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

ABSTRACT 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.

69 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Reduced activity in the OFC whilst viewing disorder-related stimuli has also been found in AN (Uher et al., 2004), and alterations in OFC volume has been reported (Frank et al., 2013). Reduced activation of the OFC during reversal learning has been found in individuals with OCD and their unaffected relatives (Chamberlain et al., 2008), and abnormalities in OFC gray matter have been found in both OCD (Menzies et al., 2008), and substance dependence (Franklin et al., 2002) Reduced functional connectivity of the right inferior and superior OFC has been related not only to self-reported compulsivity in OCD but also to compulsive drug taking in substance dependence (Meunier et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The compulsive nature of weight loss behaviors central to anorexia nervosa (AN), such as relentless self-starvation and over-exercise, has led to the suggestion of parallels between AN and other compulsive disorders such as obsessive-compulsive disorder (OCD) and addictions. There is a huge unmet need for effective treatments in AN, which has high rates of morbidity and the highest mortality rate of any psychiatric disorder, yet a grave paucity of effective treatments. Viewing compulsivity as a transdiagnostic concept, seen in various manifestations across disorders, may help delineate the mechanisms responsible for the persistence of AN, and aid treatment development. We explore models of compulsivity that suggest dysfunction in cortico-striatal circuitry underpins compulsive behavior, and consider evidence of aberrancies in this circuitry across disorders. Excessive habit formation is considered as a mechanism by which initially rewarding weight loss behavior in AN may become compulsive over time, and the complex balance between positive and negative reinforcement in this process is considered. The physiological effects of starvation in promoting compulsivity, positive reinforcement, and habit formation are also discussed. Further research in AN may benefit from a focus on processes potentially underlying the development of compulsivity, such as aberrant reward processing and habit formation. We discuss the implications of a transdiagnostic perspective on compulsivity, and how it may contribute to the development of novel treatments for AN.
    Frontiers in Psychology 07/2014; 5:778. DOI:10.3389/fpsyg.2014.00778 · 2.80 Impact Factor
Show more