Characterizing white matter microstructure of the reward system in depression

This thesis demonstrates the relationship between depression symptomatology and white matter microstructure. Chapter 1 provides a systematic literature overview on white matter microstructure alterations of the reward system in depression. Findings suggest that localization and extent of white matter microstructure alterations in depression is highly dependent on the state (depression vs. remission) and the clinical subtype. Using a novel tractography algorithm, Chapter 2 provides a comprehensive instruction on how to delineate the two different branches of the MFB (supero-lateral medial forebrain bundle (slMFB) and infero-medial medial forebrain bundle (imMFB)), the main pathway of the reward system. An association between fractional anisotropy (FA), a diffusion tensor imaging (DTI)-based measure that is supposed to reflect white matter microstructure and hedonic tone, the capacity to derive pleasure from rewarding experiences is identified across a group of remitted depressed (RD) and never depressed (ND) young women. Chapter 3 uses a longitudinal design to investigate white matter microstructural changes of different pathways of the reward system from depression to remission. A distinct pattern of changes that depends on both the tract and the age is identified. Chapter 4 investigates the structural correlates of physical activity (PA). PA is reduced in depression and its benefit for depression symptomatology is well known. Using an MRI-sequence that has been shown to be specific to myelination we identify a positive correlation between PA and myelination of the right parahippocampal cingulum (PHC). This thesis contributes to the identification of structure-function associations related to the reward system in both patients with major depressive disorder (MDD) and healthy controls (HC). Results call for a careful stratification of clinically meaningful homogeneous subgroups if investigating participants with depression. Further the benefit of novel imaging methods for reconstruction of specific pathways and for a neurobiologically meaningful interpretation of the data is clearly shown

The role of head circumference and cerebral volumes to phenotype male adults with autism spectrum disorder

Background: Autism spectrum disorder (ASD) has been repeatedly associated with enlargements of head circumference in children with ASD. However, it is unclear if these enlargements persist into adulthood. This is the first study to investigate head circumference in a large sample of adults with ASD. Methods: We apply a fully automated magnetic resonance imaging (MRI) based measurement approach to compute head circumference by combining 3D and 2D image processing. Head circumference was compared between male adults with ASD (n = 120) and healthy male controls (n = 136), from the Autism Brain Imaging Data Exchange (ABIDE) database. To explain which brain alterations drive our results, secondary analyses were performed for 10 additional morphological brain metrics. Results: ASD subjects showed an increase in head circumference (p = .0018). In addition, ASD patients had increased ventricular surface area (SA) (p = .0013). Intracranial volume, subarachnoidal cerebrospinal fluid (CSF) volume, and gray matter volume explained 50% of head circumference variance. Using a linear support vector machine, we gained an ASD classification accuracy of 73% (sensitivity 92%, specificity 68%) using head circumference and brain-morphological metrics as input features. Head circumference, ventricular SA, ventricular CSF volume, and ventricular asymmetry index contributed to 85% of feature weighting relevant for classification. Conclusion: Our results suggest that head circumference increases in males with ASD persist into adulthood. Results may be driven by morphological alterations of ventricular CSF. The presented approach for an automated head circumference measurement allows for the retrospective investigation of large MRI datasets in neuropsychiatric disorders

Myelination of the right parahippocampal cingulum is associated with physical activity in young healthy adults

Recent evidence suggests that individual differences in physical activity (PA) may be associated with individual differences in white matter microstructure and with grey matter volume of the hippocampus. Therefore, this study investigated the association between PA and white matter microstructure of pathways connecting to the hippocampus. A total of 33 young, healthy adults underwent magnetic resonance imaging (MRI). High angular resolution diffusion-weighted imaging and multi-component relaxometry MRI scans (multi-component driven equilibrium pulse observation of T1 and T2) were acquired for each participant. Activity levels (AL) of participants were calculated from 72-h actigraphy recordings. Tractography using the damped Richardson Lucy algorithm was used to reconstruct the fornix and bilateral parahippocampal cinguli (PHC). The mean fractional anisotropy (FA) and the myelin water fraction (MWF), a putative marker of myelination, were determined for each pathway. A positive correlation between both AL and FA and between AL and MWF were hypothesized for the three pathways. There was a selective positive correlation between AL and MWF in the right PHC (r = 0.482, p = 0.007). Thus, our results provide initial in vivo evidence for an association between myelination of the right PHC and PA in young healthy adults. Our results suggest that MWF may not only be more specific, but also more sensitive than FA to detect white matter microstructural alterations. If PA was to induce structural plasticity of the right PHC this may contribute to reverse structural alterations of the right PHC in neuropsychiatric disorder with hippocampal pathologies

Clinical improvements following bilateral anterior capsulotomy in treatment-resistant depression

The purpose of this study was to evaluate a programme of lesion surgery carried out on patients with treatment-resistant depression (TRD). This was a retrospective study looking at clinical and psychometric data from 45 patients with TRD who had undergone bilateral stereotactic anterior capsulotomy surgery over a period of 15 years, with the approval of the Mental Health Act Commission (37 with unipolar depression and eight with bipolar disorder). The Beck Depression Inventory (BDI) before and after surgery was used as the primary outcome measure. The Montgomery–Asberg Depression Rating Scale was administered and cognitive aspects of executive and memory functions were also examined. We carried out a paired-samples t test on the outcome measures to determine any statistically significant change in the group as a consequence of surgery. Patients improved on the clinical measure of depression after surgery by −21.20 points on the BDI with a 52% change. There were no significant cognitive changes post-surgery. Six patients were followed up in 2013 by phone interview and reported a generally positive experience. No major surgical complications occurred. With the limitations of an uncontrolled, observational study, our data suggest that capsulotomy can be an effective treatment for otherwise TRD. Performance on neuropsychological tests did not deteriorate

Hippocampal volume and parahippocampal cingulum alterations are associated with avoidant attachment in patients with depression

Background: Insecure attachment style (anxious and avoidant) predisposes to the development of depression and has been linked to hippocampal alterations in healthy individuals. However, it is unclear if there are alterations of the hippocampus and the parahippocampal cingulum (PHC) in patients with depression. Methods: Forty-eight patients with major depressive disorder and 18 healthy controls underwent MP2RAGE and diffusion-weighted magnetic resonance imaging. Attachment characteristics were assessed with the revised adult attachment scale. Patients were classified into subgroups with low (anxious: n = 27; avoidant: n = 21) and high (anxious: n = 20; avoidant: n = 28) attachment characteristics. Bilateral PHC were reconstructed using manual tractography. Hippocampal volumes, mean fractional anisotropy and mean diffusivity (MD) in bilateral PHC were compared between attachment subgroups and healthy controls. Results: Patients had higher scores of anxious and avoidant attachment, which were associated with depression severity. Patients with high avoidance had decreases in hippocampal volumes in comparison to patients with low avoidance. Furthermore, patients with high avoidance had increased MD in bilateral PHC in comparison to patients with low avoidance and in comparison to healthy controls. Limitations: Assessment of attachment characteristics may be influenced by cognitive biases due to depressive symptoms Conclusions: High attachment avoidance in patients with depression is associated with volume reductions in the hippocampus and impaired PHC-microstructure

Associations of thalamocortical networks with reduced mindfulness in alcohol use disorder.

BACKGROUND Increased mindfulness is associated with reduced alcohol consumption in patients with alcohol use disorder (AUD) after residential treatment. However, the underlying neurobiological mechanism of mindfulness in AUD is unclear. Therefore, we investigate the structural and functional alterations of the thalamocortical system with a focus on the mediodorsal thalamic nucleus (MD-TN), the default mode and the salience network (DMN/SN) which has previously been associated with mindfulness in healthy subjects. We hypothesized lower mindfulness and reduced structural and functional connectivity (FC) of the thalamocortical system, particularly in the DMN/SN in AUD. We assumed that identified neurobiological alterations in AUD are associated with impairments of mindfulness. METHODS Forty-five abstinent patients with AUD during residential treatment and 20 healthy controls (HC) were recruited. Structural and resting-state functional MRI-scans were acquired. We analysed levels of mindfulness, thalamic volumes and network centrality degree of the MD-TN using multivariate statistics. Using seed-based whole brain analyses we investigated functional connectivity (FC) of the MD-TN. We performed exploratory correlational analyses of structural and functional DMN/SN measurements with levels of mindfulness. RESULTS In AUD we found significantly lower levels of mindfulness, lower bilateral thalamic and left MD-TN volumes, reduced FC between MD-TN and anterior cingulum/insula and lower network centrality degree of the left MD-TN as compared to HC. In AUD, lower mindfulness was associated with various reductions of structural and functional aspects of the MD-TN. CONCLUSION Our results suggest that structural and functional alterations of a network including the MD-TN and the DMN/SN underlies disturbed mindfulness in AUD

Multimodal brain imaging reveals structural differences in Alzheimer's disease polygenic risk carriers: A study in healthy young adults

Background Recent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer’s disease (AD). Because neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesized that higher polygenic risk scores (PRSs) for AD would be associated with reduced volume of the hippocampus and other limbic and paralimbic areas. We further hypothesized that AD PRSs would affect the microstructure of fiber tracts connecting the hippocampus with other brain areas. Methods We analyzed the association between AD PRSs and brain imaging parameters using T1-weighted structural (n = 272) and diffusion-weighted scans (n = 197). Results We found a significant association between AD PRSs and left hippocampal volume, with higher risk associated with lower left hippocampal volume (p = .001). This effect remained when the APOE gene was excluded (p = .031), suggesting that the relationship between hippocampal volume and AD is the result of multiple genetic factors and not exclusively variability in the APOE gene. The diffusion tensor imaging analysis revealed that fractional anisotropy of the right cingulum was inversely correlated with AD PRSs (p = .009). We thus show that polygenic effects of AD risk variants on brain structure can already be detected in young adults. Conclusions This finding paves the way for further investigation of the effects of AD risk variants and may become useful for efforts to combine genotypic and phenotypic data for risk prediction and to enrich future prevention trials of AD

Reduced structural connectivity of the amygdala is associated with childhood trauma in adult patients with alcohol use disorder.

Childhood trauma (CT) is frequent in patients with alcohol use disorder (AUD) and may impact on adult drinking behaviour and treatment outcome. This study aimed to investigate the structural correlates of CT in AUD, focusing on the amygdala, which plays a crucial role in the neurobiology of trauma. We hypothesized reduced amygdala volume and reduced structural connectivity as quantified by fractional anisotropy (FA) and by number of streamlines in those AUD patients with a history of moderate to severe CT (AUD-CT). T1-weighted MP2RAGE and diffusion-weighted imaging (DWI) 3-Tesla MRI-scans were acquired in 41 recently abstinent patients with AUD. We compared bilateral amygdala volume and structural connectivity (FA and number of streamlines) of pathways emanating from the amygdala between AUD-CT (n = 20) and AUD without CT (AUD-NT, n = 21) using a mixed model multivariate analysis of variance (MANCOVA) controlling for age and gender. AUD-CT displayed reduced FA and reduced number of streamlines of amygdalar tracts. There were no differences regarding amygdala volume. The severity of physical abuse, a subscale of the childhood trauma questionnaire, was negatively correlated with FA and with number of streamlines. AUD-CT and AUD-NT differ regarding structural connectivity of pathways projecting to and from the amygdala, but not regarding amygdala volume. Those alterations of structural connectivity in AUD-CT may represent a distinguishable neurobiological subtype of AUD, which might be associated with the complex clinical picture and poorer outcome that patients with CT and AUD often present

Increased fractional anisotropy in the motor tracts of Parkinson's disease suggests compensatory neuroplasticity or selective neurodegeneration

Objective To determine the differences in motor pathways and selected non-motor pathways of the basal ganglia in Parkinson’s disease (PD) patients compared to healthy controls (HCs). Methods We analysed diffusion weighted imaging data of 24 PD patients and 26 HCs. We performed deterministic tractography analysis using the spherical deconvolution-based damped Richardson-Lucy algorithm and subcortical volume analysis. Results We found significantly increased fractional anisotropy (FA) in the motor pathways of PD patients: the bilateral corticospinal tract (right; corrected p = 0.0003, left; corrected p = 0.03), bilateral thalamus-motor cortex tract (right; corrected p = 0.02, left; corrected p = 0.004) and the right supplementary area-putamen tract (corrected p = 0.001). We also found significantly decreased FA in the right uncinate fasiculus (corrected p = 0.01) and no differences of FA in the bilateral supero-lateral medial forebrain bundles (p > 0.05) of PD patients compared to HCs. There were no subcortical volume differences (p > 0.05) between the PD patients and HCs. Conclusion These results can inform biological models of neurodegeneration and neuroplasticity in PD. We suggest that increased FA values in the motor tracts in PD may reflect compensatory reorganization of neural circuits indicative of adaptive or extended neuroplasticity. Key points • Fractional anisotropy was higher in motor pathways of PD patients compared to healthy controls. • Fractional anisotropy was lower in the uncinate fasciculus of PD patients compared to healthy controls. • Increased fractional anisotropy could suggest adaptive neuroplasticity or selective neurodegeneration