5-O-Methylvisammioside alleviates depression-like behaviors by inhibiting nuclear factor kappa B pathway activation via targeting SRC.

Multiple sclerosis (MS) is an immune-mediated, neurodegenerative disease of the central nervous system, and this disease often results in alterations in imaging-based markers of neural connectivity, such as thalamocortical resting-state functional connectivity (RSFC) []. Such disruptions of connectively, in-turn, result in the common manifestations of MS, such as cognitive processing speed (CPS) impairment []. CPS impairment is a highly prevalent and disabling outcome among the nearly 1 million adults living with MS in the United States. There are no FDA-approved pharmacological treatments or highly efficacious cognitive rehabilitation approaches that target neural networks for treating MS-related CPS impairment []. To that end, there has been increasing interest in the consideration of aerobic exercise training (ET) as an approach that targets thalamocortical RSFC for treating CPS impairment in this population. The general scientific premise for ET as an approach for improving cognition and treating impaired CPS via targeting its neural correlates in MS is based on the wealth of evidence supporting aerobic ET-related improvements in cognition that were mediated by changes in the brain in animal models and RCTs of older adults from the general population [,]. We hypothesize that thalamocortical RSFC represents a neural mechanism of ET effects on CPS in MS, as well as on potential downstream exercise-related improvements in everyday life and functional mobility outcomes in this population []. This expectation is based on our PRIMERS (PRocessing & Integration of Multisensory Exercise-Related Stimuli) conceptual framework and model for explaining integrative brain plasticity with ET in MS []. PRIMERS posits that the processing and integration of multisensory input associated with the physiological regulation of ET enhances neural communication among major neural networks, resulting in downstream cognitive improvements in MS []. Indeed, thalamic dysfunction and atrophy have been identified as major correlates of MS neurodegeneration and associated CPS impairment and decline []. Moreover, aerobic treadmill walking exercise represents an exercise behavior that is associated with a particularly large degree of multisensory input for persons with MS based on our previous research [–]. Specifically, such research adopted a discovery model and involved non-RCTs that reported on associations among aerobic fitness and CPS, experimental studies that reported on acute aerobic treadmill walking exercise-related improvements on CPS, and small, pilot trials that reported on aerobic walking ET-related improvements in CPS and fMRI outcomes relative to different control conditions in non CPS-impaired persons with MS [–]. We provide the original position paper that established the agenda for ET/cognition research in MS []. However, a recent meta-analysis [] reported that the overall data in MS are mixed and do not yet support the benefits of ET on cognition. That meta-analysis of 13 studies reported an overall null effect of ET (across modalities) on global cognition (g=0.04) and CPS (g=0.17) relative to control conditions []. Importantly, the meta-analysis reported numerous fieldwide methodological limitations that likely explained the overall null effects – including sample-related weaknesses (e.g., not pre-screening MS patients for CPS impairment, low statistical power), trial issues (e.g., lack of efficacy evidence from RCTs), inadequate reporting of ET prescriptions, lack of data on neural mechanisms of ET effects on CPS, and lack of data on ET effects on everyday life [].