Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov.

Background: Although deep brain stimulation (DBS) has established uses for patients with movement disorders and epilepsy, it is under consideration for a wide range of neurologic and neuropsychiatric conditions. Objective: To review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination. Methods: The ClinicalTrials.gov database was screened for all studies related to DBS. Information regarding condition of interest, study aim, trial design, trial success, and, if applicable, reason for failure was collected. Trials were compared and logistic regression was utilized to identify independent factors associated with trial termination. Results: Of 325 identified trials, 79.7% were successful and 20.3% unsuccessful. Patient recruitment, sponsor decision, and device issues were the most cited reasons for termination. 242 trials (74.5%) were interventional with 78.1% successful. There was a statistically significant difference between successful and unsuccessful trials in number of funding sources (p = 0.0375). NIH funding was associated with successful trials while utilization of other funding sources (academic institutions and community organizations) was associated with unsuccessful trials. 83 trials (25.5%) were observational with 84.0% successful; there were no statistically significant differences between successful and unsuccessful observational trials. Conclusion: One in five clinical trials for DBS were found to be unsuccessful, most commonly due to patient recruitment difficulties. The source of funding was the only factor associated with trial success. As DBS research continues to grow, understanding the current state of clinical trials will help design successful future studies, thereby minimizing futile expenditures of time, cost, and patient engagement.

Impact of Cerebral Revascularization on Pial Collateral Flow in Patients With Unilateral Moyamoya Disease Using Quantitative Magnetic Resonance Angiography.

BACKGROUND AND OBJECTIVES: Moyamoya disease (MMD) is a chronic steno-occlusive disease of the intracranial circulation that depends on neoangiogenesis of collateral vessels to maintain cerebral perfusion and is primarily managed with cerebral revascularization surgery. A quantitative assessment of preoperative and postoperative collateral flow using quantitative magnetic resonance angiography with noninvasive optimal vessel analysis (NOVA) was used to illustrate the impact of revascularization on cerebral flow distribution. METHODS: A retrospective review of patients with unilateral MMD who underwent direct, indirect, or combined direct/indirect cerebral revascularization surgery was conducted between 2011 and 2020. Using NOVA, flow was measured at the anterior cerebral artery (ACA), ACA distal to the anterior communicating artery (A2), middle cerebral artery (MCA), posterior cerebral artery (PCA), and PCA distal to the posterior communicating artery (P2). Pial flow (A2 + P2) and collateral flow (ipsilateral [A2 + P2])-(contralateral [A2 + P2]) were measured and compared before and after revascularization surgery. Total hemispheric flow (MCA + A2 + P2) with the addition of the bypass graft flow postoperatively was likewise measured. RESULTS: Thirty-four patients with unilateral MMD underwent cerebral revascularization. Median collateral flow significantly decreased from 68 to 39.5 mL/min (P = .007) after bypass. Hemispheres with maintained measurable bypass signal on postoperative NOVA demonstrated significant reduction in median collateral flow after bypass (P = .002). Median total hemispheric flow significantly increased from 227 mL/min to 247 mL/min (P = .007) after bypass. Only one patient suffered an ipsilateral ischemic stroke, and no patients suffered a hemorrhage during follow-up. CONCLUSION: NOVA measurements demonstrate a reduction in pial collateral flow and an increase in total hemispheric flow after bypass for MMD, likely representing a decrease in leptomeningeal collateral stress on the distal ACA and PCA territories. Further studies with these measures in larger cohorts may elucidate a role for NOVA in predicting the risk of ischemic and hemorrhagic events in MMD.

Flow diverter surface modifications for aneurysm treatment: A review of the mechanisms and data behind existing technologies.

Flow diversion (FD) has become a mainstay treatment for large wide-necked aneurysms. Despite excellent safety and efficacy, the risk of thromboembolic complications necessitates the use of dual antiplatelet therapy (DAPT). The use of DAPT makes hemorrhagic complications of stenting carry high morbidity and mortality. Additionally, DAPT usage carries a risk of "nuisance" complications that do not directly impact intracranial circulation but need to be managed nonetheless. To circumvent this issue, the most recent generation of flow diverters have undergone surface modification with various compounds to confer blood compatibility to limit clotting and thrombosis. While these newer generation flow diverters are marketed to enhance ease of deployment, the goal is to eventually facilitate single antiplatelet use with flow diverter treatment. This generation of FDs have potential to expand indications beyond unruptured wide-necked aneurysms to include ruptured intracranial aneurysms without the necessity of DAPT. Currently, no comprehensive review details the molecular mechanisms and pre-clinical and clinical data on these modifications. We seek to fill this gap in the literature by consolidating information on the coating technology for four major FDs currently in clinical use-PipelineTM Flex and Vantage Shield TechnologyTM, FREDTMX, p48/64 hydrophilic coating, and Acandis Dervio® 2heal-to serve as a reference guide in neurointerventional aneurysm treatment. Although the Balt silkTM was one of the first FDs, it is uncoated, thus we will not cover this device in our review. A literature review was performed to obtain information on each coating technology for the major flow diverters currently on the market using international databases (PUBMED, Embase, Medline, Google Scholar). The search criteria used the keywords for each coating technology of interest "phosphorylcholine," "poly 2-methoxyethyl acrylate," "hydrophilic polymer coating," and "fibrin-heparin" Keywords related to the device names "Pipeline Shield," "Pipeline Shield with Flex Technology," "FRED," "FREDX," "p64," "p64-HPC," "Derivo 2heal" were also used. Studies that detailed the mechanism of action of the coating, any pre-clinical studies with surface-modified intravascular devices, and any clinical retrospective series, prospective series, or randomized clinical trials with surface-modified devices for aneurysm treatment were included.

Woven EndoBridge Device Migration and Microsnare Retrieval Strategy: Single Institutional Case Reports with Technical Video Demonstration.

The Woven EndoBridge (WEB) (MicroVention/Terumo) device is a treatment option for wideneck bifurcation aneurysms. An uncommon adverse effect is WEB device migration. While certain bailout strategies for WEB recovery have been described, there is still a paucity of information on optimal strategies to maximize both short and long-term post-operative outcomes. We add 2 cases at our institution to the existing literature of WEBectomy in the setting of complicated intracranial aneurysm treatment. We discuss the long-term imaging outcomes with additional fluoroscopy video demonstrating our technique. Our findings reflect a clear benefit for the use of the Amplatz GooseneckTM microsnare (Medtronic) device as a means of WEB recovery, coupled with potential stent-assisted WEB embolization to remove the aneurysm from the parent circulation, while minimizing recurrence and thromboembolic complications.

Sex-Specific Regulation of Fear Memory by Targeted Epigenetic Editing of Cdk5.

BACKGROUND: Sex differences in the expression and prevalence of trauma- and stress-related disorders have led to a growing interest in the sex-specific molecular and epigenetic mechanisms underlying these diseases. Cyclin-dependent kinase 5 (CDK5) is known to underlie both fear memory and stress behavior in male mice. Given our recent finding that targeted histone acetylation of Cdk5 regulates stress responsivity in male mice, we hypothesized that such a mechanism may be functionally relevant in female mice as well. METHODS: We applied epigenetic editing of Cdk5 in the hippocampus and examined the regulation of fear memory retrieval in male and female mice. Viral expression of zinc finger proteins targeting histone acetylation to the Cdk5 promoter was paired with a quantification of learning and memory of contextual fear conditioning, expression of CDK5, and enrichment of histone modifications of the Cdk5 gene. RESULTS: We found that male mice exhibit stronger long-term memory retrieval than do female mice, and this finding was associated with male-specific epigenetic activation of hippocampal Cdk5 expression. Sex differences in behavior and epigenetic regulation of Cdk5 occurred after long-term, but not short-term, fear memory retrieval. Finally, targeted histone acetylation of hippocampal Cdk5 promoter attenuated fear memory retrieval and increased tau phosphorylation in female but not male mice. CONCLUSIONS: Epigenetic editing uncovered a female-specific role of Cdk5 activation in attenuating fear memory retrieval. This finding may be attributed to CDK5 mediated hyperphosphorylation of tau only in the female hippocampus. Sex-specific epigenetic regulation of Cdk5 may reflect differences in the effect of CDK5 on downstream target proteins that regulate memory.