Disturbed moods

Bipolar disorder comes under the cognitive neuroscience spotlight with Camille Piguet.

The physiopathological mechanisms that lie behind mood disorders are poorly understood. Although psychiatrists and researchers recognise that genetic and environmental factors play a part, they know very little about how these aspects influence the onset of such disorders. The members of the fifth SYNAPSY project, including Camille Piguet, are focusing their work on identifying endophenotypes and vulnerability markers linked to mood disorders. Piguet is investigating the problem from a new angle: cognitive neuroscience. The former winner of the SYNAPSY clinician-researcher scholarship is endeavouring to spotlight the neuronal circuits involved in certain impairments in cognitive functioning.

Genetic and environmental heredity

In the context of this research, at-risk populations need to be pinpointed. Martin Preisig in Lausanne and Kathleen Merikangas at the NIH (a member of the SYNAPSY advisory board) have been genuine pioneers in this field: they were the first to tackle population issues relating to mood disorders. Over the past two decades, they have drawn on epidemiological data that demonstrates there is a trend among offspring of individuals with severe mood disorders — such as major depressive disorder (MDD) and bipolar disorder (BP) — to develop the same illnesses as their parents. With Preisig and Merikangas focusing their research on this population at risk of suffering psychological problems, it makes sense that the same group was chosen by Piguet and SYNAPSY.

The various known biomarkers and endophenotypes include genetic factors. Family studies clearly reveal that heritability exists. Although some of the genes at play have been identified, we are still ignorant about the causes. Bipolar disorder is complex and doubtless multi-systemic, meaning that there are numerous genes, including (inter alia) circadian and serotonergic and genes linked to the cortisol system. Under these conditions, it is difficult to link a specific gene to the symptomatic of the illness and to determine which system influences the disorder. Nevertheless, a recurring system is the response to stress: for example, a high incidence of childhood trauma promotes the early onset of illness. Furthermore, epidemiological and genetic studies show that negative life experiences have an impact on the occurrence of mood disorders, although less clearly than childhood trauma.

Cognitive neuroscience’s perspective

From a cognitive neuroscience standpoint, bipolar disorder and depression are disorders linked to dysregulated emotional responses. In MRI, it is partly in the same neuronal circuits that effects are observed in each type of patient. However, certain differences are also noted, and the overall dynamic seems different, with emotional dysregulation being a periodic phenomenon in bipolar patients who have similar emotional responses to normal subjects in between episodes (if they do not have personality disorders associated with their bipolarity).

By combining emotional and cognitive investigations, Piguet aims to establish (i) whether a form of vulnerability to stress is a precursor of the disorder; and (ii) whether it is also present in stabilised bipolar patients, since poor stress management is a type of emotional dysregulation. Piguet plans to use brain imaging to ascertain whether bipolar patients have less control over their responses to stress and whether this correlates with less activity in the prefrontal region, especially the dorsolateral cortex, and limbic hyperactivity. In other words, Piguet is attempting to prove that bipolar patients and their offspring have high emotional reactivity by focusing on the cerebral circuits involved in stress reactivity and emotional control.

Customised protocol

Piguet and her colleagues have devised a powerful multi-modal protocol that includes a mechanism for measuring stress reactivity. Epigenetic and biological parameters (cortisol, pupillometry, physiological constant, auto-immunity test) are calculated concurrently with tasks that combine cognitive control and emotional response while undertaking functional and structural neuro-imaging measurements and a clinical diagnosis. For stress reactivity, patients and their offspring have to perform mental calculations in a set time. They then receive either positive (« Well done ») or negative (« You are not good; you can do better ») feedback while being compared to the rest of the imaginary group. There is a rest period of one minute and thirty seconds after the calculation task. It is these periods of rest and « social » feedback that are analysed. The assumption is that patients and their offspring do not differ in their ability to perform mental calculations in a given time compared to healthy subjects (since they do not have known cognitive disorders in this area). By contrast, patients with mood disorders should be more socially sensitive and take longer to recover (regain their balance) after stress.

Poor management of positive emotions

Encouraging — though not definitive — results are beginning to emerge. A specific difference is observed between patients and their offspring compared to the control groups during the recovery period. They activate the brain regions linked to processing emotions and the reward system to a lesser degree after experiencing stress with a positive connotation than stress with a negative connotation. Bipolar patients, therefore, respond normally to negative stress but seem to have an attenuated response to positive emotions. Interestingly, this also appears to be the case for their offspring, even if they do not show any symptoms. This may represent a vulnerability trait; other studies have shown that the quest for positive sensations may be more intense in bipolar patients, even when they are not in their “high” phases, and could lead to behaviour that is more impulsive.

Patients also activate the amygdala region to a greater extent; this is involved in the « salience » of an emotion, proving once more that such patients have a more sensitive emotional recognition system. The more specific differences in the dynamics of recovery after stress still need to be analysed so that the connectivity aspects between these networks can be highlighted.

It has taken a long time to collect data from the project because it is difficult to find subjects for this type of study, which is relatively complex. Nevertheless, the research team is coming towards the end of the recruitment phase and the data is very rich. It will provide answers to several questions about this cognitive vulnerability to bipolar disorder.

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