On the Quality, Statistical Efficiency, and Safety of Simultaneously Recorded Multiband fMRI/EEG.

The recent development of multiband functional magnetic resonance imaging (MB-fMRI) allows for the reduction of sampling period by simultaneously exciting multiple slices-the number of which is referred to as the multiband factor. Simultaneously recorded electroencephalography (EEG)/MB-fMRI has yet to be validated for data quality against conventional single band (SB)-fMRI. Pilot scans were conducted on phantoms twice and on a healthy volunteer to ensure no heating effects. In the main study, two thermometer probes were attached to 16 healthy individuals (ages 20-39, 9 females) whilst they completed two sets of 16-min resting-state and two sets of 9-min n-back task scans-each set consisting of one MB4 and one SB pulse sequence. No heating effects were reported and thermometer data showed mean increases of < 1.0 °C. Minimal differences between the two scan types were found in EEG channel variance and spectra. Expected decreases in MB4-fMRI tSNR were observed. In n-back task scans, little to no differences were detected in both EEG source analyses and fMRI local analyses for mixed effects. Resting-state posterior cingulate cortex seed-based analyses of the default mode network along with EEG-informed fMRI analysis of the occipital alpha anticorrelation effect showed improved statistical and spatial sensitivity at lower scan durations. Using EEG/MB4-fMRI for n-back tasks provided no statistical advantages nor disadvantages. However, for studying the resting-state, MB4-fMRI potentially allows for reduced scanning durations for equivalent statistical significance to be obtained or alternatively, larger effect sizes for the same scanning duration. As such, simultaneous EEG/MB4-fMRI is a viable alternative to EEG/SB-fMRI.

A Randomized Controlled Trial of Intravenous Scopolamine Versus Active-Placebo Glycopyrrolate in Patients With Major Depressive Disorder.

Objective: To investigate scopolamine's rapid-acting antidepressant effects using an active placebo comparator. Most prior intravenous scopolamine studies reduced depressive symptomatologies compared to saline placebo infusions within 3 days. However, the confounding effect of placebo is unknown given that only saline placebo has been used in prior studies.Methods: In this trial, 40 patients with major depressive disorder were randomized to receive single intravenous doses of either scopolamine hydrobromide (4-6 µg/kg) or glycopyrronium bromide (4 µg/kg) between August 2019 and April 2021 in Auckland, New Zealand. Glycopyrronium was chosen as the active placebo due to its similar antimuscarinic properties to scopolamine but inability to cross the blood-brain barrier. The primary mood outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS) administered pre-infusion and 1, 3, 7, 14, 28, and 42 days post-infusion.Results: Per protocol, this trial was abandoned for futility at n = 40. While scopolamine reduced MADRS scores by 12.6 (± 8.7 SD) points at day 3, glycopyrronium showed similar reductions (11.2 ± 9.6 SD). Frequentist linear mixed models showed no antidepressant effects of scopolamine versus placebo (d = 0.17), and Bayesian mixed effect models showed moderate evidence in favor of the null hypothesis at day 3 (Bayes factor = 0.32). Participants remained well-blinded to drug allocation, with 50% of participants correctly guessing their allocation.Conclusions: The observed MADRS improvement was larger than in prior studies, but no antidepressant effects were observed. This study using an active placebo confirms recent studies demonstrating the lack of antidepressant efficacy of scopolamine.Trial Registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12619000569101.

Extent of resection affects prognosis for patients with glioblastoma in non-eloquent regions.

Glioblastoma (GBM) is a malignant cerebral neoplasm carrying poor prognosis. The importance of extent of resection (EoR) in GBM patient outcomes has been argued in the literature. Previous studies included tumors in eloquent regions of the brain. This confounds the role of EoR by including patients with intrinsically worse outcomes but will be over-represented in the reduced EoR category. In a homogenous group of patients in whom GTR was considered achievable, we investigated the effect of increasing EoR on survival. A retrospective review of 51 patients was undertaken. Quantitative, volumetric analysis of pre-operative and post-operative magnetic resonance image was compared with corresponding clinical details. The primary outcome measured was post-operative overall survival. Median overall survival was 18.3 months for GTR patients compared to 11.6 months for non-GTR (p = 0.025). Median pre-operative contrast-enhancing tumor volume for GTR patients was 54.7 cm3 and 24.9 cm3 for non-GTR. Post-operative median residual tumor volume was 1.1 cm3 in the non-GTR cohort. In multivariate analyses, GTR (HR [95% CI] = 0.973 [0.954-0.994], p = 0.00559) and increasing EoR (HR [95% CI] = 0.964 [0.944-0.985], p = 0.000665) remained predictors of survival. Centile dichotomization of EoR revealed 74% (HR [95% CI] = 0.351 [0.128-0.958], p = 0.0409) as the lowest threshold conferring statistically significant survival benefit. Where technically feasible, both GTR and EoR remained as independent prognostic factors for survival. GTR remains the gold standard for surgical treatment of GBM in patients, 74% being the minimum EoR required to confer survival benefit.

A randomised, double-blind, active placebo-controlled, parallel groups, dose-response study of scopolamine hydrobromide (4-6 µg/kg) in patients with major depressive disorder.

BACKGROUND: Depressive disorders are a leading cause of disability, but current behavioural and pharmacological therapies have a slow onset of response, typically taking several weeks before achieving efficacy. Prior studies using triplicate intravenous scopolamine infusions have been shown to reduce depressive symptomologies within days compared to saline placebo infusions. However, several parameters of scopolamine's potential antidepressant effect remain unknown, such as its dose-response profile and its washout period. There is also the question as to whether the previously reported antidepressant responses were confounded by unblinding effects due to the lack of an active placebo control. Glycopyrronium bromide was selected as placebo for this trial given it has similar antimuscarinic properties to scopolamine hydrobromide but an inability to cross the blood-brain barrier, thereby hypothetically mimicking only the peripheral effects of scopolamine. METHODS/DESIGN: A parallel group trial of single intravenous scopolamine infusions at three doses (4, 5, and 6 µg/kg) along with one glycopyrronium bromide 4 µg/kg group will be administered to 40 participants with major depressive disorder in a 1:1:1:2 ratio, respectively. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 4 hours, 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks post-infusion to determine antidepressant efficacy. As a secondary measure, the Quick Inventory of Depressive Symptomatology will be administered alongside the MADRS to further track potential antidepressant responses. Other secondary measures include electroencephalography, blood samples, and Bowdle visual acuity scales recorded at baseline, 5, 10, 15, 20, 30, 60, 120, and 240 min post-infusion to determine the pharmacokinetic-pharmacodynamic profile of scopolamine in depressed participants. DISCUSSION: This trial contributes to the literature surrounding the efficacy of scopolamine as an antidepressant. Determining the dose-response profile and washout period of scopolamine's antidepressant effect will also provide important information for designing and conducting crossover trials. The use of an active placebo is important to reduce potentially confounding expectancy effects. TRIAL REGISTRATION: The trial was registered in the Australian New Zealand Clinical Trials Registry (registration number ACTRN12619000569101). Registered on 11 April 2019.