Functional and structural neural indices of risk aversion in obsessive–compulsive disorder (OCD)
Introduction
The daily function of obsessive–compulsive disorder (OCD) patients is severely impaired by their inability to face situations involving uncertainty due to their inappropriate aversion to even the slightest risk (Steketee and Frost, 1994). This maladaptive behavior is commonly thought to stem from their perception of situations as much more threatening than they actually are, with exaggerated evaluation of the possible negative consequences (Sookman and Pinard, 2002) leading them to develop avoidance strategies to protect themselves. Nevertheless, OCD patients' insensitivity to rewarding signals should also be considered as a contributing component to risk aversion, as it diminishes the appeal of achieving the goal at stake (Szechtman and Woody, 2004). Indeed, both reward and threat perception appear to be abnormal in OCD (Del Casale et al., 2011).
Current neurobiological models of OCD indicate that dysfunction in the orbito-frontal-cortex (OFC) striatal circuit and connected structures such as the anterior cingulate cortex (ACC) and amygdala contribute to the OCD pathology (Saxena et al., 1998, Menzies et al., 2008a, Del Casale et al., 2011, Milad and Rauch, 2012). Abnormal activations within those brain regions were indeed found to mediate OCD patients' exaggerated concern with potential threat (i.e., OFC, amygdala and ACC) (van den Heuvel et al., 2004, Ursu and Carter, 2009, Simon et al., 2010), and diminished response to reward (i.e., OFC, ventral striatum) (Remijnse et al., 2006, Chamberlain et al., 2008, Figee et al., 2011).
Recent studies have started to explore the neural abnormalities in OCD patients at the circuit level, either by measuring the functional synchronization of a brain region with other regions via functional magnetic resonance imaging (fMRI) (i.e., functional connectivity), or by measuring the structural integrity of specific white matter fiber tracts that anatomically connect different regions via diffusion tensor imaging (DTI) (i.e., structural connectivity). Such studies have associated OCD with functional connectivity deficits between cortical to striatal brain regions as well as with white matter abnormalities in a wide range of fiber tracts including the cingulum bundle (Szeszko et al., 2005, Cannistraro et al., 2007, Menzies et al., 2008b, Harrison et al., 2009, Sakai et al., 2010). Some of those studies have further correlated these connectivity deficits with OCD symptom severity, yet none have associated it with behavioral dysfunctions as inappropriate responses to threat or reward. Furthermore, as far as we know, no study to date has attempted to characterize brain abnormalities in OCD by combining both structural and functional indices at regional and circuit levels in the same patient. Thus, the exact neural circuitries that mediate the two components of risk aversion in OCD have yet to be fully revealed.
To address these issues, we used a multi-parametric MRI approach that included an fMRI brain scan of 13 OCD patients and 13 healthy matched controls and a complementary anatomical DTI scan. During the fMRI scan, participants played an interactive naturalistic risky choice game encompassing distinct time intervals of both threatening anticipation to punishment and acceptance of unpredicted rewarding outcome (see Fig. 1). Prior work from our laboratory has already shown that these exact intervals evoke selective responses in the amygdala and the striatal nucleus accumbens (Nacc), respectively (Kahn et al., 2002, Assaf et al., 2009, Admon et al., 2012); findings that correspond to the notion that these areas are central nodes within the neural circuits that mediate responsivity to threat and reward signals (Davis, 1992, Depue and Collins, 1999, Zald, 2003, Hariri, 2009, Haber and Knutson, 2010). We hypothesized that OCD patients would show diminished willingness to make risky choices throughout the game. Furthermore, at the neural level, OCD would be characterized by marked abnormalities in the amygdala's and Nacc's activation and functional connectivity in response to threatening and rewarding stimuli, which would be accompanied by structural deficits.
Section snippets
Participants
Thirteen OCD patients were recruited from outpatient departments at Tirat Carmel Mental Health Center. Thirteen healthy control subjects, matched to the patients on age, gender and years of education, were recruited from the community (see Table 1). Participants with any medical or neurological illness or substance abuse were excluded from the study. Furthermore, all participants were right-handed and provided written informed consent after receiving a full explanation of the nature of the
Behavioral indices of risk taking
A calculated risk index (see Section 2) revealed that during the game OCD patients chose significantly fewer non-match ‘risky’ choices compared to healthy controls (t24 = 2.44; P = 0.02; Fig. 2a). This could not be explained by a change in the total amount of choices made throughout the game as it did not differ between the groups (average ± SEM 55.7 ± 2.7 choices made by healthy controls and 55.5 ± 3.8 choices made by OCD patients; t24 = 1.37; P = 0.19, not shown), or by patients' misunderstanding of the
Discussion
By using a game paradigm that mimics real life interactive situations of threatening anticipation to punishment and acceptance of unpredicted rewarding outcome, we were able to show that compared to healthy controls, OCD patients are reluctant to take risky choices, in accordance with previous findings (Steketee and Frost, 1994). In addition, OCD patients displayed abnormal neural functional response to punishment anticipation and rewarding outcome both at the regional and circuit levels.
Acknowledgments
This research was supported by the Levy Edersheim Gitter Institute for Neuroimaging and the Adams Super Center for Brain Studies, Tel Aviv University (R.A. and T.H.). Many thanks to Mrs. Vicki Myers and Dr. Itamar Kahn for their support at various stages of the project.
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