James Loughead, Ph.D.

This study will elucidate the cognitive mechanisms of response to opioid agonists and antagonists used to prevent relapse in OUD through investigation of the underlying neural circuits. We shall use previously validated cognitive probes, functional Magnetic Resonance Imaging (fMRI), and extended-release injectable preparations of opioid partial agonist buprenorphine (XRBUP, Brixadi) and opioid antagonist naltrexone (XRNTX, Vivitrol), in OUD patients. Using two medications with opposing mu opioid receptor action will allow a comprehensive evaluation of the mechanisms of response to relapse prevention pharmacotherapy in OUD. The study will determine the presence of treatment effects in the domains of executive function, incentive salience, and resting functional connectivity and the interaction that will indicate a difference between the two medications. Then we will evaluate the ability of the brain fMRI signal to explain relapse defined by % of opioid-positive urine tests and adherence to the study interventions. Participants will be recently detoxified treatment-seeking patients with OUD who will receive 2 monthly injections of XR-NTX or XR-BUP and have weekly urine toxicology monitoring. The proposal would be the first neural systems’ level investigation of the cognitive effects of the next generation extended release preparation of buprenorphine and naltrexone to explain the individual heterogeneity of OUD treatment response and failure.

Following initial smoking cessation, smokers increase their daily caloric intake significantly, an effect observable on day one and lasting for weeks or months. Indeed, within one year, ~50% of abstaining smokers gain >11 lbs. and ~15% gain >22lbs. As such, weight gain is often cited as a primary reason for returning to smoking. While many pharmacologic and behavioral interventions to reduce post-cessation weight gain (PCWG) have been tested, these tend to be ineffective or to have short-lived benefits. Thus, novel therapeutic approaches are urgently needed. This will require identifying new intervention targets based on an improved understanding of the neurobehavioral mechanisms linking smoking cessation and overeating. Toward this end, this project breaks new ground by integrating concepts and tools from the fields of behavioral economics and cognitive neuroscience to accelerate the study of neurobehavioral mechanisms underlying PCWG. The primary aims of this functional magnetic resonance imaging (fMRI) study are: (1) To identify effects of initial smoking cessation on food-related brain activity and behavior; (2) To evaluate the relative contribution of these brain and behavioral processes to post-cessation caloric intake; and (3) To compare baseline differences between smokers and non-smokers. This study will use a validated within-subject cross-over fMRI study design to compare working memory, food cue reactivity, reinforcing value of food, and caloric intake during a 4-day period of “smoking as usual” vs. a 4-day period of mandatory abstinence (order of conditions counterbalanced). On day 4 of each period, participants will undergo fMRI while completing measures of working memory, food cue reactivity, and food reinforcement. 24-hour daily food recalls will be completed at baseline and during each study period to calculate overall caloric intake and intake of high fat and high sugar foods. The study will include a non-smoking comparison group that undergoes one phase of the study. Support for our predictions would inform testing of novel adjunctive treatments to prevent PCWG, such as computerized neurocognitive exercise training. Further, pretreatment measures of cognitive function may identify smokers who are most likely to need more intensive treatment to manage PCWG.

Risk-reduction bilateral salpingo-oophorectomy (RRSO) after completion of childbearing has become the standard-of-care for prevention of gynecologic and breast cancer in BRCA1 or BRCA2 gene mutation carriers. Although surgery reduces the risk of death due to cancer by over 75%, knowledge regarding the impact of this procedure and subsequent hypogonadism on brain structure, function and neurotransmitter systems is limited. Menopause before the age of 40 is associated with significant cognitive decline in the years that follow and an almost 2-fold increased risk of dementia if a woman does not supplement with estradiol (E2) However, E2 is not an option for many post-RRSO women due to enhanced risk of cancer. Systematic assessment of a large group of women who underwent RRSO suggests subjective deficits in executive functions (EF), with severity inversely correlated with age at RRSO. As the prefrontal cortex is impacted by loss of E2 and is critical for working memory and other EFs, we propose to examine the biological and behavioral impact of the psychostimulant lisdexamfetamine (LDX) in 100 women between the ages of 35 and 55 with post-RRSO EF complaints. Participants will undergo multi-modal imaging (functional magnetic resonance spectroscopy, fMRI; and proton magnetic resonance spectroscopy, 1H-MRS) using the ultrahigh magnetic field strength of 7 Tesla pre and post a 6-week course of the psychostimulant lisdexamphetamine (LDX; Vyvanse®) or placebo followed by a 3-week washout before crossing over to the other condition. Our overarching aim is to determine the impact of LDX treatment on brain function (neural activation and chemistry) as it relates to subjective and objective measures of EFs such as 1) organization and activation for work, 2) attention and concentration, 3) alertness, effort, processing speed, 4) managing affective interference, and 5) working memory, accessing recall. While an unconventional use of psychostimulants, this novel approach has already demonstrated the potential to improve new-onset EF difficulties among women who underwent a natural menopause and has provided important information regarding a potential mechanism of therapeutic action, specifically LDX-induced changes in dorsolateral prefrontal cortex (dlPFC) glutamate (GLUT) levels.

Smoking is the greatest preventable cause of mortality and a significant economic burden. Even with the best available treatments, most smokers relapse within days or weeks after a quit attempt. To improve quit rates significantly, we need a more refined mechanistic understanding of why so many smokers who attempt to quit will relapse quickly. The proposed functional magnetic resonance imaging (fMRI) study integrates concepts and tools from the fields of cognitive neuroscience and behavioral science to determine how brain states in early abstinence influence clinical outcomes among treatment-seeking smokers. The primary aims of this hypothesis-driven study are: (1) to identify brain mechanisms that increase vulnerability to smoking relapse, and (2) to test an integrated brain-behavior model of smoking relapse. Using our validated fMRI-based abstinence challenge paradigm, 200 treatment-seeking smokers will complete two 1-hour pretreatment fMRI scans: after smoking satiety and after 24 hours of confirmed abstinence. We will examine neural and behavioral responses during performance of validated tasks probing working memory, cue reactivity, and stress response as well as resting state functional connectivity. Participants will then set a target quit date, receive smoking cessation counseling, and be monitored for 6-months to assess time (days) to relapse, using a validated smoking relapse protocol. The primary outcome is time to relapse. Secondary outcomes include abstinence symptoms and smoking status at 30 days. For human subjects reasons, relapsing smokers will be offered an opportunity to receive 8 weeks of nicotine patch treatment and counseling free of charge following study completion. Although neuroimaging is not likely to become a standard pre-cessation assessment the near future, this study will elucidate pathological neurobehavioral processes and specific neurocognitive domains that can be targeted in new treatments to aid smoking cessation.