Increased Medial Orbitofrontal and Amygdala Activation: Evidence for a Systems-Level Endophenotype of Bipolar I Disorder

Linke, Julia; King, Andrea; Rietschel, Marcella; Strohmaier, Jana; Hennerici, Michael G.; Gass, Achim; Meyer‐Lindenberg, Andreas; Wessa, Michèle

doi:10.1176/appi.ajp.2011.11050711

Cited by 112 publications

(87 citation statements)

References 34 publications

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“…During euthymia, Nusslock et al (2012) reported elevated ventral striatal and orbitofrontal activity during reward anticipation, but not outcome, in bipolar I patients, while Caseras et al (2013) found elevated ventral striatal activity in bipolar II patients rather than in bipolar I patients. A study by Linke et al (2012) using a probabilistic reversal learning task showed increased activity of the orbitofrontal cortex in response to reward and an attenuated prediction error signal in euthymic bipolar patients.…”

Section: Introductionmentioning

confidence: 99%

Disturbed Anterior Prefrontal Control of the Mesolimbic Reward System and Increased Impulsivity in Bipolar Disorder

Trost

Diekhof

Zvonik

et al. 2014

Neuropsychopharmacol

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Bipolar disorder (BD) is characterized by recurrent mood episodes ranging from severe depression to acute full-blown mania. Both states of this severe psychiatric disorder have been associated with alterations of reward processing in the brain. Here, we present results of a functional magnetic resonance imaging (fMRI) study on the neural correlates and functional interactions underlying reward gain processing and reward dismissal in favor of a long-term goal in bipolar patients. Sixteen medicated patients diagnosed with bipolar I disorder, euthymic to mildly depressed, and sixteen matched healthy controls performed the 'desire-reason dilemma' (DRD) paradigm demanding rejection of priorly conditioned reward stimuli to successfully pursue a superordinate goal. Both groups exhibited significant activations in reward-related brain regions, particularly in the mesolimbic reward system. However, bipolar patients showed reduced neural responses of the ventral striatum (vStr) when exploiting a reward stimulus, and exhibited a decreased suppression of the rewardrelated activation of the mesolimbic reward system while having to reject immediate reward in favor of the long-term goal. Further, functional interaction between the anteroventral prefrontal cortex and the vStr in the 'DRD' was significantly impaired in the bipolar group. These findings provide evidence for a reduced responsivity of the vStr to reward stimuli in BD, possibly related to clinical features like anhedonia. The disturbed top-down control of mesolimbic reward signals by prefrontal brain regions in BD can be interpreted in terms of a disease-related enhanced impulsivity, a trait marker of BD.

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Section: Introductionmentioning

confidence: 99%

Disturbed Anterior Prefrontal Control of the Mesolimbic Reward System and Increased Impulsivity in Bipolar Disorder

Trost

Diekhof

Zvonik

et al. 2014

Neuropsychopharmacol

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“…Interestingly, heightened reward sensitivity and reduced prediction error signal, as coded by the medial orbitofrontal cortex, was significantly correlated with the score of the behavioral activation system scale, lending further support to the behavioral system dysregulation model [2]. Last but not least, increased activity in the lateral orbitofrontal cortex, the dorsal anterior cingulate cortex, and the putamen in response to changing reward contingencies was also observed; it was suggested that this might represent a compensatory mechanism that aids in suppressing previously rewarded responses, thus allowing adequate performance during euthymia [104]. Interestingly, despite the significant negative correlation between amygdala response and psychotropic medication observed by Linke and coworkers (2012), no influence of psychotropic medication on brain responses upon delivery of reward or punishment have been observed in other studies [96,97,99,101].…”

Section: Delivery Of Positive and Negative Consequencesmentioning

confidence: 59%

“…Furthermore, decreased activation of the ventral prefrontal cortex and increased activation of the anterior cingulate cortex in response to the receipt of reward during a gambling task were reported for euthymic bipolar disorder patients [103]. In a recent study of our group, greater activation in response to reward and decreased deactivation in response to reversal of reward contingencies were observed in the medial orbitofrontal cortex in euthymic bipolar patients [104]. Further, activation of the amygdala in response to reversal of reward contingencies was increased.…”

Section: Delivery Of Positive and Negative Consequencesmentioning

confidence: 59%

“…However, there is one study investigating the neural responses to the delivery of reward and punishment in healthy first-degree relatives of bipolar disorder patients. Similar to bipolar disorder patients, the authors observed greater activation in response to reward in the medial prefrontal cortex and the amygdala, which was interpreted as heightened reward sensitivity [104]. Further, in response to negative feedback, which was followed by a change in behavior (reversal of reward contingencies), decreased deactivation in the medial orbitofrontal cortex and increased activation in the amygdala was observed, which is thought to represent an attenuated prediction error signal.…”

Section: Motivationmentioning

confidence: 65%

“…Further, it has been hypothesized that the impaired development of white matter results in impaired prefrontal-limbic modulation in two networks comprising either the ventrolateral or ventromedial prefrontal cortex as well as the amygdala, ventral striatum, and thalamus [76]. And, indeed, hyper-activation of the amygdala has also been observed during early emotional processes [22], generation of an affective response [204], emotion regulation (unpublished manuscript of our group), and motivational processes [104] in unaffected relatives. Thus, we conclude that both impaired white matter of the corpus callosum and the anterior limb of the internal capsule likely disturb fronto-limbic feedback-and feedforwardloops, leading to hyper-activity of the amygdala that precede bipolar symptoms.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Emotional and Motivational Processes in Bipolar Disorder: A Neural Network Perspective

Wessa¹,

Linke²

2013

Psychiatric Disorders - New Frontiers in Affective Disorders

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Reward Processing in Healthy Offspring of Parents With Bipolar Disorder

et al. 2014

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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 PARTICIPANTSThis 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 MEASURESNeural 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 (t 19 = −2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t 43 = −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 (t 19 = −4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t 24 = 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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Increased Medial Orbitofrontal and Amygdala Activation: Evidence for a Systems-Level Endophenotype of Bipolar I Disorder

Cited by 112 publications

References 34 publications

Disturbed Anterior Prefrontal Control of the Mesolimbic Reward System and Increased Impulsivity in Bipolar Disorder

Disturbed Anterior Prefrontal Control of the Mesolimbic Reward System and Increased Impulsivity in Bipolar Disorder

Emotional and Motivational Processes in Bipolar Disorder: A Neural Network Perspective

Reward Processing in Healthy Offspring of Parents With Bipolar Disorder

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