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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    • "Impaired behavioural flexibility is often associated with clinically diagnosed pathological symptoms such as deficient executive functions, undirected repetitive thoughts, and rigid behaviours as observed in obsessive compulsive disorder (OCD). The behavioural rigidity of this disorder has been associated with altered functioning of several brain regions in the frontostriatal circuit (Aouizerate et al., 2004) such as reduced activation of the orbitofrontal cortex (OFC) (Chamberlain et al., 2008) and hyperactivity of the head of the caudate nucleus (Guehl et al., 2008; Whiteside, Port, & Abramowitz, 2004). Interestingly, despite an overactive caudate nucleus, the functional connectivity between the caudate head and the dorsolateral prefrontal cortex (DLPFC) is reduced in obsessive compulsive disorder (Harrison et al., 2009). "
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    ABSTRACT: Behavioral flexibility is an important aspect of self-regulation and involves effectively learning, unlearning, and relearning associations between actions and outcome. Using a probabilistic reversal learning paradigm (PRL), the neural correlates of flexibility have previously been associated with brain regions implicated in cognitive control, including the anterior cingulate cortex (ACC) and lateral prefrontal cortex, and with the nucleus accumbens (Nacc) implicated in reward. The current study on healthy young males (n = 40) extends this previously published work in 3 ways. First we corroborate the involvement of ACC, VLPFC, and DLPFC at the exact moment of behavioral switches. Second, we report increased activation of the dACC and caudate head with increasing number of perseverating errors preceding a behavioral switch. Third, better performance on the task is associated with increased activation of rACC and VLPFC during switching, suggesting that these regions contribute to individual differences in behavioral flexibility. These findings cannot be extended to individual differences in a self-reported measure of self-regulation. (PsycINFO Database Record (c) 2014 APA, all rights reserved)
    Journal of Neuroscience Psychology and Economics 12/2014; 7(4-4):203-218. DOI:10.1037/npe0000026
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    • "These questions are of importance not only because they would provide an understanding of the function of S–R associations. How S–R associations are strengthened, and how durable they are, are also questions that relate to disorders such as obsessive compulsive disorder characterized by the inability to inhibit the execution of habitual behaviours thought to be related to a dysfunction in cortical areas responsible for reversal learning (Chamberlain et al., 2008). Below we consider each of the three questions addressed by the current study, in turn. "
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    ABSTRACT: ABSTRACT It has been shown that acquired Stimulus-Response associations result from at least two types of associations from the stimulus to the task (Stimulus-Task or Stimulus-Classification; S-C) and from the stimulus to the motor response (Stimulus-Response or Stimulus-Action; S-A). These types of associations have been shown to independently affect behaviour. This finding suggests that they are processed in different pathways/ different parts of a pathway at the neural level. Here we test a hypothesis that such associations may be differentially affected by repetition learning and that such effects may be detected by measuring their durability against overwriting. We show that both S-C and S-A associations are in fact strengthened when learning is boosted by increasing repetitions of the primes. However, the results further suggest that associations between stimuli and actions have less durable effects on behaviour and that the durability of S-C and S-A associations is independent of repetition learning. This is an important finding for the understanding of the underlying mechanisms of associative learning and particularly raises the question of which processes may affect flexibility of learning.
    Quarterly journal of experimental psychology (2006) 11/2014; 68(9):1-36. DOI:10.1080/17470218.2014.984232 · 2.13 Impact Factor
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    • "Therefore, it is striking that the region that emerged from our whole-brain analysis as most relevant for predicting improvements in contamination anxiety was in our target area of the OFC/BA 10. Taken together with a large body of data highlighting the importance of the OFC and anterior prefrontal cortex in obsessive-compulsive symptoms (Swedo et al., 1992; Chamberlain et al., 2008; Menzies et al., 2008; Harrison et al., 2009; Sakai et al., 2011; Anticevic et al., 2014; Beucke et al., 2013), this gives us confidence that we are targeting a biologically relevant brain area. Notably, OFC/BA 10 connectivity predicted the response to the intervention in both healthy subjects and OCD patients, suggesting a shared neurobiological mechanism for improved control over contamination anxiety across groups. "
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    ABSTRACT: Tailoring treatments to the specific needs and biology of individual patients-personalized medicine-requires delineation of reliable predictors of response. Unfortunately, these have been slow to emerge, especially in neuropsychiatric disorders. We have recently described a real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback protocol that can reduce contamination-related anxiety, a prominent symptom of many cases of obsessive-compulsive disorder (OCD). Individual response to this intervention is variable. Here we used patterns of brain functional connectivity, as measured by baseline resting-state fMRI (rs-fMRI), to predict improvements in contamination anxiety after neurofeedback training. Activity of a region of the orbitofrontal cortex (OFC) and anterior prefrontal cortex, Brodmann area (BA) 10, associated with contamination anxiety in each subject was measured in real time and presented as a neurofeedback signal, permitting subjects to learn to modulate this target brain region. We have previously reported both enhanced OFC/BA 10 control and improved anxiety in a group of subclinically anxious subjects after neurofeedback. Five individuals with contamination-related OCD who underwent the same protocol also showed improved clinical symptomatology. In both groups, these behavioral improvements were strongly correlated with baseline whole-brain connectivity in the OFC/BA 10, computed from rs-fMRI collected several days prior to neurofeedback training. These pilot data suggest that rs-fMRI can be used to identify individuals likely to benefit from rt-fMRI neurofeedback training to control contamination anxiety.
    Frontiers in Behavioral Neuroscience 09/2014; 8:338. DOI:10.3389/fnbeh.2014.00338 · 3.27 Impact Factor
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