Lawrence H. Sweet, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The goal of this project is to use functional magnetic resonance imaging (FMRI) and arterial spin labeling (ASL) to examine how cardiovascular disease (CVD) affects cognitive function and the measurement of brain function. CVD is associated with cognitive deficits; however, it is not understood how abnormal cardiac output associated with severe CVD leads to impaired cognitive function. There is increasing evidence that patients with severe CVD experience diminished cerebrovascular function, which ultimately affects cognitive performance. FMRI and ASL provide reliable methods to examine the intervening links between systemic vascular dysfunction and cognitive performance. The blood oxygen level dependent (BOLD) FMRI response itself has been assumed to be constant across patient populations in previous research. Yet, there is evidence that the integrity of the BOLD response changes with vascular integrity. Studies have found that patients with CVD exhibit changes in the BOLD response; however, it remains to be determined if this observation is due to neural function, cerebrovascular perfusion, or both. There are two likely mechanisms to explain the relationship between systemic vascular dysfunction and observed reductions on measures of cognitive function: 1) chronic cerebrovascular dysfunction (e.g., hypoperfusion) secondary to severe CVD might cause neural changes and subsequently diminished cognitive function; 2) since BOLD FMRI assesses the delivery of oxygen-rich blood in excess of demand, acute cerebral hypoperfusion might also directly attenuate the hemodynamic response measured by FMRI, independent of neuronal function. This potential decoupling of neural demands and observed BOLD response needs to be examined to address validity and reliability of FMRI among this population. We will directly examine these possibilities by assessing systemic cardiovascular function, cerebrovascular hemodynamic functions, and cognitive performance among 60 elderly patients with severe CVD and 30 age-matched controls. Cognitive measures were chosen because they have elicited performance and FMRI abnormalities among CVD patients in the past. Control paradigms will be administered to assess BOLD response itself. Groups will be contrasted on BOLD response to three levels of cognitive challenge: none (i.e., hypercapnia), matched (sensory and motor), and difficult cognitive paradigms. Further analyses will be conducted among the CVD group to quantify the contributions of blood perfusion. We predict that BOLD response will be diminished during all conditions among the CVD group, and that a significant portion of this reduction will be attributed vascular hypoperfusion. With rapidly growing clinical and experimental applications, it is important to demonstrate reliability and validity of FMRI in CVD. Findings are expected to provide data and methods that will increase the clinical utility of FMRI for the assessment of CVD patients, and a better understanding of the mechanisms causing cognitive impairment. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Although nicotine dependent cigarette smokers who quit are less likely to experience life threatening health problems and improve their quality of life, unfortunately, long-term abstinence rates are low. Models of nicotine dependence suggest the importance of multifaceted approach to understanding relapse involving biological, motivational, cognitive, and behavioral factors. While biological factors, such as genetic predisposition are directly observable, other known risk factors for relapse such as craving and impulsivity are often indirectly measured using self-report questionnaires and behavioral observations. We propose to examine predictors of smoking cessation outcome by directly measuring neural activity associated with managing cravings, decision- making about rewards, and cognitive persistence using functional magnetic resonance imaging (FMRI). Assessed behaviorally, these constructs have been shown to predict smoking cessation outcome; however, it is expected that more direct fMRI assessment of neural activity will enhance sensitivity and specificity of quantitative measurement and avoid confounds associated with subjective ratings and behavioral observation of these factors. We expect fMRI activity to yield more sensitive markers of relapse relative to behavioral and subjective measures. To accomplish this we will challenge motivational and cognitive systems while measuring activity in brain regions normally associated with these functions. When grouped by cessation outcome (i.e., lapse) we predict different brain activity in regions of interest related to these systems. Specifically, we will demonstrate that nicotine-dependent smokers who lapse early exhibit different levels of brain activity compared to smokers who exhibit prolonged abstinence. We expect that groups will also differ on behavioral ratings of craving and measures of accuracy and impulsivity during these challenges. The results of the proposed study will refine understanding the neurobehavioral correlates of known risk factors for smoking relapse, and advance development of neurobehavioral models of neural activity that predispose smokers to relapse. Neurobehavioral methods can facilitate identification of smokers at greater risk for relapse, isolate targets of neural activity for clinical interventions and facilitate delivery of specialized behavioral and pharmacologic cessation treatments. Characterization of expected brain recruitment, compensatory responses, and disorganization of active and deactivated networks provide novel information that is likely to complement our existing knowledge on the neural mechanisms related to relapse risk.

PROJECT SUMMARY/ABSTRACT The novel field of neuroeconomics integrates concepts and methods from psychology, economics, and cognitive neuroscience to understand the neurobiological foundations of decision making, and has been increasingly applied to understanding alcohol use disorder (AUD). A novel focus in neuroeconomics is alcohol demand, or the value of alcohol as measured by cost-benefit preferences. Behaviorally, alcohol demand has been found to be elevated among individuals with higher levels of alcohol misuse and to predict treatment response. In addition, alcohol demand can also be dynamically increased via acute stress. These findings are consistent with theoretical perspectives that emphasize both stable tonic and acute phasic aspects of motivation. The overall goal of the proposed studies is to characterize the neural activity that subserves these established behavioral findings using a novel functional magnetic resonance imaging paradigm. The first aim is to examine how the brain represents the value of alcohol in individuals with AUD compared to a control group. To do so, the first study will use a between-subjects case-control design to identify differences in neural activity associated with elevations in alcohol demand in individuals with AUD (i.e., cases) versus individuals who drink regularly but do not have an AUD and are matched on key variables (i.e., controls). The second aim is to investigate the changes in neural activity associated with stress-elicited increases in the value of alcohol. To do so, a second study will use a within-subjects design, comparing demand-associated neural activity following a neutral induction to neural activity following a stress induction in individuals with AUD. The third aim is to investigate the relationship between patterns of neural activity during alcohol demand decision making and intervention response. To do so, all participants with AUD in Study #1 and Study #2 will receive Motivational Enhancement Therapy, a previously validated four-session manualized motivational interviewing intervention, and neural activity during the alcohol demand paradigm will be used to predict subsequent drinking at 1-month and 6-month follow-up. Collectively, these aims will systematically apply a novel neuroeconomic approach to diverse aspects of AUD across the translational spectrum, from basic differences in neural activity to predictors of intervention response.