The course of the neural correlates of reversal learning in obsessive–compulsive disorder and major depression: A naturalistic follow-up fMRI study

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Highlights

  • Frontal-striatal and reversal learning dysfunction in OCD and MDD were partly state-dependent.

  • Opposite task-related frontal-striatal changes were found over time in OCD and MDD.

  • In OCD normalization was characterized by improved dorsal frontal-striatal failure.

Abstract

Objectives

Reversal learning (RL) is impaired in obsessive–compulsive disorder (OCD) as well as in major depressive disorder (MDD). It is yet unknown to what extent pathophysiological mechanisms are state-dependent.

Methods

Neural activation patterns during RL were measured using event-related functional magnetic resonance imaging (fMRI) reversal learning in patients with OCD (N=18) and MDD (N=15). A naturalistic follow-up design enabled investigation of the relationship between changes in clinical state, task performance and task-related neural activation over time.

Results

During follow-up, disease severity decreased significantly in both groups. Whereas task speed improved trend-significantly, task accuracy was unchanged. Task-related dorsal frontal-striatal activation decreased at follow-up in MDD, but increased in OCD. In both groups, symptom improvement was associated with reward-related changes in neural activation in the putamen and the orbitofrontal cortex.

Conclusions

In both OCD and MDD, symptom reduction over time was associated with partial normalization of task-related activation patterns in brain regions. Whereas in OCD this normalization was characterized by increased recruitment of previously hypoactive frontal-striatal brain regions (i.e. dorsal frontal-striatal failure), in MDD previously hyperactive brain regions (frontal-striatal inefficiency), were recruited less after recovery. These results show that in both disorders frontal-striatal dysfunction is at least partly state-dependent.

Introduction

Major depressive disorder (MDD) and obsessive–compulsive disorder (OCD) are the first and fourth most common psychiatric disorders, respectively, and both may have severe repercussions on daily functioning (El-Sayegh et al., 2003, Fava and Kendler, 2000). Both disorders are frequently co-morbid and show overlap in symptoms, including cognitive rigidity (Ninan and Berger, 2001, Overbeek et al., 2002). Depressed patients experience negative emotions, motivational impairments, cognitive slowing and excessive rumination (Lyness, Conwell, King, Cox, & Caine, 1997), whereas OCD is characterized by recurrent, intrusive and persistent thoughts (obsessions) and/or repetitive behaviors (compulsions) (APA, 2005). The inability to halt obsessions and compulsions in OCD and rumination in MDD is thought to reflect deficits in cognitive and behavioral flexibility (Gotlib and Joormann, 2010, Kim et al., 2011, Levens et al., 2009, Remijnse, 2011). OCD and MDD patients are not only prone to cognitive rigidity (Bradbury et al., 2011, Remijnse et al., 2013, Vriend et al., 2013) but also show other cognitive deficits, such as impairments in decision making, planning and behavioral inhibition (Cavedini et al., 2006, de Wit et al., 2012, Godard et al., 2011, Gotlib and Joormann, 2010, Huyser et al., 2010, Kathmann et al., 2005, Linden et al., 2011, Murrough et al., 2011, Segalas et al., 2010, Tukel et al., 2011, van den Heuvel et al., 2005, Zucco and Bollini, 2011).

Reversal learning (RL) is defined as the ability to alter a response upon changing stimulus-reinforcement contingencies by means of motivational feedback (i.e. punishment and reward) (Cools et al., 2002, O’Doherty et al., 2001). RL thus is an executive function calling upon both cognitive and affective flexibility which is vital for normal socio-emotional learning and behavior (Dias, Robbins, & Roberts, 1996). It has been hypothesized that anxiety relief and compulsive urge in OCD patients resemble reward and punishment, respectively (Huey et al., 2008). MDD patients tend to be oversensitive to negative feedback (i.e. punishment) (Chamberlain and Sahakian, 2006, Elliott et al., 1996, Taylor Tavares et al., 2008) and show blunted reward responses (Henriques et al., 1994, Must et al., 2006).

Lesions in the orbitofrontal cortex (OFC) in humans (Rolls, 2004) and ventral striatum and dorsolateral prefrontal cortex (DLPFC) in non-human primates lead to RL deficits (Clarke, Robbins, & Roberts, 2008). RL relies on proper functioning of the frontal-striatal circuits which have been implicated in various psychiatric disorders (Phillips et al., 2003a, Phillips et al., 2003b, van den Heuvel et al., 2010), and include a dorsal ‘executive’ circuit (involving the DLPFC, dorsal ACC, caudate nucleus and anterior prefrontal cortex (aPFC)), and a ventral ‘affective’ circuit (involving the OFC and ventral striatum) (Alexander, Crutcher, & DeLong, 1990). During RL activation of the OFC is related to the magnitude and value of the feedback (O’Doherty et al., 2001). RL-related activation of the OFC and ventral striatum is mostly associated with reward processing, whereas insular cortex activation is mainly associated with punishment (O’Doherty et al., 2001, Remijnse et al., 2005). Relearning stimulus-reward associations (i.e. affective switching) is related to activation of both the ventral and the dorsal frontal-striatal circuit (Cools et al., 2002, Remijnse et al., 2005). OCD (Britton et al., 2010, Chamberlain et al., 2008, Dickstein et al., 2010, Figee et al., 2011, Remijnse et al., 2006, Saxena et al., 1998, Valerius et al., 2008) and MDD (Remijnse et al., 2009) are both associated with abnormal RL performance and alterations in task-related brain activation.

In our previous published study, regarding the baseline results of the same samples, we found in MDD patients compared with controls specific hyperactivity of the putamen during reward, and precuneus and insular cortex during punishment processing (Remijnse et al., 2009), whereas OCD patients showed decreased responsiveness of the OFC and caudate nucleus in response to reward (Remijnse et al., 2006). At baseline MDD and OCD patients, compared with controls, both showed decreased activation of the insula, aPFC and DLPFC during affective switching, and OFC during reward processing (Remijnse et al., 2006, Remijnse et al., 2009).

Until now, some studies on OCD, but none in MDD, have evaluated the effects of treatment on specific aspects of RL, e.g. pharmacotherapy on task switching (Han et al., 2011) and cognitive behavioral therapy (CBT) on strategy change (Freyer et al., 2011). At follow-up, OCD patients showed increased activation in ventral frontal-striatal regions during switching events, and were correlated with symptom improvement (Freyer et al., 2011, Han et al., 2011). However, neither study employed motivational feedback (punishment/reward) in their task-switching paradigms. Sensitivity to motivational feedback and relearning rewarding associations in relation to recovery-related changes have not been studied across MDD and OCD. Such comparisons are important because it allows one to differentiate between general treatment- or recovery-induced changes and disorder-specific changes in cognitive functioning. It has been suggested that with symptom improvement, some neuropsychological deficits may recover (Maalouf et al., 2011) (state-dependent changes), while other impairments persist (trait characteristics) (Douglas et al., 2011, Fava, 2003, Kerestes et al., 2011, Li et al., 2009, Milne et al., 2011, Paelecke-Habermann et al., 2005).

Using a naturalistic follow-up design, our aim was to investigate general and disorder-specific changes in RL-related frontal-striatal activation during fMRI scanning and relate these to clinical improvement in OCD and MDD over time. Specifically, in OCD, we hypothesized that clinical improvement would be associated with normalization of reduced activation at baseline of the ventral frontal-striatal regions during reward, and dorsal and ventral frontal-striatal regions during affective switching. In MDD, we expected to find that the initially enhanced activation of putamen and insular cortex on reward and punishment would normalize. In addition, we expected dorsal frontal-striatal normalization during affective switching in MDD.

Section snippets

Subjects

Baseline data of all patients (OCD n=28, MDD n=21) have been reported previously (Remijnse et al., 2006, Remijnse et al., 2009). From these, ten OCD and six MDD patients were lost for follow-up, leaving data from 18 OCD and 15 MDD patients. See Table 1 for demographic and clinical details. Main diagnosis and co-morbid diagnoses were established using the Structured Clinical Interview for DSM-IV Axis-I disorders (SCID) (Spitzer, Williams, Gibbon, & First, 1992).

Eligible patients were not

Demographic, clinical and behavioral data

Table 1 summarizes demographic and clinical characteristics of the patient groups at follow-up (T1). The OCD and MDD groups did not differ in age, handedness and educational level. There were relatively more females in the OCD group than the MDD group. The time-interval between baseline and follow-up (OCD mean: 26±6, MDD 22±10 weeks) did not differ between groups. Based on the Padua-IR scores the following subdimensions were present in the OCD group: checking (59%), rumination (29%), washing

Discussion

In the present naturalistic follow-up study we showed disorder-specific patterns of change in performance and neural correlates of reversal learning (RL) in OCD and MDD. These changes over time were associated with clinical improvement. An important finding of this study is the disease-specific task-related activation patterns over time with decreased activation at follow-up in frontal-striatal regions in MDD patients, but increased activation of these brain regions in OCD patients. In the OCD

Conflict of interests

None.

Acknowledgments

This work was supported by two grants (Nos. 912-02-050 and 907-00-012) from the Dutch Organization for Scientific Research (NWO).

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