Glossop Road, United Kingdom

PET/MRI/EEG Imaging Study in Epilepsy

Transcranial Magnetic Stimulation Treatment for Alzheimer's Disease

A Preventive Behavioral Intervention for Young Adults With Psychotic Experiences

TMS for Cognitive Decline in Aging and Preclinical AD

Effects of Caffeine on Reinforcement Learning in Healthy Adults Using PET/MRI

Adenosine 2A receptors (A2AR) colocalize with and exerts allosteric antagonism to dopamine D2 receptors (D2R) by co-forming functional heterodimers in the striatum. Preliminary studies using positron emission tomography (PET) with [11C]Raclopride have shown increased D2/D3R availability by A2AR antagonism with caffeine and decreased D2/D3R availability by enhanced adenosine signaling during sleep deprivation, supporting the notion of A2AR-D2R interactions in vivo. However, how A2AR-D2R interactions contribute to D2R-mediated neurocognitive functions is scarcely investigated. Reinforcement learning, a dopamine-mediated cognitive process crucially involved in various human behaviors including habit, preference, belief, and resistance to change, is often found altered in dopamine-associated disorders. For instance, hyper-dopaminergic function in the striatum, as observed in psychosis, leads to a reduction in reward learning and a blunted task-related neural activity. Through the antagonistic effect of A2AR on D2R signaling, blocking A2AR can potentially enhance D2R-mediated negative reinforcement, a.k.a. a "no-go" response. In rodents, A2AR agonists diminish reinforcement of psychostimulants, while an A2AR antagonist can facilitate reward-seeking effects of reinforcers. Hence, in this double-blind randomized crossover study, the investigators aim to use caffeine, an adenosine antagonist as well as a commonly used psychostimulant by nearly 80% of the worldwide population, to examine whether blocking A2AR will enhance D2R-modulated reinforcement learning/no-go responses through modulating D2R signaling pharmacologically. The long-term goal of this study is to further the understanding of molecular mechanisms related to A2AR-D2R heterodimers and the clinical potential of modulating A2AR-D2R interactions. Twelve young healthy non-smokers will enroll in this study. Each participant will undergo a caffeine and a placebo condition. In each condition, participants will first go through a 6-day ambulatory washout period where participants will be asked to abstain from caffeinated dietary, alcohol, and drugs, and stay in regular bed- and wakeup time. On day 7, a PET/fMRI scan will take place at noon, and a caffeine or placebo tablet will be administered orally 20 mins prior to the scan. Simultaneous PET/fMRI will be used to examine the association between the neurochemical changes (i.e., D2/D3R availability as quantified by [11C]Raclopride) and the hemodynamic responses (i.e., task-related blood oxygen level-dependent fMRI activity) during reinforcement learning in the caffeine condition compared to placebo. It is hypothesized that enhanced D2/D3R availability mediates the facilitating effect of caffeine on reinforcement learning. Specifically, the investigators expect that caffeine will enhance fMRI responses in reward-related brain regions, and that the increased fMRI response will positively correlate with a change in D2/D3R availability.

Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People With HIV-1

Effects Multimodal Mind and Body Approach for MCI

The goal of this Phase I R41 (STTR) application is to develop a computer-based multimodal mind and body approach (cbMMBA) to improve the cognitive function for mild cognitive impairment (MCI). This application, if successful, will provide a cost-effective and easily accessible treatment option for MCI and other age-related dementia, significantly improve the prevention of MCI development, and directly benefit patients suffering from the highly prevalent disorder, particularly for those who may have limited access to in-person mind and body interventions.

Virtual Reality Guided Acupuncture Imagery Treatment for Chronic Low Back Pain

The aim of this study is to develop a Virtual Reality guided acupuncture imagery treatment system for the treatment of chronic low back pain. This product will provide a new cost-effective treatment option for chronic low back pain and potentially other chronic pain disorders.

Dalfampridine Combined With Physical Therapy for Mobility Impairment in Multiple Sclerosis

Multiple sclerosis (MS) is a degenerative disease process that disrupts the transmission of nerve impulses, resulting in a range of neurological signs and symptoms. Walking-related impairment is one of the most common symptoms, reported to affect more than 90% of people with MS. The leading non-pharmacological intervention for walking-related deficits in people with MS is rehabilitation, such as physical therapy. Rehabilitation is believed to restore function through experience-dependent neuroplasticity. There is strong evidence that physical therapy can improve mobility-related function in people with MS, and emerging evidence that motor-relearning approaches to rehabilitation may be associated with changes in brain structure and function that correlate with improvements in functional performance. The leading pharmacological intervention for walking-related deficits in people with MS is dalfampridine. Dalfampridine improves motor function by increasing nerve conduction through demyelinated axons, however, dalfampridine alone is not likely to generate neuroplastic changes needed for lasting benefits, because neural plasticity requires salient and task-specific practice with high repetition at adequate intensity, as well as complex environments that stimulate opportunities for movement to facilitate synthesis of neurotrophic factors. Indeed, the treatment effects of dalfampridine are reversed as soon as the treatment was discontinued. However, it is possible that improved nerve conduction velocity provided by dalfampridine may accelerate neuroplasticity generated from rehabilitation. Yet, combining dalfampridine with concurrent rehabilitation has never been studied. The objective of the proposed study is to test our central hypothesis that providing a motor-relearning physical therapy intervention in combination with dalfampridine will produce superior gains to either intervention alone in mobility through augmented neuroplasticity. Aim 1 will determine if dalfampridine can augment the effects of physical therapy in restoring function in people with MS by comparing the combined intervention to physical therapy without dalfampridine. Aim 2 will explore the comparative effectiveness between the combined intervention with dalfampridine alone, and between physical therapy alone and dalfampridine alone. In Aim 3, the investigators will investigate mechanisms of treatment effects by evaluating functional connectivity before and after each intervention arm. Exploratory Aim 4 will examine whether there are specific clinical and personal factors associated with treatment responsiveness to each type of treatment. The primary efficacy outcome will be percent change from baseline in Timed 25-Foot Walk to enable direct comparison to previous dalfampridine studies. A range of secondary and tertiary clinical outcomes, both objective and self-reported, will examine restoration of function (objective and perceived) beyond just walking speed. The investigators will enroll 48 participants with MS-related mobility deficits and EDSS ≤6.5. In the first treatment phase, all participants will receive 6 weeks of dalfampridine treatment to assess the effects of this treatment and determine individual responder status for stratified randomization in phase 2. Following 2-week dalfampridine washout and new off-drug baseline assessment, stratified randomization will allocate participants to either 6 weeks of physical therapy with resumed dalfampridine or 6 weeks of physical therapy without dalfampridine. Outcomes will be reassessed after the physical therapy treatment phase. This project tests a novel combination of two traditional interventions to improve mobility in people with MS, with specific aims that investigate both restoration of function and mechanisms of treatment effects using brain imaging outcomes. These two leading, yet distinct approaches for improving mobility in people with MS, may have complementary mechanisms of action leading to enhanced outcomes when combined. The findings generated by this research will inform the design of further studies exploring longer-term outcomes and disease progression trajectories associated with the interventions found to be most effective and tolerable for individuals with MS in this stage of the research.

Cerebrospinal Fluid Biomarkers of Myotonic Dystrophy