Research report
Prefrontal cortical and striatal activity to happy and fear faces in bipolar disorder is associated with comorbid substance abuse and eating disorder

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Abstract

Background:

The spectrum approach was used to examine contributions of comorbid symptom dimensions of substance abuse and eating disorder to abnormal prefrontal-cortical and subcortical-striatal activity to happy and fear faces previously demonstrated in bipolar disorder (BD).

Method:

Fourteen remitted BD-type I and sixteen healthy individuals viewed neutral, mild and intense happy and fear faces in two event-related fMRI experiments. All individuals completed Substance-Use and Eating-Disorder Spectrum measures. Region-of-Interest analyses for bilateral prefrontal and subcortical-striatal regions were performed.

Results:

BD individuals scored significantly higher on these spectrum measures than healthy individuals (p < 0.05), and were distinguished by activity in prefrontal and subcortical-striatal regions. BD relative to healthy individuals showed reduced dorsal prefrontal-cortical activity to all faces. Only BD individuals showed greater subcortical-striatal activity to happy and neutral faces. In BD individuals, negative correlations were shown between substance use severity and right PFC activity to intense happy faces (p < 0.04), and between substance use severity and right caudate nucleus activity to neutral faces (p < 0.03). Positive correlations were shown between eating disorder and right ventral putamen activity to intense happy (p < 0.02) and neutral faces (p < 0.03). Exploratory analyses revealed few significant relationships between illness variables and medication upon neural activity in BD individuals.

Limitations:

Small sample size of predominantly medicated BD individuals.

Conclusion:

This study is the first to report relationships between comorbid symptom dimensions of substance abuse and eating disorder and prefrontal-cortical and subcortical-striatal activity to facial expressions in BD. Our findings suggest that these comorbid features may contribute to observed patterns of functional abnormalities in neural systems underlying mood regulation in BD.

Introduction

Bipolar disorder (BD) is a most debilitating psychiatric disorder, with a high rate of late or mis-diagnoses, often as unipolar depression (Bowden, 2001). The research agenda for DSM-V emphasizes the need for a new classification system for all psychiatric disorders based upon pathophysiologic and etiological processes (e.g. Phillips and Frank, 2006), that may represent biomarkers of a disorder (e.g. Kraemer et al., 2002). For disorders such as BD, the identification of these biomarkers would be a major step toward improving diagnostic accuracy (e.g. Hasler et al., 2006). Functional neuroimaging can examine abnormalities that may reflect pathophysiological neural mechanisms underlying core clinical features of psychiatric illnesses. Several recent neuroimaging studies in adult BD reported inconsistent findings of dysfunctional dorsal and ventral prefrontal-cortical and subcortical-striatal neural systems implicated in mood-regulation. Specifically, patterns of increased amygdala and striatal, and decreased dorsal prefrontal-cortical (DPFC) activity to emotionally-salient stimuli, and during cognitive control tasks have been shown (e.g. Green et al., 2007, Phillips et al., 2008a).

Although present studies in BD have focused on neural systems associated with mood-regulation, they have largely ignored common disabling comorbid features that characterize the disorder (Kupfer, 2005) and contribute to its psychopathology. The spectrum approach to BD includes measures of lifetime experiences of symptoms, clinical features and temperamental traits that aim to improve assessing the clinical phenotype of BD, and contains an integrated view of common comorbidities (e.g. Cassano et al., 1999). Comorbid symptom dimensions of BD are associated with more severe illness course, poorer treatment compliance and worse outcomes related to suicide (Krishnan, 2005). They include substance abuse, eating disorders, psychosis, obsessive–compulsive and anxiety symptoms (Krishnan, 2005). For example, an increased risk for substance abuse has been observed in BD (e.g. Regier et al., 1990), and is associated with more severe mood episodes and worse illness course (Nolen et al., 2004). It may be explained in terms of self-medication, improving self-image, or alleviating symptoms of anxiety (Sonne et al., 1994). Eating disorders, particularly binge eating or weight gain, other than those associated with medication effects, are common in BD (e.g. Angst et al., 2002).

There is increasing evidence of overlap between functional abnormalities in neural systems implicated in BD and those associated with the above comorbid symptom dimensions. For example, BD-like reduced activity in right dorsolateral prefrontal-cortical (DLPFC) regions during decision making tasks have been demonstrated in currently dependant amphetamine and opiate users (Ersche et al., 2005a, Ersche et al., 2005b), and in abstinent cocaine users (Bolla et al., 2003, Yucel and Lubman, 2007). In contrast to findings in BD, decreased rather than increased ventral striatal activity has been reported to formerly rewarding cues in detoxified alcoholics (Wrase et al., 2007). These findings support the growing literature in substance abuse showing patterns of decreased ventral striatal dopamine release also during pharmacologic challenge with amphetamine (Martinez et al., 2005, Volkow et al., 2007a, Volkow et al., 2007b).

The overlap between neural systems underlying mood regulation and appetitive behaviors is well documented (Beaver et al., 2006, Kaye, 2007). Abnormally increased striatal activity during reward processing has been reported in eating-disordered individuals (Wagner et al., 2007), similar to the patterns of elevated ventral striatal and amygdala activity observed in BD adults (Green et al., 2007, Phillips et al., 2008a).

The above findings suggest that dysfunctional prefrontal-cortical and subcortical-striatal neural regions previously observed in BD may be a reflection, at least in part, of comorbid symptom dimensions that characterize the illness. Using an implicit emotion labeling task associated with subcortical limbic activity, we previously demonstrated, in a group of remitted BD individuals, greater striatal activity to happy faces and decreased dorsal prefrontal-cortical (DPFC) activity to both happy and fear face (Hassel et al., 2008). In these BD individuals, most common comorbid features were substance use and eating disorders, but the contribution of these to abnormal prefrontal-cortical and striatal activity was unexamined. The present study aimed to assess, in these remitted BD individuals, the relationship between comorbid symptom dimensions of substance abuse and eating disorders, and patterns of abnormal prefrontal-cortical and subcortical-striatal activity. Based on the above findings we hypothesized: (1) Severity of comorbid symptom dimensions of substance abuse would be negatively associated with both, the magnitude of striatal activity to happy faces, and the magnitude of DLPFC activity, to happy and fear faces. (2) Severity of comorbid symptom dimensions of eating disorders would be positively associated with the magnitude of amygdala and striatal activity to happy faces.

Section snippets

Participants

Fourteen BD-subtype-I individuals (23–52 years; 63% female) from our previous sample (Hassel et al., 2008) were recruited from Western Psychiatric Institute and Clinic, Mood Disorders Treatment and Research Program, University of Pittsburgh. All were in remission (DSM-IV criteria; Structured Clinical Interview for DSM-IV (SCID-I); First et al., 1995). Euthymic status was defined, a-priori, as having been in remission for at least 2 months as assessed by SCID and clinical interview. All BD

Participants

BD and healthy individuals were gender-ratio-matched. There was no significant between-group difference in age or weight (p > 0.05), although eight BD individuals had comorbid eating disorders. IQ, estimated by North American Reading Test (NART; Blair and Spreen, 1989) differed between BD and healthy individuals, t = 2.364, p = 0.026 (Table 1). However, there were no significant differences between groups for gender labeling accuracy performed during the scan (p < 0.05), and only a trend towards

Discussion

To our knowledge, this is the first study examining the extent to which patterns of abnormal activity in prefrontal-cortical and striatal regions to facial expressions of happiness and fear, previously reported in remitted BD (Hassel et al., 2008, Lawrence et al., 2004, Malhi et al., 2007), are associated with severity of comorbid symptom dimensions of substance abuse and eating disorders. These comorbid illness features were endorsed by most BD individuals in this study. Relative to healthy

Role of funding support

Funding for this study was provided in part by a NARSAD Independent Investigator Award to MLP, who is the NARSAD Nellie Blumenthal Investigator, and by NIMH Grant 5R01MH076971-01. Neither funding agency had any further role in study design, data collection, analyses or interpretation, nor in the writing of this manuscript or the decision to submit for publication.

Conflict of Interest

The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.

Acknowledgements

All work was carried out within the Department of Psychiatry, University of Pittsburgh. All neuroimaging data was collected at the Brain Imaging Research Center (BIRC), University of Pittsburgh and Carnegie Mellon University. We thank Dr. K.J. Jung, S. Kurdilla and D. Vizslay for their help in acquiring the neuroimaging data.

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