Protocol for a randomised trial of a self-directed digital pain management intervention (Empowered Relief) tailored to adults with chronic pain and prescription opioid misuse/disorder: the MOBILE Relief study.

INTRODUCTION: Chronic pain increases the risk of prescription opioid misuse or opioid use disorder (OUD). Non-pharmacological treatments are needed to dually address pain and opioid risks. The purpose of the Mobile and Online-Based Interventions to Lessen Pain (MOBILE Relief) study is to compare a one-session, video-based, on-demand digital pain relief skills intervention for chronic pain ('Empowered Relief' (ER); tailored to people at risk for opioid misuse or with opioid misuse/OUD) to a one-session digital health education intervention ('Living Better'; no pain management skills). METHODS AND ANALYSIS: MOBILE Relief is an international online randomised controlled clinical trial. Study participants are adults with chronic, non-cancer pain (≥6 months) with daily pain intensity ≥3/10, taking ≥10 morphine equivalent daily dose and score ≥6 on the Current Opioid Misuse Measure. Participants are recruited through clinician referrals and clinic advertisements. Study procedures include electronic eligibility screening, informed consent, automated 1:1 randomisation to the treatment group, baseline measures, receipt of assigned digital treatment and six post-treatment surveys spanning 3 months. Study staff will call participants at baseline and 1-month and 3 months post-treatment to verify the opioid prescription. The main statistical analyses will include analysis of covariance and mixed effects model for repeated measurements regression. MAIN OUTCOMES: Primary outcomes are self-reported pain catastrophising, pain intensity, pain interference, opioid craving and opioid misuse at 1-month and 3 months post-treatment. We will determine the feasibility of ER (≥50% participant engagement, ≥70% treatment appraisal ratings). We hypothesise the ER group will be superior to the Living Better group in the reduction of multiprimary pain outcomes at 1-month post-treatment and opioid outcomes at 1-month and 3 months post-treatment. ETHICS AND DISSEMINATION: The study protocol was approved by the Stanford University School of Medicine Institutional Review Board (IRB 61643). We will publish results in peer-reviewed journals; National Institute of Drug Abuse (funder) and MOBILE Relief participants will receive result summaries. TRIAL REGISTRATION NUMBER: NCT05152134.

Foundational Number Sense Training Gains Are Predicted by Hippocampal-Parietal Circuits.

The development of mathematical skills in early childhood relies on number sense, the foundational ability to discriminate among quantities. Number sense in early childhood is predictive of academic and professional success, and deficits in number sense are thought to underlie lifelong impairments in mathematical abilities. Despite its importance, the brain circuit mechanisms that support number sense learning remain poorly understood. Here, we designed a theoretically motivated training program to determine brain circuit mechanisms underlying foundational number sense learning in female and male elementary school-age children (7-10 years). Our 4 week integrative number sense training program gradually strengthened the understanding of the relations between symbolic (Arabic numerals) and nonsymbolic (sets of items) representations of quantity. We found that our number sense training program improved symbolic quantity discrimination ability in children across a wide range of math abilities including children with learning difficulties. Crucially, the strength of pretraining functional connectivity between the hippocampus and intraparietal sulcus, brain regions implicated in associative learning and quantity discrimination, respectively, predicted individual differences in number sense learning across typically developing children and children with learning difficulties. Reverse meta-analysis of interregional coactivations across 14,371 fMRI studies and 89 cognitive functions confirmed a reliable role for hippocampal-intraparietal sulcus circuits in learning. Our study identifies a canonical hippocampal-parietal circuit for learning that plays a foundational role in children's cognitive skill acquisition. Findings provide important insights into neurobiological circuit markers of individual differences in children's learning and delineate a robust target for effective cognitive interventions.SIGNIFICANCE STATEMENT Mathematical skill development relies on number sense, the ability to discriminate among quantities. Here, we develop a theoretically motivated training program and investigate brain circuits that predict number sense learning in children during a period important for acquisition of foundational cognitive skills. Our integrated number sense training program was effective in children across a wide a range of math abilities, including children with learning difficulties. We identify hippocampal-parietal circuits that predict individual differences in learning gains. Our study identifies a brain circuit critical for the acquisition of foundational cognitive skills, which will be useful for developing effective interventions to remediate learning disabilities.

Contralateral Hemispheric Cerebral Blood Flow Measured With Arterial Spin Labeling Can Predict Outcome in Acute Stroke.

Background and Purpose- Imaging is frequently used to select acute stroke patients for intra-arterial therapy. Quantitative cerebral blood flow can be measured noninvasively with arterial spin labeling magnetic resonance imaging. Cerebral blood flow levels in the contralateral (unaffected) hemisphere may affect capacity for collateral flow and patient outcome. The goal of this study was to determine whether higher contralateral cerebral blood flow (cCBF) in acute stroke identifies patients with better 90-day functional outcome. Methods- Patients were part of the prospective, multicenter iCAS study (Imaging Collaterals in Acute Stroke) between 2013 and 2017. Consecutive patients were enrolled after being diagnosed with anterior circulation acute ischemic stroke. Inclusion criteria were ischemic anterior circulation stroke, baseline National Institutes of Health Stroke Scale score ≥1, prestroke modified Rankin Scale score ≤2, onset-to-imaging time <24 hours, with imaging including diffusion-weighted imaging and arterial spin labeling. Patients were dichotomized into high and low cCBF groups based on median cCBF. Outcomes were assessed by day-1 and day-5 National Institutes of Health Stroke Scale; and day-30 and day-90 modified Rankin Scale. Multivariable logistic regression was used to test whether cCBF predicted good neurological outcome (modified Rankin Scale score, 0-2) at 90 days. Results- Seventy-seven patients (41 women) met the inclusion criteria with median (interquartile range) age of 66 (55-76) yrs, onset-to-imaging time of 4.8 (3.6-7.7) hours, and baseline National Institutes of Health Stroke Scale score of 13 (9-20). Median cCBF was 38.9 (31.2-44.5) mL per 100 g/min. Higher cCBF predicted good outcome at day 90 (odds ratio, 4.6 [95% CI, 1.4-14.7]; P=0.01), after controlling for baseline National Institutes of Health Stroke Scale, diffusion-weighted imaging lesion volume, and intra-arterial therapy. Conclusions- Higher quantitative cCBF at baseline is a significant predictor of good neurological outcome at day 90. cCBF levels may inform decisions regarding stroke triage, treatment of acute stroke, and general outcome prognosis. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02225730.