Orbitofrontal Dysfunction in Patients with Obsessive-Compulsive Disorder and Their Unaffected Relatives

Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Box 189, Cambridge CB2 0QQ, UK.
Science (Impact Factor: 33.61). 07/2008; 321(5887):421-2. DOI: 10.1126/science.1154433
Source: PubMed


Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors associated with underlying dysregulation of frontostriatal circuitry. Central to neurobiological models of OCD is the orbitofrontal cortex, a neural region that facilitates behavioral flexibility after negative feedback (reversal learning). We identified abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder.

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    • "Although other tasks from the CANTAB were also performed, our analyses focused on CGT, as performance on this type of task is sensitive to serotonin manipulations in healthy volunteers (Merens et al. 2007) and it may tap into neural substrates that tie in closely with those often implicated in OCD (the orbitofrontal cortices and insula, for example) (e.g. Chamberlain et al. 2008; Menzies et al. 2008; Saxena et al. 2001). On the CGT, for each trial, subjects were presented with a row of ten boxes across the top of the screen, each box being blue or red. "
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    ABSTRACT: Rationale Obsessive-compulsive disorder (OCD) implicates dysfunction of orbitofrontal and insula-related circuitry and of the serotonin system. There is an on-going search in psychiatry for intermediate biological markers, termed ‘endophenotypes’, that exist not only in patients with a given disorder but also in their clinically unaffected first-degree relatives. Objective Pharmacological challenge is recognized as a means of eliciting an endophenotype, but this strategy has yet to be used in OCD. Methods Twenty-three OCD patients without comorbidities (12 [52.2 %] female), 13 clinically asymptomatic first-degree relatives of OCD patients (11 [84.6 %] female) and 27 healthy controls (16 [59.3 %] female) received single-dose escitalopram (20 mg) and placebo in a randomized double-blind crossover design. Effects of treatment on decision-making were quantified using the Cambridge Gamble Task (CGT) in conjunction with a mixed model analysis of covariance (ANCOVA). Results There was a significant interaction between serotonergic challenge and group for risk adjustment on the CGT (F = 4.1406; p = 0.02). Only controls showed a significant placebo-drug change in risk adjustment (p = 0.02; versus p > 0.10). Numerically, escitalopram was associated with increase in risk adjustment in controls and reductions in the other groups. Change in risk adjustment was similar in OCD patients and relatives (p = 0.806) and differed significantly from controls (p = 0.007; p = 0.041, respectively). Conclusions Individuals with OCD, and first-degree relatives, showed an altered cognitive response to serotonin challenge. This is the first demonstration of a candidate pharmacological challenge endophenotype for the disorder. Future work should confirm these findings in a larger sample size and ideally extend them to other cognitive paradigms, utilizing functional neuroimaging.
    No preview · Article · Dec 2015 · Psychopharmacology
    • "Impaired probabilistic reversal learning in OCD is associated with hypofunction of bilateral orbitofrontal and parietal cortices, both in patients with OCD and unaffected relatives (Chamberlain et al., 2008). Similarly, Remijnse et al. (2013) showed decreased lateral orbitofrontal activation in OCD during probabilistic reversal learning, accompanied by increased putamen and anterior cingulate activation. "
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    ABSTRACT: Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.
    No preview · Article · Dec 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
    • "These included Stroop and other interference tasks (Flanker Interference, Multi-Source Interference, Error-Eliciting Interference, and Suppression tasks), Go/No-Go, N-back, 1-back with biological motion, Switch, Verbal Fluency Test, Time-Estimation, Serial Reaction Time, Reversal Learning, Tower of London, Moral Dilemma, and Monetary Incentive Delay and other reward/loss tasks. Finally, on the basis of these criteria, we included 28 studies published prior to the 3 September 2014 (Table 1a and 1b) (van der Wee et al. 2003; Fitzgerald et al. 2005; Nakao et al. 2005a, 2009a, 2009b; van den Heuvel et al. 2005; Remijnse et al. 2006; 2009; Rauch et al. 2007; Roth et al. 2007; Yü cel et al. 2007; Chamberlain et al. 2008; Gu et al. 2008; Henseler et al. 2008; Nabeyama et al. 2008; Jung et al. 2009,2011; Page et al. 2009; Schlosser et al. 2010; Freyer et al. 2011; Koçak et al. 2011; Stern et al. 2011; Choi et al. 2012; Harrison et al. 2012; Koch et al. 2012; Woon et al. 2012; Kaufmann et al. 2013; Becker et al. 2014). In the context of these studies, we obtained additional within-group coordinates of three studies directly from corresponding authors (Koçak et al. 2011, Koch et al. 2012; Becker et al. 2014). "
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    ABSTRACT: Objectives: To identify activation changes assessed in functional magnetic resonance imaging (fMRI) studies of obsessive–compulsive disorder (OCD) through Activation Likelihood Estimate meta-analysis. Methods: We included 28 peer-reviewed standard stereotactic space studies assessing adult OCD patients (OCDpts) vs. healthy controls (HCs) with fMRI during executive task performance. Results: In within-group analyses, HCs showed task-related activations in bilateral inferior frontal gyri, right middle frontal gyrus, right inferior parietal lobule, right claustrum, bilateral cingulate gyri, and left caudate body. OCDpts showed task-related left-sided activations in the superior, medial, and inferior frontal gyri, and thalamus, and bilateral activations in the middle frontal gyri, inferior parietal lobule, and insular cortices. Subtraction analysis showed increased left middle frontal gyrus activation in OCDpts. In between-groups analyses, OCDpts hypoactivated the right caudate body, left putamen, left ACC, and right medial and middle frontal gyri. Right caudate hypoactivation persisted also after applying Family‐wise error algorithms. Conclusions: This meta-analysis confirms that during executive functioning OCDpts show a functional deficit of the right caudate body, which could represent a major neural functional correlate of their illness.
    No preview · Article · Oct 2015 · The World Journal of Biological Psychiatry
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