Implications for future research

The results of Paper I clearly indicate a role of distributed regions in the affective and fronto-limbic circuits in OCD, including the amygdala, and shows how the relatively

subtle differences between patients and healthy controls can be influenced by comorbidity, medication status, and other clinical characteristics (Thorsen, Hagland, et al., 2018). Only a few cross-disorder comparisons have investigated shared and distinct mechanisms of emotional and cognitive processing in OCD, obsessive-compulsive spectrum disorders and anxiety disorders (Marin et al., 2017; Milad et al., 2013; O. A. van den Heuvel et al., 2011). Given the substantial comorbidity between such disorders, future research should help uncover why some develop these

disorders and how treatment can be improved. One method to answer this question would be to use population-based studies to separate vulnerability to a disorder from consequences of having lived with a disorder (including effects of treatment and chronic medication use). Finally, treatment studies with a lifespan perspective may show whether children, adolescents, and adults are similar or different in the neurobiological correlates of recovery.

The results of Paper II further support the role of the fronto-limbic circuit during emotional provocation, as well as altered dmPFC and temporo-occipital activation during OCD-related emotion regulation in unaffected siblings of OCD patients.

However, further work is needed to uncover the mechanisms underlining emotion regulation, and how treatment affects the way OCD patients confront and manage their symptoms. These questions cannot be adequately answered by commonly used tasks of today, nor by correlations between brain activation and clinical measures.

Rather, the field needs to develop more ecologically valid paradigms that can, for example, show what happens when a patient chooses to avoid or confront an aversive stimulus (Banca et al., 2015). This could involve developing paradigms that are closer to how psychological therapies are actually done, such as the B4DT. For instance, performing ERP during fMRI or mobile EEG (Ladouce, Donaldson, Dudchenko, & Ietswaart, 2016) could allow for imaging the emotional and cognitive processes during exposure.

The implication of sensitivity to artifacts, uncertain reliability, and few consistent findings in the field is that large-scale replication efforts with harmonized data acquisition and analysis is required. The Enhancing NeuroImaging Genetics through

Meta-Analysis (ENIGMA) Consortium is a much needed step in the right direction (Thompson et al., 2014), which pools neuroimaging and genetic data across the world using harmonized data processing. A next step would be to harmonize data collection of clinical, neuroimaging and other measures to give better opportunities for cross-country comparisons. Another step would be to increase the number of replication studies, which can both test the robustness of earlier findings and provide a good use of previously collected data (Dinga et al., 2019; Heinzel et al., 2018). The subtle results found in all three papers of this dissertation highlight the need for more powerful studies in the future, where sample size is preferably informed by power analyses rather than tradition (Mumford & Nichols, 2008). This is further supported by findings from the OCD working group in the ENIGMA consortium, where the difference between patients and controls are very small when sample sizes are very large (Boedhoe et al., 2018; Boedhoe et al., 2017).

Paper III was able to highlight short-term changes in resting-state network

communication due the concentrated treatment, which few studies have been able to investigate so far. However, it cannot speak to the eventual long-term effects of psychological treatment on the brain. There are very few studies with measurements at more than two time points, and none that can investigate how the brain changes in relation to a rapid, non-gradual decrease in symptom severity (Morgieve et al., 2014).

Future studies should investigate treatment-related changes in both the short- and long-term. The resting-state fMRI data in Paper III has also been collected three months after treatment, and will be analyzed shortly. These analyses can show if the short-term changes are stable over time or if other changes emerge after longer periods of normalized behavior. I would expect that the decrease in frontoparietal-limbic connectivity will still be present after three months in remitted patients, but not in those experiencing relapse. Future work at the Bergen Center for Brain Plasticity will also investigate short- and long-term changes in the brain after B4DT in a larger sample of OCD and anxiety disorder patients, enabling more specific analyses on clinical heterogeneity.

Finally, many studies in the field only use one source of neurobiological information, for instance sMRI or fMRI. This could be expanded by including

psychophysiological measures (e.g. skin conductance or heart rate variability) or multimodal imaging to understand the disorder, and changes after treatment, at different timescales and biological levels (Robbins, Vaghi, & Banca, 2019). There are some examples of such studies in the literature and more are underway (Moreira et al., 2017; Tadayonnejad et al., 2018). One of the aims of the future work at the Bergen Center for Brain Plasticity is to combine MRI and other biological measures to a contribute to a more integrated view of the psychobiology of OCD and anxiety disorders. We also aim to combine these measures with genetics and epigenetics to better understand how changes in the body and brain are reflected in DNA and its methylation (Todorov, Mayilvahanan, Ashurov, & Cunha, 2019).