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Cognitive Inflexibility and Phenotypic Heterogeneity in Anorexia Nervosa

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Anorexia nervosa (AN) in adults is a serious and often refractory psychiatric illness, yet little is known about underlying mechanisms that might serve as targets for the development of novel interventions. One challenge in advancing research on the pathophysiology of AN relates to the substantial within-group heterogeneity that characterizes the illness. For example, the Diagnostic and Statistical Manual of Mental Disorders includes two subtypes of AN - restricting (AN-R) and binge-eating/purging (AN-BP) that differ with respect to the presence of binge eating or purging (i.e., self-induced vomiting or the misuse of laxative, diuretics or enemas) episodes. Although there is some evidence that AN-R and AN-BP are distinct, the mechanisms that separate these groups remain elusive. Moreover, similarities and distinctions between AN-BP and bulimia nervosa (BN) underscore the need to identify processes that are shared by and unique to AN-R, AN-BP and BN. Accordingly, the overall goal of this study is to test a conceptual model linking heterogeneity in symptom presentation across the AN-BN spectrum to variations in the salience of two facets of cognitive inflexibility - attentional set-shifting (i.e., the ability to shift attention between two abstract stimulus dimensions) and reversal learning (i.e., the ability to alter behavior in response to changes in reinforcement contingencies). Importantly, attentional set-shifting and reversal learning are neurobiologically distinct, with correlates in the ventrolateral prefrontal cortex/anterior cingulate cortex and orbitofrontal cortex/ventral striatum, respectively. Cognitive inflexibility has received much attention as a putative biomarker of AN, but previous studies have relied primarily on multidimensional clinical neuropsychological measures that do not map on well to underlying neural mechanisms, and findings have been mixed. This study is guided by the hypothesis that heterogeneity in AN can be elucidated by identifying distinct aspects of altered function in fronto-cingulate circuitry mediating attentional set-shifting and fronto-striatl circuitry mediating reversal learning. Thus, this study will use both behavioral tasks outside of the scanner (i.e., Intradimensional/Extradimensional shift task from the Cambridge Neuropsychological Test Automated Battery and a probabilistic reversal learning task) and functional magnetic resonance imaging with conceptually-relevant neurocognitive probes to assess and separate behavioral and neural facets of attentional set-shifting and reversal learning across the AN-BN spectrum. Four groups of participants aged 18-55 years will be recruited: 1) AN-R with no history of binge eating or purging (n = 30); 2) AN-BP (n = 30); 3) BN with no history of AN (n = 30); and 4) psychiatrically healthy controls (n = 30). This study is innovative and significant as the first effort to examine the separate contributions of attentional set-shifting and reversal learning to phenotypic heterogeneity across the AN-BN spectrum. Findings will have important implications for neurobiological models of eating disorders and the development of novel interventions designed to target subgroup-specific pathophysiological processes.

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