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

Decreased Resting-State Connectivity between Neurocognitive Networks in Treatment Resistant Depression

Contains fulltext : 154946.pdf (publisher's version ) (Open Access)Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission after various treatment options and develop treatment resistant depression (TRD). So far, little is known about the pathophysiology of TRD. Studies in MDD patients showed aberrant functional connectivity (FC) of three "core" neurocognitive networks: the salience network (SN), cognitive control network (CCN), and default mode network (DMN). We used a cross-sectional design and performed resting-state FC MRI to assess connectivity of the SN, CCN, and both anterior and posterior DMN in 17 severe TRD, 18 non-TRD, and 18 healthy control (HC) subjects. Relative to both non-TRD and HC subjects, TRD patients showed decreased FC between the dorsolateral prefrontal cortex and angular gyrus, which suggests reduced FC between the CCN and DMN, and reduced FC between the medial prefrontal cortex and precuneus/cuneus, which suggests reduced FC between the anterior and posterior DMN. No significant differences in SN FC were observed. Our results suggest that TRD is characterized by a disturbance in neurocognitive networks relative to non-TRD and HC

Doubt in the insula: risk processing in obsessive-compulsive disorder.

Extensive cleaning or checking of patients with obsessive-compulsive disorder (OCD) are often interpreted as strategies to avoid harm and as an expression of the widespread belief that OCD patients are more risk-averse. However, despite its clinical significance, the neural basis of risk attitude in OCD is unknown. Here, we investigated neural activity during risk processing using functional magnetic resonance imaging and simultaneously assessed risk attitude using a separate behavioral paradigm in OCD patients with different symptoms versus healthy controls (HCs). We found opposite insula responses to high versus low risk in OCD patients compared to HCs: a positive correlation between insula activity and risk-aversion in patients versus a negative correlation in controls. Although OCD patients overall were not more risk-averse than controls, there were differences between subgroups of OCD patients: patients with doubt/checking symptoms were more risk-averse than other patients. Taken together, OCD patients show a reversed pattern of risk processing by the insula compared to HCs. Moreover, the data suggest that increased activation of the insula signals an abnormal urge to avoid risks in the subpopulation of OCD patients with doubt and checking symptoms. These results indicate a role for the insula in excessive risk-avoidance relevant to OC

Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders

Contains fulltext : 154675.pdf (publisher's version ) (Open Access)BACKGROUND: Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia. METHODS: We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori-defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored. RESULTS: We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found. LIMITATIONS: We were unable to correct for possible confounding effects of smoking or antipsychotic medication. CONCLUSION: Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume