition of hybrid depth electrodes for the purpose of in vivo single neuron recording in robot-enhanced stereoencephalography procedures is safe and does not impact the accuracy of targeting or patient safety., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Endovascular delivery of current using 'stentrodes' - electrode bearing stents - constitutes a potential alternative to conventional deep brain stimulation (DBS). The precise neuroanatomical relationships between DBS targets and the vascular system, however, are poorly characterized to date., Objective: To establish the relationships between cerebrovascular system and DBS targets and investigate the feasibility of endovascular stimulation as an alternative to DBS., Methods: Neuroanatomical targets as employed during deep brain stimulation (anterior limb of the internal capsule, dentatorubrothalamic tract, fornix, globus pallidus pars interna, medial forebrain bundle, nucleus accumbens, pedunculopontine nucleus, subcallosal cingulate cortex, subthalamic nucleus, and ventral intermediate nucleus) were superimposed onto probabilistic vascular atlases obtained from 42 healthy individuals. Euclidian distances between targets and associated vessels were measured. To determine the electrical currents necessary to encapsulate the predefined neurosurgical targets and identify potentially side-effect inducing substrates, a preliminary volume of tissue activated (VTA) analysis was performed., Results: Six out of ten DBS targets were deemed suitable for endovascular stimulation: medial forebrain bundle (vascular site: P1 segment of posterior cerebral artery), nucleus accumbens (vascular site: A1 segment of anterior cerebral artery), dentatorubrothalamic tract (vascular site: s2 segment of superior cerebellar artery), fornix (vascular site: internal cerebral vein), pedunculopontine nucleus (vascular site: lateral mesencephalic vein), and subcallosal cingulate cortex (vascular site: A2 segment of anterior cerebral artery). While VTAs effectively encapsulated mfb and NA at current thresholds of 3.5 V and 4.5 V respectively, incremental amplitude increases were required to effectively cover fornix, PPN and SCC target (mean voltage: 8.2 ± 4.8 V, range: 3.0-17.0 V). The side-effect profile associated with endovascular stimulation seems to be comparable to conventional lead implantation. Tailoring of targets towards vascular sites, however, may allow to reduce adverse effects, while maintaining the efficacy of neural entrainment within the target tissue., Conclusions: While several challenges remain at present, endovascular stimulation of select DBS targets seems feasible offering novel and exciting opportunities in the neuromodulation armamentarium., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In this article we demonstrate the effect of mechanical compression on the behavior of cultured neural stem cells using a microelectromechanical system platform. Polydimethylsiloxane (PDMS)-based stretchable substrates were used on a neurosphere (NS) assay to investigate the role of mechanical forces on the formation of radial glial processes and neuronal migration. To induce mechanical compression on NS, the PDMS culturing substrate was patterned with micron-sized wells. NS were cultured on the prestretched device. After 48 hours, when the NS had grown to the size of the well's width, the stretched substrate was released. The experimental results showed that applied mechanical compression on neural stem cells could be a factor accelerating the radial glial formation, which is associated with neurogenesis and neuronal migration., From the Clinical Editor: This study demonstrates that mechanical compression on neural stem cells could be a factor accelerating the radial glial formation, which is associated with neurogenesis and neuronal migration., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A gradient anion-exchange high-performance liquid chromatographic assay was developed for the simultaneous determination and quantitation of the cytotoxic triphosphates of arabinosylguanine (ara-GTP) and fludarabine (F-ara-ATP). The method was validated with respect to selectivity, recovery, linearity, precision, and accuracy using authentic standards. To test this assay in a more complex biological matrix, perchloric acid extracts of circulating human leukemia cells spiked with known concentrations of ara-GTP and F-ara-ATP were examined. Finally, to assess the clinical utility of our method, perchloric acid extracts of circulating human leukemia cells isolated from patients treated with fludarabine and nelarabine were analyzed. The range of quantitation was 0.0125-10 nmol for the ara- and native NTPs in cellular extracts. This assay should be helpful in establishing the mechanistic rationales for drug scheduling and combinations of nelarabine and fludarabine, and for correlating the therapeutic efficacy and levels of the cytotoxic triphosphates in target cells.