Document text
Principal Investigator: Heather Burrell Ward
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $185,544
Funding agency: National Institute on Drug Abuse
PROJECT SUMMARY
Tobacco use is the top preventable cause of early mortality in schizophrenia, leading to a 20-year decreased life
expectancy compared to the general population. Current smoking cessation treatments are derived from people
without psychosis and are significantly less effective for people with schizophrenia. We used a data-driven,
agnostic approach to identify a schizophrenia-specific circuit of nicotine dependence (the Default Mode Network,
DMN) then tested pharmacologic and neuromodulation interventions on this circuit. We observed craving was
bidirectionally mediated by DMN connectivity: 1) nicotine administration (which reduces craving) decreased DMN
connectivity in schizophrenia, while 2) a single session of intermittent theta burst stimulation (iTBS), which
increases connectivity, applied to a DMN node acutely increased craving in schizophrenia. This provides
evidence that 1) nicotine craving is mediated by this network and 2) this target can be engaged bidirectionally
via multiple interventions. This K23 mentored patient-oriented career development award proposes to test if
multiple repetitive transcranial magnetic stimulation (rTMS) sessions lead to enduring circuit change and reduce
nicotine craving. Our central hypothesis is that the brain circuit most effective to reduce nicotine craving in
schizophrenia is distinct from the pathway identified in a non-schizophrenia population. To test this hypothesis,
we will compare 1) DMN-targeted continuous theta burst stimulation (cTBS) to 2) iTBS targeted to the left
dorsolateral prefrontal cortex (L DLPFC), which reduces cigarette consumption and craving in smokers without
psychosis. cTBS has been shown to decrease network connectivity. By applying cTBS to the DMN, we aim to
decrease connectivity, thereby decreasing craving. We will determine if rTMS manipulates functional connectivity
and craving and if craving change correlates with connectivity change for each rTMS target. To optimize rTMS
response, we will also test if variability in rTMS response is explained by individual differences in network
controllability. The applicant is a psychiatrist with fellowship-level training in neuroimaging and rTMS for
substance use disorders in schizophrenia. Her long-term career goal is to build an independent research
program using neuroimaging to identify brain networks linked to substance use in psychotic disorders then test
neuroscience-based, network-targeted rTMS interventions in clinical trials for co-occurring substance use
disorders in schizophrenia. To accomplish these goals, the applicant requires additional training in: 1) design
and conduct of personalized network-targeted rTMS interventions, 2) individualized neuroimaging to optimize
rTMS response, and 3) clinical trials and biostatistics. Training will include formal coursework, didactics, and on-
site trainings, guided under a mentorship team of experts in network-targeted rTMS interventions in psychotic
disorders, computational analysis of networks in psychotic disorders, and clinical trials design for rTMS and
smoking cessation. Mentored training and completion of the proposed project will provide the applicant the skills
and experience necessary to launch a successful independent research career.
Terms: <Acute><Affect><Biometrics><Biometry><Biostatistics><Brain><Brain Nervous System><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Causality><Central Lobe><Cigarette><Clinical Trials><Clinical Trials Design><Computer Analysis><Consumption><Cross-Over Designs><Crossover Design><Cues><Data><Diagnosis><Dose><Dysfunction><Educational Achievement><Educational Status><Encephalon><Etiology><FDA approved><Fellowship><Functional disorder><Future><General Population><General Public><Goals><Heterogeneity><Individual><Individual Differences><Insula><Insula of Reil><Intervention><Intervention Strategies><Island of Reil><K-Awards><K-Series Research Career Programs><Lead><Left><Life Expectancy><Link><Mediating><Mentors><Mentorship><Network Analysis><Neurosciences><Nicotine><Nicotine Dependence><Pathologic><Pathology><Pathway Analysis><Pathway interactions><Pattern><Pb element><Persons><Pharmacology><Physiopathology><Population><Prefrontal Cortex><Preparation><Prevalence><Psychiatrist><Psychoses><Psychotic Disorders><Research><Research Career Program><Schizophrenia><Schizophrenic Disorders><Severities><Site><Smoker><Smoking Cessation Intervention><Substance Use Disorder><Testing><Tobacco Consumption><Tobacco use><Training><career><career development><causation><cease smoking><clinical efficacy><co-clinical trial><cohort><computational analyses><computational analysis><computer analyses><craving><dementia praecox><design><designing><disease causation><educational level><experience><heavy metal Pb><heavy metal lead><individual heterogeneity><individual response><individual variability><individual variation><individualized response><interventional strategy><mortality><neural control><neural imaging><neural regulation><neuro-imaging><neuroimaging><neurological imaging><neuromodulation><neuromodulatory><neuroregulation><nicotine addiction><nicotine consumption><nicotine craving><nicotine dependent><nicotine treatment><nicotine use><pathophysiology><pathway><patient centered><patient oriented><pharmacologic><preparations><programs><psychotic illness><quit smoking><relapse prediction><repetitive transcranial magnetic stimulation><response><schizophrenic><skills><smoking cessation><smoking cessation treatment><stop smoking><substance use><substance use and disorder><substance using><tobacco product use><training achievement><training level><training status><ward>