1. Identification of neurocognitive and neuroimaging biomarkers of affective disorders
Affective disorders are characterized by a high rate of misdiagnosis
which results in delay in appropriate treatment and thus a high rate of
recurrence and disability. In studies using functional magnetic resonance
imaging (fMRI) and neurocognitive testing of affected, high-risk (twins and
other first-degree relatives, respectively) and healthy control participants,
we have found (I) that high-risk individuals display different neurocognitive
processing of emotional information and aberrant neuronal activity to emotional
information and reward anticipation in fronto-limbic and striatal regions,
respectively, and (II) that symptomatically stable individuals with a history
of manic and/or depressive episodes exhibit impairments in emotional and
non-emotional cognition - albeit with substantial heterogeneity - and aberrant
fronto-limbic and fronto-striatal activity during emotional and reward
processing, respectively. Whether these neurocognitive and neuronal changes
reflect compensatory mechanisms or trait-related vulnerability markers will be
investigated in our planned follow-up of these cohorts.
2. Exploring neurocognitive screening tools and methods to reduce risk of
Pregnancy and childbirth are among the strongest risk factors for depression, but the neurocognitive mechanisms underlying this enhanced risk are unknown. We found in a study of asymptomatic pregnant women with and without a history of affective disorder that negative bias in the processing of infant signals of emotion predicted subsequent postpartum depression. Based on this finding, we have set up a larger-scale ongoing study with to investigate whether an online neurocognitive screening tool can predict the risk of postpartum depression in pregnant women.
For parents with bipolar disorder, there is a 50-60 % risk that the child will develop a psychiatric disorder. Genetic factors play a key role in the intergenerational transmission of risk of psychiatric disorder, but it is unclear how early environmental risk factors interact with genetic vulnerability in this process. In a multidisciplinary study, we found that clinically stable mothers with affective disorders displayed abnormal neurocognitive, psychophysiological and neuronal response to infant signals of emotion and that this correlated with poorer real-life mother-infant interactions. If the findings are replicated, they warrant investigation of ultra-early preventive strategies to improve mental health outcomes in genetically predisposed children.
3. Development of novel biological and psychological 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 a key 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). We found in two randomised, placebo-controlled phase II trials that eight weeks of EPO treatment has mood-independent and enduring beneficial effects on cognition across depression and bipolar disorder.
Cognitive remediation (CR) interventions have recently shown promising effects on cognitive impairments in affective disorders. Our group conducted randomized controlled trials investigating two type of CR interventions in remitted patients with bipolar disorder. While the first intervention og 12 week of weekly group-based CR showed no treatment-related cognitive improvements, our second trial of 10 weeks of intensive bi-weekly Action-Based Cognitive Remediation (ABCR) revealed promising effects on executive function.
4. Exploring neurocognitive and neuronal mechanisms of established and novel treatments
A key obstacle in the detection of new pro-cognitive interventions is the limited insight into the neurocircuitry changes involved in cognitive improvement. Using prospective MRI in the EPO trials, we demonstrated that EPO-treatment prevented subfield hippocampal volume loss across and that this structural change mediated patients' memory improvement.
In addition, fMRI in the EPO and ABCR trials revealed common treatment-associated changes in dorsolateral prefrontal activity during working memory, which correlated with and predicted treatment effects on working memory and executive function, respectively. Together, the fMRI findings from these pharmacological and psychological intervention studies provide key proof of principle for the use of neuroimaging biomarker models to detect pro-cognitive effects of pro-cognitive interventions.
In a parallel fMRI study of electroconvulsive therapy (ECT), we found that ECT modulated the neuronal response in prefrontal regions to emotional information. These effects are in line with the putative neurocognitive actions of antidepressant drugs. This suggests that modulation of neurocognitive response to emotional information is a common mechanism of different treatments for depression.