Reward and stress: Developing neuroimaging biomarkers for bipolar depression

Bipolar disorder (BD) is an important cause of morbidity and mortality in the UK, and is costly to both the individual and society. Bipolar disorder is associated with around a ten-year reduction in life expectancy and a fifteen-fold increased risk of death by suicide. Despite the importance of bipolar depression (which includes people with both bipolar I or II disorder), the brain mechanisms which mediate depression are very poorly understood and no reliable biomarkers exist to support disease stratification or predict treatment response.

Previous neuroimaging studies on bipolar depression have typically focused on bipolar II disorder. Studies in bipolar disorder have examined both structural and functional alterations in BP-II disorder relative to healthy controls, unipolar depression, and BD-I. While earlier studies suggested structural changes, the ENIGMA consortium analysis of over 1700 individuals with bipolar disorder did not support any differences in either subcortical volumes or cortical metrics for BD-II. For functional neuroimaging studies, a relatively clear picture emerges of dysfunctional emotion and reward circuitry as well as fronto-parietal abnormalities in bipolar disorder, including BD-II.

Depressive symptoms experienced by people with bipolar disorder are distressing and increase self-harm risks. People with bipolar depression often don't enjoy their lives, experience difficulties with reward and motivation, and show abnormal stress hormone responses measured by the dexamethasone - corticotropin releasing hormone challenge (DEX-CRH) test. The DEX-CRH is an integrated test of HPA axis function. Of all the available neuroendocrine function tests, the DEX/CRH test has proven to be the most sensitive tool for detecting an HPA axis abnormality in depressed individuals. For now, little is known about how abnormal brain signalling causes symptoms and how these are linked to stress hormone responses. Impaired stress resilience and disturbances in hypothalamic-pituitary-adrenocortical (HPA) axis function have been suggested to play key roles in major depressive disorder (MDD) and BD.

Neuroimaging methods offer the opportunity to non-invasively examine the changes that take place in the central nervous system in response to an acute psychological stressor. Task-based fMRI can be useful in this context, as it allows the exploration of the networks involved in the stress response and in the regulation of the HPA axis, both in healthy and in psychiatric populations. Some studies have either employed stress induction to elicit neural and neuroendocrine responses or have investigated the effect of externally administered cortisol on brain function and resting state measures. However, to the best of our knowledge, no studies have combined administration of the DEX/CRH and fMRI in depressed individuals with BD or MDD.

To identify functional MRI (fMRI) neuroimaging biomarkers of bipolar depression by examining differences in emotional, effort and reward processing brain activity in the subgenual cingulate-limbic-amygdala pathway in people with bipolar depression compared to people with MDD and healthy controls. Additionally, to examine whether the extent of impairments in fMRI signals detected in the mood disorder participant groups (BD or MDD) correlates with abnormalities in the HPA axis as measured by the Dex/CRH test.