This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although OCD is primarily marked by compulsive behaviors and pathological gambling is primarily marked by impulsive behaviors, these disorders have been conceptualized as obsessive-compulsive (OC) spectrum disorders because they share a number of phenomenological features (e.g., obsessionality and compulsivity) (Bartz & Hollander, in press; Stein & Hollander, 1993). More research, however, is needed to investigate the similarities and differences between these disorders as well as their neurobiological underpinnings. The objective of this pilot study research is to identify cognitive and neurobiological endophenotypes associated with these two OC spectrum disorders. Endophenotypes, which can be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological in nature, have become an important focus in the study of psychiatric disorders because they are thought to be indicators of the genetic underpinnings of disorders and, therefore, can be used to guide and inform genetic research, and aid in disease classification, diagnosis and treatment (Gottesman & Gould, 2003). Inherent in the notion of an OC spectrum of disorders is that although these disorders have different phenotypes, they likely share some common endophenotypes. Response inhibition deficits are a core feature of OCD and may also be characteristic of pathological gambling. Moreover, altered processing of rewards and/or punishments may be implicated in these two disorders. Preliminary findings (Bartz et al., 2005) suggest that deficient anticipation of rewards may underlie the pathological gambler's need to engage in risky gambling behavior. Along similar lines, increased sensitivity to punishments may be a factor in the OCD individual's difficulty resisting compulsions. The primary objective of this pilot study is to investigate the underlying neurocircuitry associated with response inhibition and reward processing in individuals diagnosed with treatment resistant OCD and in those diagnosed with pathological gambling in an effort to identify endophenotypic markers of these two disorders. First, we will attempt to show that pathological gamblers exhibit hypoactivation of the caudate, dorsolateral prefrontal and lateral orbitofrontal cortex as well as the anterior cingulate cortex during the go-nogo test, whereas those with treatment-resistant OCD will exhibit hyperactivation of these regions on the same task. Second, we will attempt to show that pathological gamblers exhibit hypoactivation of the ventral striatum during the anticipatory phase of reward processing, whereas those with treatment-resistant OCD exhibit hyperactivation of the ventral striatum during the anticipatory phase of reward processing. Finally, we will attempt to show that pathological gamblers are more sensitive to potential rewards, whereas those with treatment-resistant OCD are more sensitive to potential punishments/loses. In addition to the theoretical contribution this pilot research will make to understanding important processes underlying OCD and pathological gambling, by identifying cognitive and neurophysiological endophenotypic markers of these two disorders, the findings from this pilot studyresearch can be used to direct the focus of genetic research and to identify individuals who will respond to specific treatments. In addition to the theoretical contribution this pilot research will make to understanding important processes underlying OCD and pathological gambling, by identifying cognitive and neurophysiological endophenotypic markers of these two disorders, the findings from this pilot studyresearch can be used to direct the focus of genetic research and to identify individuals who will respond to specific treatments. Hypotheses: 1. To explore abnormalities in activation of the frontostriatal circuit involved in response inhibition in pathological gamblers and those with treatment-resistant OCD a) Pathological gamblers vs. normal controls will exhibit decreased activity in the caudate, dorsolateral prefrontal and lateral orbitofrontal cortex as well as the anterior cingulate cortex during the go-nogo test (a measure of response inhibition); in addition, pathological gamblers may exhibit decreased activity in the ventromedial prefrontal cortex compared to normal controls. b) Individuals diagnosed with treatment resistant OCD vs. normal controls will exhibit increased activity in the caudate, dorsolateral prefrontal and lateral orbitofrontal cortex as well as anterior cingulate cortex during the go-nogo test. 2. To explore abnormalities in the neurocircuitry involved in the anticipation and outcome phases of reward processing in pathological gamblers and treatment-resistant OCD a) In response to monetary rewards (versus no reward), pathological gamblers vs. normal controls will exhibit decreased activity in the ventral striatum, nucleus accumbens, and anterior and medial caudate during the anticipatory phase of the MID task; in addition, the insula and structures associated with the dopamine pathway such as the dorsal thalamus and dorsal midbrain may similarly be hypoactivated during the anticipation of monetary rewards; b) Individuals diagnosed with treatment resistant OCD vs. normal controls will exhibit increased activation of the ventral striatum, nucleus accumbens, and anterior and medial caudate during the anticipatory phase of the MID task; in addition, the right insula and structures associated with the dopamine pathway such as the dorsal thalamus and dorsal midbrain may also be hyperactivated during reward anticipation; c) Pathological gamblers and those with OCD vs. normal controls will not exhibit differential activation during the outcome phase of the MID task; 3. To explore differences in the neurocircuitry in individuals diagnosed with treatment resistant OCD and PG with respect to response inhibition and reward processing a) While both the PG and OCD subjects will exhibit altered neurocircuitry in response to the go-nogo task, individuals diagnosed with PG will exhibit hypoactivation whereas those diagnosed with OCD will exhibit hyperactivation of the frontostriatal circuits during the go-nogo task. b) Pathological gamblers will primarily respond to potential rewards in the MID task, whereas those with OCD will primarily respond to potential losses.