1. Identification of neurocognitive and neuroimaging biomarkers of affective disorders
Using functional magnetic resonance imaging (fMRI) study of healthy monozygotic twins at high vs. low heritable risk for depression, we showed that familial risk was associated with aberrant functional connectivity in fronto-limbic and occipito-parietal regions during emotional face processing and enhanced fear vigilance. Based on this we have initiated a large nation-wide twin study to explore neuroimaging, cognitive, cellular and epigenetic endophenotypes (biomarkers) for affective disorders and their interactions.
2. Development of novel treatments targeting cognitive dysfunction
Cognitive dysfunction in attention, memory and executive function occurs across a range of neuropsychiatric disorders including depression and bipolar disorder and is an emerging common therapeutic target. However, there is currently no approved effective treatment for cognitive dysfunction in affective disorders.
A compound that shows particular promise for targeting cognitive dysfunction is the endogenous growth-factor erythropoietin (EPO). EPO and its receptors are expressed in the brain and stimulate neuroplasticity and cognition. When administered as injections, it crosses the blood-brain barrier, exerts neurotrophic effects and improves cognition in animal models of neurodegenerative conditions and in healthy animals. We showed that the preclinical effects of EPO translate into improvement of neural and cognitive function in patients with affective disorders. Specifically, we demonstrated in two randomised, placebo-controlled phase II trials that 8 weeks of EPO treatment has mood-independent and enduring beneficial effects on cognition across depression and bipolar disorder.
Our group conducted the first randomized, controlled trial of the effects of 12-weeks group-based cognitive remediation treatment on cognitive function in bipolar disorder. The study revealed no beneficial effects on objectively-measured cognitive function (primary trial outcome), although patients reported some improvement in subjective mental sharpness and quality of life. A more intensive, individualised intervention thus seems necessary. Another potential reason for the negative finding was that patients turned out to have no objectively-measured cognitive deficits despite their subjective (self-reported) cognitive difficulties. This is consistent with the finding in studies by our and other groups of poor correlation between subjective and objective measures of cognition. In particular, subjective cognitive difficulties are closely related to depressive symptoms and not a direct assay of objective cognition per se. Objective neuropsychological screening for cognitive dysfunction is therefore warranted in future cognition trials in affective disorders. Based on this evidence, we recently conducted two studies to validate new tools to screen for cognitive dysfunction in depression and bipolar disorder, respectively.
3. Exploring neurocognitive and neuroimaging mechanisms of established and novel treatments
Using prospective MRI in the EPO trials, we demonstrated that EPO-treatment prevented subfield hippocampal volume loss across both unipolar and bipolar disorder and that this structural change mediated patients’ memory improvement. In addition, fMRI assessments revealed EPO-associated changes in dorsolateral prefrontal and default-mode network activity during working memory which correlated with improved working memory performance and in a fronto-parietal network during memory encoding, which correlated with subsequent recall success. Together, these findings provide key proof of principle for the use of neuroimaging biomarker models to detect pro-cognitive effects of novel compounds.
In a parallel study, we are exploring the neurocognitive mechanisms of action of electroconvultive treatment (ECT) in depression using fMRI and neurocognitive tests. We have completed recruitment for the study and data analysis is in progress.