Using Neuroplasticity-Based Computerized Training to Improve Emotion Regulation in Bipolar Disorder (BRAINS)

Difficulty with emotion regulation is a central feature of Bipolar Disorder (BD) that is not only apparent during mood episodes but also persists in between episodes and contributes to the onset, chronicity, and severity illness. Successful emotion regulation requires the cognitive control of emotion (CCE) - i.e. the ability to control emotions and the influence of emotions on behavior. CCE is dependent on the coordinated activity of two neural systems: 1) the cognitive control network includes the lateral prefrontal cortex and superior parietal cortex and supports a range of skills (e.g. attention, inhibition, working memory) to control and manipulate information from multiple sensory domains; and 2) the emotion processing network, which includes the amygdala, insula, and ventral striatum, and supports the experience, expression, and perception of emotion. CCE consists of several processes in which the cognitive control network modulates neural response in emotion processing regions to control the impact of emotion on experience and behavior. Poor recruitment of frontoparietal control functions when processing negative emotional stimuli (measured with fMRI) prospectively predicts mood and behavioral problems after an interpersonal conflict in daily life (Hooker et al 2010). Together the data suggests that compromised CCE capacity makes a person more vulnerable to experiencing negative psychological consequences after a stressful event (e.g. Hooker et al 2010; Hooker et al 2013; Tully et al 2014).

Individuals with bipolar disorder have deficits on both behavioral and neural measures of CCE (Phillips and Swartz 2014). Typical CCE tasks require identifying a target stimulus (e.g. word, facial expression, etc.) while inhibiting irrelevant or conflicting emotional information. During such tasks, people with bipolar disorder have difficulty controlling the distracting influence of irrelevant emotional information. These behavioral deficits are associated with neural abnormalities in both cognitive control and emotion processing neural systems. These neural abnormalities are characterized, primarily, by abnormally low activity in the cognitive control network, particularly the lateral prefrontal cortex, and abnormally high activity in emotion processing regions, particularly the amygdala and ventral striatum. Bipolar disorder is also associated with abnormalities in structural elements of these neural systems, including abnormal gray matter volume and white matter tracks. Research suggests that deficits in CCE and related neural networks are an underlying cause of characteristic symptoms of bipolar disorder, including emotional lability, extreme mood states, and disinhibited behavior (reviewed in Phillips and Swartz 2014 and Wegbreit et al. 2014). These findings point to CCE as a clinically relevant and scientifically tractable treatment target for bipolar.

Study Design \& Specific Aims The primary goal of this project is to investigate, in young adults with bipolar disorder, whether a computerized training program of CCE exercises improves CCE as measured with a range of assessment tasks that require flexible deployment of CCE skills. The long-term goal is to evaluate whether CCE training improves emotion regulation and maladaptive mood symptoms.The overarching hypothesis is that training-related improvement in CCE will facilitate improvements in emotion regulation across multiple contexts, and, thus, reduce the symptoms and consequences of emotion dysregulation in bipolar.

The second goal of the project is to collect pilot data, establish feasibility, and gather other information necessary to acquire federal funding for a large-scale, double-blind, randomized control trial of CCE training for bipolar. To ensure subsequent federal funding, the current project design is consistent with an experimental medicine model and NIMH guidelines for clinical trial research. NIMH has a progressive funding structure for the development of novel biological or behavioral interventions. The current project is designed to satisfy requirements of the first phase in this funding structure. Consistent with NIMH guidelines for exploratory clinical trials, the current project has a clearly defined treatment target (i.e. CCE skills) and a theoretical model regarding how the target mechanism is related to psychopathology. The main purpose of an exploratory trial is to verify 'target engagement' - i.e. that the intervention influences the intended treatment target. It is not necessary to have a comparison group. However, evidence of target engagement in a single, active treatment group is a requirement for obtaining more advanced levels of NIMH funding. The current project will evaluate target engagement in a single group that completes CCE training. The study maximize the potential to detect target engagement by using behavioral and neural measures of CCE that are valid, reliable, and sensitive to treatment-related improvement.

Another purpose of the exploratory phase is to gather information about feasibility, tolerability, dose, and other potential factors that could influence treatment effectiveness, patient compliance, and broad implementation, particularly in non-academic settings. Data from the current project will address these issues and provide salient information to guide treatment development and implementation in the next phase. This information includes data on participants' motivation to continue training, enjoyment of training exercises, compliance to the training schedule (e.g. number of days missed, real or perceived obstacles to training, strategies that enhance motivation and compliance, etc.).

In summary, the investigators will conduct an exploratory clinical trial that is consistent with NIMH guidelines for clinical trial research and addresses the goals of an initial (first phase) NIMH grant for novel interventions. Results from the study will provide the pilot data necessary to obtain additional funding for the next phase of treatment development - i.e. An "Exploratory/Developmental Grant for Novel Interventions Phase II (R33)" or a "Confirmatory Efficacy Clinical Trial of Non-Pharmacological Interventions for Mental Disorders (R01)".