Neurocognitive endophenotypes of obsessive-compulsive disorder

Brain Mapping Unit, University of Cambridge, Cambridge, UK.
Brain (Impact Factor: 9.2). 01/2008; 130(Pt 12):3223-36. DOI: 10.1093/brain/awm205
Source: PubMed


Endophenotypes (intermediate phenotypes) are objective, heritable, quantitative traits hypothesized to represent genetic risk for polygenic disorders at more biologically tractable levels than distal behavioural and clinical phenotypes. It is theorized that endophenotype models of disease will help to clarify both diagnostic classification and aetiological understanding of complex brain disorders such as obsessive-compulsive disorder (OCD). To investigate endophenotypes in OCD, we measured brain structure using magnetic resonance imaging (MRI), and behavioural performance on a response inhibition task (Stop-Signal) in 31 OCD patients, 31 of their unaffected first-degree relatives, and 31 unrelated matched controls. Both patients and relatives had delayed response inhibition on the Stop-Signal task compared with healthy controls. We used a multivoxel analysis method (partial least squares) to identify large-scale brain systems in which anatomical variation was associated with variation in performance on the response inhibition task. Behavioural impairment on the Stop-Signal task, occurring predominantly in patients and relatives, was significantly associated with reduced grey matter in orbitofrontal and right inferior frontal regions and increased grey matter in cingulate, parietal and striatal regions. A novel permutation test indicated significant familial effects on variation of the MRI markers of inhibitory processing, supporting the candidacy of these brain structural systems as endophenotypes of OCD. In summary, structural variation in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCD, representing the first evidence for a neurocognitive endophenotype of OCD.

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    • "Cognitive and behavioral inflexibility represent core features of compulsivity in OCD (Chamberlain et al., 2006;Menzies et al., 2007), substance-use disorders (Izquierdo and Jentsch, 2012;Ersche et al., 2008;Van Holst and Schilt, 2011) and some behavioral addictions (Goudriaan et al., 2006;Vanes et al., 2014). Contingency-related flexibility refers to the adaptation of behavior or cognitive strategies after positive or negative contingencies. "
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    ABSTRACT: Compulsive behaviors are driven by repetitive urges and typically involve the experience of limited voluntary control over these urges, a diminished ability to delay or inhibit these behaviors, and a tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity is not only a central characteristic of obsessive-compulsive disorder (OCD) but is also crucial to addiction. Based on this analogy, OCD has been proposed to be part of the concept of behavioral addiction along with other non-drug-related disorders that share compulsivity, such as pathological gambling, skin-picking, trichotillomania and compulsive eating. In this review, we investigate the neurobiological overlap between compulsivity in substance-use disorders, OCD and behavioral addictions as a validation for the construct of compulsivity that could be adopted in the Research Domain Criteria (RDoC). The reviewed data suggest that compulsivity in OCD and addictions is related to impaired reward and punishment processing with attenuated dopamine release in the ventral striatum, negative reinforcement in limbic systems, cognitive and behavioral inflexibility with diminished serotonergic prefrontal control, and habitual responding with imbalances between ventral and dorsal frontostriatal recruitment. Frontostriatal abnormalities of compulsivity are promising targets for neuromodulation and other interventions for OCD and addictions. We conclude that compulsivity encompasses many of the RDoC constructs in a trans-diagnostic fashion with a common brain circuit dysfunction that can help identifying appropriate prevention and treatment targets.
    Full-text · Article · Dec 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "This study is very interesting because it teased apart two types of impulsivity: dysfunctional impulsivity, described as rapid reactions with a less adaptive approach (Dickman, 1990) and functional impulsivity, characterised as rapid responses in situations where this is more optimal (a more adaptive approach). Having a relationship between reactive inhibition and dysfunctional impulsivity is consistent I n r e v i e w with neuropsychological disorders where impulsive behaviours are inappropriate and less adaptive (Aron & Poldrack, 2005; Barkley, 1997; Bohne et al., 2008; Enticott et al., 2008; Kiehl et al., 2000; Menzies et al., 2007; Penadés et al., 2007; Rubia, Russell, et al., 2001). Although, the evidence from manual response inhibition studies suggests that impulsivity is also related to longer SSRTs (Logan et al., 1997), van den Wildenberg and Christoffels (2010) only found that dysfunctional impulsivity was related with vocal responses (not manual responses), possibly because of the relatively small sample size (14 participants). "
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    ABSTRACT: This study measured proactive and reactive response inhibition and their relationships with self-reported impulsivity. We examined the domains of both vocal and manual responding using a stop signal task (SST) with two stop probabilities: high and low probability stop (1/3 and 1/6 stops respectively). Our aim was to evaluate the effect stop probability would have on reactive and proactive inhibition. We tested 44 subjects and found that for the high compared to low probability stop signal condition, more proactive inhibition was evident and this was correlated with a reduction in the stop signal reaction time (SSRT). We found that reactive inhibition had a positive relationship with dysfunctional but not functional impulsivity in both vocal and manual domains of responding. These findings support the hypothesis that proactive inhibition may pre-activate the network for reactive inhibition.
    Full-text · Article · Sep 2015 · Frontiers in Human Neuroscience
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    • "One possible difference is that probabilistic tasks (for example, the beads task or Information Sampling Task) require an active accumulation of information (drawing another bead or opening another box), whereas in the perceptual RDMT motor inhibition is necessary (waiting longer results in more evidence accumulation). Motor inhibition as tested using the stop signal task has been shown to be impaired in OCD (Menzies et al, 2007), which may be relevant in any differential impairment of the RDMT. We tested decision thresholds across a range of coherence levels to control for visual processing and compared high and low uncertainty conditions, thus linking decision-making to perceptual uncertainty. "
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    ABSTRACT: Objective The compulsive behaviour underlying Obsessive-Compulsive Disorder (OCD) may be related to abnormalities in decision-making. The inability to commit to ultimate decisions, e.g. patients unable to decide whether their hands are sufficiently clean, may reflect failures in accumulating sufficient evidence prior to a decision. Here we investigate the process of evidence accumulation in OCD in perceptual discrimination, hypothesizing enhanced evidence accumulation relative to healthy volunteers. Method Twenty-eight OCD patients and 35 healthy control subjects were tested with a low-level visual perceptual task (random dot motion task), whereby different coherent levels for motion were defined to measure high and low uncertainty, and two response conflict tasks as control tasks (flanker task and probabilistic selection task). Logistic regression analysis across all coherence levels (which accounted for visual detection threshold) and hierarchical drift diffusion modelling (HDDM) were used to characterize response strategies between patients with OCD and healthy controls in the random dot motion task. Results Patients required more evidence under high uncertainty perceptual contexts, as indexed by longer response time and higher decision boundaries. HDDM, which defines a decision when accumulated noisy evidence reaches a decision boundary, further showed slower drift rate towards the decision boundary reflecting poorer quality of evidence entering the decision process in patients under low uncertainty. With monetary incentives emphasizing speed, patients decreased the decision thresholds relative to controls, accumulating less evidence in low uncertainty. These findings were unrelated to visual perceptual deficits and response conflict. Conclusion This study provides evidence for impaired decision-formation processes in OCD, with a differential influence of high and low uncertainty contexts on evidence accumulation (decision threshold) and on the quality of evidence gathered (drift rates). It further emphasizes that OCD patients are sensitive to monetary incentives heightening speed in the speed-accuracy tradeoff, improving evidence accumulation and shifting away from pathological internal monitoring. These findings may have relevance for therapeutic approaches.
    Full-text · Article · Sep 2015 · Journal of Neurology Neurosurgery & Psychiatry
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