Neurobiological mechanisms of treatment resistant depression: Functional, structural and molecular imaging studies

This thesis investigated the neurobiological mechanisms of TRD using functional, structural and molecular imaging studies. First the neurobiological mechanisms of MDD were investigated and revealed decreased functional connectivity between the ventral and dorsal network. Thereafter, structural connectivity analyses of the uncinate fasciculus showed decreased integrity of this white matter tract in MDD patients. These structural abnormalities were negatively associated with the functional connectivity between the subgenual ACC and medial temporal lobe in MDD patients which suggests that structural abnormalities may lead to functional abnormalities. Regarding TRD, this thesis showed that TRD patients are characterized by a specific decreased functional connectivity between neurocognitive networks relative to both non-TRD and healthy controls. Furthermore, a preliminary [123I]IBZM SPECT study showed no difference in striatal D2/3R availability between TRD patients and healthy controls which suggests TRD is not characterized by altered dopaminergic transmission. Furthermore, this thesis showed that resting state DMN connectivity is a predictive marker for the clinical response to nucleus accumbens DBS in severe TRD patients. These findings together suggests that MDD is characterized by a pathological interaction between the dorsal and ventral network which corroborates the limbic-cortical dysregulation model. TRD is specifically characterized by abnormal network interaction between two neurocognitive networks; the cognitive control network and default mode network. Future work should perform longitudinal analyses to determine how functional connectivity of neural networks evolves over time, and to develop a general definition of TRD preferably for different stages of the disease.