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Original Investigation |

Reward Processing in Healthy Offspring of Parents With Bipolar Disorder ONLINE FIRST

Manpreet K. Singh, MD, MS1; Ryan G. Kelley, BS1; Meghan E. Howe, MSW1; Allan L. Reiss, MD1; Ian H. Gotlib, PhD2; Kiki D. Chang, MD1
[+] Author Affiliations
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
2Department of Psychology, Stanford University, Stanford, California
JAMA Psychiatry. Published online August 20, 2014. doi:10.1001/jamapsychiatry.2014.1031
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Importance  Bipolar disorder (BD) is highly familial and characterized by deficits in reward processing. It is not known, however, whether these deficits precede illness onset or are a consequence of the disorder.

Objective  To determine whether anomalous neural processing of reward characterizes children at familial risk for BD in the absence of a personal history of a psychopathologic disorder.

Design, Setting, and Participants  This study compared neural activity and behaviors of children at high and low risk for mania while they anticipate and respond to reward and loss. The study was performed from September 15, 2009, through February 17, 2012, in a university functional magnetic resonance imaging facility and included 8- to 15-year-old children without disorders born to a parent with BD (n = 20 high-risk children) and demographically matched healthy comparison children (n = 25 low-risk children).

Main Outcomes and Measures  Neural activity, as measured with functional magnetic resonance imaging, during anticipation and receipt of reward and loss during a monetary incentive delay task.

Results  While anticipating losses, high-risk children had less activation in the pregenual cingulate than did their low-risk counterparts (t19 = −2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t43 = −3.04, P = .004). High-risk children also had weaker functional connectivity between the pregenual cingulate and the right ventrolateral prefrontal cortex while anticipating rewards than did low-risk children (t19 = −4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t24 = 2.76, P = .01). Finally, in high- but not low-risk children, novelty seeking was associated with increased striatal and amygdalar activation in the anticipation of losses, and impulsivity was associated with increased striatal and insula activation in the receipt of rewards.

Conclusions and Relevance  Aberrant prefrontal activations and connectivities during reward processing suggest mechanisms that underlie early vulnerabilities for developing dysfunctional regulation of goal pursuit and motivation in children at high risk for mania. Longitudinal studies are needed to examine whether these patterns of neural activation predict the onset of mania and other mood disorders in high-risk children.

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Figure 1.
Voxel-wise Brain Activation Group by Anticipation Interaction

Significant threshold for analysis of variance (ANOVA) clusters were determined at P < .05 (family-wise error corrected). The group-by-anticipation valence interaction found a significant cluster in the pregenual cingulate (pgCC) (F1,39 = 11.94, P = .001). Extracted contrast estimates from the pgCC cluster were used for post hoc comparisons and displayed in the histogram to the right. During the anticipation of losses, the low-risk group had significantly higher pgCC activation (P = .02) than the high-risk group. The high-risk group had significantly higher pgCC activation during anticipation of rewards compared with anticipation of losses (P = .02). Error bars indicate SE.

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Figure 2.
Voxel-wise Brain Activation Group by Feedback Interaction

Significant threshold for analysis of variance (ANOVA) clusters were determined at P < .05 (family-wise error corrected). The group by feedback valence interaction found a significant cluster in the left lateral orbitofrontal cortex (F1,39 = 23.28, P < .001). Extracted contrast estimates from the left lateral orbitofrontal cortex were used for post hoc comparisons and displayed in the histogram to the right. During the feedback of successful rewards, the high-risk group had higher activation in this region than the low-risk group (P = .004), whereas during the feedback of losses, the high-risk group had lower activation than the low-risk group (P = .001) in this region. The high-risk group had greater activation during feedback of rewards compared with losses (P = .002). The low-risk group had lower activation during feedback of rewards compared with losses (P = .001). Error bars indicate SE.

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Figure 3.
Psychophysiologic Interaction (PPI) Pregenual Cingulate (pgCC) Connectivity Group by Anticipation Interaction

The PPI analysis was conducted seeding the pgCC during anticipation. The pgCC seed along with an arrow indicating connectivity is displayed in green. Significant threshold for analysis of variance (ANOVA) clusters were determined at P < .05 (family-wise error corrected). The PPI group by anticipation interaction found a significant cluster in the right ventrolateral prefrontal cortex (VLPFC) (F1,39 = 20.04, P < .001). Extracted connectivity estimates from the right VLPFC were used for post hoc comparisons and displayed in the histogram to the right. The pgCC connectivity associated with anticipation of rewards had lower right VLPFC connectivity in the high-risk group compared with the low-risk group (P < .001), whereas the high-risk group had higher connectivity compared with the low-risk group during anticipation of losses (P = .005). Error bars indicate SE.

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