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In this thesis we investigated structural and functional brain characteristics related to obsessive-compulsive symptoms (OCS) in children from the general population. In Chapter 1, we gave an introduction on OCD and outlined the rationale and aims for this thesis. In Chapter 2, we studied the brain morphology related to OCS in 2551 children aged 9 to 12 years from the Generation R Study. We also defined a subgroup of 164 children with symptoms above a clinical cut-off (‘probable OCD’) and with controls. Consistent with clinical OCD studies, children with probable OCD had a larger thalamus than controls. Our results in the general population are highly consistent with prior clinical studies. In Chapter 3, we studied thalamic subregional volumes in relation to OCS in 9-12 year old children from the Generation R Study. We used an automated thalamic segmentation pipeline to compare volumes of the anterior, ventral, intralaminar/medial, lateral and pulvinar subregions. Children with probable OCD had a larger ventral subregion compared with controls. Severity of OCS was negatively associated with pulvinar volume after accounting for overall thalamic volume. These results did not survive multiple comparisons correction, but do suggest that thalamic enlargement in probable OCD may be explained in varying degrees by multiple rather than a single thalamic subregion. In Chapter 4, we studied thalamic subregions in relation to clinical OCD within the ENIGMA-OCD Working group. We used an automated thalamic segmentation pipeline to compare volume of the anterior, ventral, intralaminar/medial, lateral and pulvinar subregions of the thalamus between 2,649 OCD patients and 2,774 healthy controls. Unmedicated pediatric OCD patients under the age of 12 years had larger lateral, pulvinar, ventral and whole thalamus volumes. Adult OCD patients compared with controls had smaller volumes across all subregions and smaller whole thalamic volume, which was mostly accounted for by the medicated patients and associated with symptom severity. The anterior thalamus was smaller in patients after adjusting for total thalamus volume. Consistent with findings from the Generation R Study, we conclude that thalamic volume differences related to OCD are global rather than driven by particular subregions. In Chapter 5, we investigated the longitudinal relationship between brain morphology and OCS in children from the Generation R Study between the ages of 9 to 16 years. Longitudinal relationships between thalamus, cortical morphology and OCS were investigated. We found no difference in thalamic volume between adolescents (at the age of 13 to 16 years) with probable OCD and controls. Thalamic volume at baseline (age 9-12) predicted a relative persistence of OCS at follow-up (age 13-16). Linear-mixed effect models showed that baseline thalamic volume predicts the change in cortical thickness of 12 OCD-relevant cortical regions. These findings suggest OCS-related thalamic volume differences diminish with age in the general population, consistent with findings from cross-sectional clinical studies. Further, thalamic volume at age 9-12 years is associated with change in OCS between 9-12 years and 13-16 years in the general population. In Chapter 6, we studied the functional brain characteristics of children aged 9-12 years from the Generation R Study. We used a combination of graph theoretical and subnetwork connectivity analysis to study the brain network at multiple scales: global network topology, subnetwork connectivity and network participation of thalamic nodes. We showed that children endorsing at least one OCS had higher modularity, lower connectivity between frontoparietal, limbic and visual networks as well as altered participation of the lateral prefrontal thalamus node. Further analysis revealed that these associations were primarily accounted for by hand washing symptoms. These results suggest that the network characteristics of OCS in children from the general population are partly symptom-specific and severity-dependent.

The overall aim of this thesis was to gain a better understanding of the clinical and neurobiological characteristics of cognitive impairment in Parkinson’s disease (PD) and the efficacy of cognitive training for its treatment. We used neuropsychological and neuroimaging data from a large outpatient cohort of PD patients to study cognitive heterogeneity and the underlying dopaminergic and serotonergic deficiencies. We further systematically reviewed the literature on the neural correlates of cognitive training (CT) and performed a randomized controlled trial in 140 PD patients on the neuropsychological and brain network effects of an eight-week online cognitive training program. We performed a cluster analysis in a large sample of 226 mostly early-stage PD patients to assess the heterogeneity in the clinical symptom profile of PD, with a focus on cognitive heterogeneity. We distinguished four symptom profiles, including two symptom profiles with similar mean age and disease stage, but significant differences in their clinical cognitive symptom profile. Briefly, the results suggest the existence of parallel disease pathways that may have predictive value for the rate of cognitive decline, for the profile and course of neuropsychiatric symptoms and for treatment efficacy. To evaluate the dopaminergic and serotonergic deficiencies associated with cognitive impairment in PD, we performed a dopamine transporter SPECT study in the same patient cohort. Binding of 123I-FP-CIT in the caudate head and anterior putamen was associated with processing speed tasks, while extra-striatal binding did not show any significant associations with cognitive function. This study showed that deterioration of the striatal dopamine system may be involved in impairment of mental processing speed. We additionally performed a randomized controlled trial, the COGnitive Training In Parkinson Study (COGTIPS), to study the effects of home-based, multi-domain CT in PD patients with subjective cognitive complaints. In this thesis, we describe the study protocol, primary results and effects on functional connectivity and network topology. 140 PD patients were randomized into an experimental adaptive and challenging cognitive training or an active control condition. The eight-week cognitive training did not improve planning accuracy, but did produce small significant differences between the groups on processing speed during executive function tasks. Improvement on the experimental training games correlated with the improvement on the Tower of London and Stroop Color Word Test. Interestingly, post-hoc sub-group analyses suggested that CT was more efficacious in patients that were cognitively more impaired and fulfilled the diagnostic criteria for PDD, but this sub-sample was small. At six-months follow-up, the initial positive effects were no longer present. To improve our understanding of the neural processes underlying the effects of CT on cognitive function, we performed a systematic review of studies that used functional MRI (fMRI) before and after CT in healthy elderly and subjects with a neurodegenerative disease. This literature study provided convincing evidence that CT can alter brain activation and connectivity. In healthy populations, CT induced lower regional brain activity potentially as a result of enhanced neural efficiency. Conversely, in individuals with neurodegenerative diseases brain activity increased after CT, presumably showing that CT increased the neural effort that can be delivered to successfully fulfill task demands. Resting-state fMRI studies showed that CT increased connectivity and enhanced segregation between task-positive and task-negative resting-state networks. We aimed to replicate these findings in the COGTIPS sample, where we studied the effects of CT on resting-state network connectivity and the brain network topology. This study showed that our eight-week intervention did not affect global brain network connectivity and topology. Post-hoc analyses at the nodal level showed that CT enhanced connectivity of the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex.

Parkinson’s disease (PD) is characterized by its main motor symptoms bradykinesia, rigidity and tremor, and additional motor and non-motor symptoms. Non-motor characteristics may include cognitive dysfunction, autonomic failure, and neuropsychiatric symptoms and disorders such as anxiety, depression, psychosis, impulse control disorders, sleep disorders, and apathy. As compared to the motor symptoms, neuropsychiatric symptoms are often reported to have a higher impact on quality of life of both patients and their caregivers. Amongst neuropsychiatric symptoms, anxiety and depression are considered major predictors of reduced quality of life, followed by cognitive dysfunction. Currently, up to 45% of PD patients experience either clinically relevant anxiety symptoms or fulfill the criteria for an anxiety disorder. Anxiety in PD can also occur in the context of response fluctuations in PD symptoms, especially related to wearing-off, i.e., the re-emergence of PD symptoms while transitioning from an ‘on’ state to an ‘off’ state, typically occurring prior to the next scheduled dose of dopaminergic medication taking effect. About 75% of patients with motor fluctuations experience fluctuations in mood and/or anxiety in parallel. Diagnosing and treating anxiety in PD is complicated, due to overlapping motor and autonomic symptoms, comorbid psychiatric symptoms, and the interplay between anxiety and motor symptoms over time. This thesis mainly focuses on understanding (part 1) and treating (part 2) anxiety symptoms in the context of motor symptoms. Chapter 1 provides a general introduction on anxiety in PD including the multiple factors that complicate diagnosis and treatment. In chapter 2 we investigated the phenomenology of anxiety in PD by performing a principal component analysis on the items of the Beck Anxiety Inventory (BAI) in a sample of 294 PD patients. To investigate the generalizability of the findings in chapter 2, chapter 3 describes the replication of the principal component analysis in 123 PD patients that were referred for neuropsychiatric evaluation to a specialized neuropsychiatric outpatient department. To investigate whether the associations between motor symptoms and anxiety differed in strength between high- versus low-anxiety PD patients, we used an explorative network analysis to study these associations in chapter 4. As symptom intensity may vary over time, we investigated the longitudinal associations between anxiety, fear of falling, and freezing of gait in 153 PD patients in chapter 5. After a description of the phenomenology of anxiety, and its cross-sectional and longitudinal associations with motor and other non-motor symptoms, part 2 of this PhD thesis focuses on the treatment of these complex symptom interactions in PD patients. In chapter 6, we describe two meta-analyses on the effects of cognitive behavioral therapy and mindfulness-based therapies on psychological distress in patients with neurodegenerative disorders. Chapters 7 and 8 present the study protocol and results of a pilot randomized controlled trial (RCT) in which we described and investigated a newly developed multidisciplinary group treatment for wearing-off related anxiety in PD named BEWARE, in which we combine elements from acceptance and commitment therapy (ACT) with physical therapy. Finally, in Chapter 9, the findings of this thesis are summarized and reflected upon. I describe the reciprocal interactions between anxiety, motor, and autonomic symptoms. I link our findings to the research field on body awareness in psychosomatic disorders, discussing the commonalities in the inaccuracy of interpretation of bodily symptoms that is seen in both PD patients with wearing-off related anxiety and patients with psychosomatic disorders. Subsequently, I provide suggestions for improving this inaccuracy. This thesis helps to understand and treat anxiety symptoms in the context of motor symptoms in PD patients.