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A neuroimaging study to characterise adolescent major depressive disorder, the effects of cognitive behavioural therapy, and potential subtypes based on familial loading



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Adolescent major depressive disorder (MDD) can have devastating consequences that remain into adulthood. Although the severe effects on those that suffer from MDD are well understood, the neural mechanisms underpinning the illness are still unclear, as the past literature exploring adolescent MDD has suffered greatly from a lack of consistency. In particular, it is still unclear as to what deviations of brain structure and function actually occur in adolescent MDD. Furthermore, though much of the past literature has claimed that cognitive behavioural therapy (CBT) has a normalising effect on disrupted brain function in adolescent MDD, this has not been directly tested. Additionally, past literature has found that adult MDD patients with a high familial loading for MDD, defined as having at least one first degree relative with MDD, show different symptom profiles to MDD patients with a low familial loading for the illness. However, it is not yet clear whether these symptom differences also occur in adolescent MDD patients with differing familial loadings, nor is it clear whether these two patient groups also differ with respect to brain structure and function. If so, familial loading for MDD could potentially be used to subtype adolescent MDD patients. This thesis aimed to further elucidate the neural processes that may be unfolding within the depressed adolescent brain by investigating pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity, using the largest studied sample of adolescent MDD patients under the age of 18 years. This thesis further aimed to investigate CBT’s effects on brain function, and whether adolescent MDD patients could be subtyped based on familial loading for MDD. Before receiving treatment, adolescent MDD patients showed structural deviations in the form of greater cortical thickness and white matter volume within frontal and limbic regions of the brain. Furthermore, adolescent MDD patients also showed extensive pre-treatment overconnectivity within multiple functional brain networks, being the fronto-limbic, default mode, central executive, and salience networks. Moreover, when investigating the CBT-related changes to resting-state functional connectivity, in adolescent MDD patients, and how they relate to regions showing pre-treatment functional disruption, it was found that regions showing the greatest pre-treatment functional disruption actually showed the weakest CBT-related changes in resting-state functional connectivity. This suggests that CBT does not have a normalising effect on brain function in adolescent MDD but instead may have a rehabilitative effect on resting-state functional connectivity. Finally, when separating adolescent MDD patients into those with a high or low familial loading for MDD, the two patient groups differed with respect to the structure and function of the default mode network, as well as differing in rumination symptoms. Together, this work demonstrates the need for larger sample sizes to be used when investigating an illness as heterogenous as adolescent MDD, as well as direct investigations into the potential mechanisms of CBT. Moreover, it appears that some of this heterogeneity found in adolescent MDD may be partly addressed by subtyping patients, which may have implications for how the illness is viewed and treated in the future.





Suckling, John


Major Depressive Disorder, MRI, Cortical Thickness, Resting state functional connectivity, Neuroimaging, Grey Matter Volume, Adolescent Depression


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Oon Khye Beng Ch’hia Tsio Studentship in preventative medicine, Downing College, University of Cambridge