Disrupted structural connectivity of fronto-deep gray matter pathways in progressive supranuclear palsy

Background: Structural connectivity is a promising methodology to detect patterns of neural network dysfunction in neurodegenerative diseases. This approach has not been tested in progressive supranuclear palsy (PSP). Objectives: The aim of this study is reconstructing the structural connectome to characterize and detect the pathways of degeneration in PSP patients compared with healthy controls and their correlation with clinical features. The second objective is to assess the potential of structural connectivity measures to distinguish between PSP patients and healthy controls at the single-subject level. Methods: Twenty healthy controls and 19 PSP patients underwent diffusion-weighted MRI with a 3T scanner. Structural connectivity, represented by number of streamlines, was derived from probabilistic tractography. Global and local network metrics were calculated based on graph theory. Results: Reduced numbers of streamlines were predominantly found in connections between frontal areas and deep gray matter (DGM) structures in PSP compared with controls. Significant changes in structural connectivity correlated with clinical features in PSP patients. An abnormal small-world architecture was detected in the subnetwork comprising the frontal lobe and DGM structures in PSP patients. The classification procedure achieved an overall accuracy of 82.23% with 94.74% sensitivity and 70% specificity. Conclusion: Our findings suggest that modelling the brain as a structural connectome is a useful method to detect changes in the organization and topology of white matter tracts in PSP patients. Secondly, measures of structural connectivity have the potential to correctly discriminate between PSP patients and healthy controls

Generative models of the human connectome

The human connectome represents a network map of the brain's wiring diagram and the pattern into which its connections are organized is thought to play an important role in cognitive function. The generative rules that shape the topology of the human connectome remain incompletely understood. Earlier work in model organisms has suggested that wiring rules based on geometric relationships (distance) can account for many but likely not all topological features. Here we systematically explore a family of generative models of the human connectome that yield synthetic networks designed according to different wiring rules combining geometric and a broad range of topological factors. We find that a combination of geometric constraints with a homophilic attachment mechanism can create synthetic networks that closely match many topological characteristics of individual human connectomes, including features that were not included in the optimization of the generative model itself. We use these models to investigate a lifespan dataset and show that, with age, the model parameters undergo progressive changes, suggesting a rebalancing of the generative factors underlying the connectome across the lifespan.Comment: 38 pages, 5 figures + 19 supplemental figures, 1 tabl

Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study

Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.DTI scans were acquired for 19 children and adolescents with ASD (∼8-18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8-18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder

Neurobiological Underpinnings of Trauma-related Psychopathology

The understanding and treatment of trauma-related psychopathology is a crucial challenge in the field of global mental health today. The etiology and mechanisms of two common trauma-related symptoms – intrusive re-experiencing and dissociative symptomatology – are still not well understood. The present work aims to advance the understanding of these phenomena by investigating their neurobiological underpinnings in two disorders: depersonalization/derealization disorder (DPD), in which dissociation depicts the core feature, and the dissociative subtype of posttraumatic stress disorder (PTSD-D), in which dissociative symptomatology and intrusive re-experiencing co-occur and correlate in regard to their severity. Alterations in fiber tract networks in white matter, which are crucial for communicating between brain regions, have not yet been investigated in DPD or PTSD-D. In Study I, white matter network alterations were explored in 23 patients with DPD compared to 23 matched healthy controls. Results yielded relatively lower structural connectivity in left and right temporal regions in DPD, which have previously been associated with dissociative symptomatology in DPD and in other disorders. Furthermore, a trend indicated alterations in a fronto-limbic circuit, which a neurobiological model proposes underlies dissociation in DPD as well as PTSD-D. In Study II, we tested whether fronto-limbic circuits are also altered in PTSD-D (n=23) compared to ‘classic’ PTSD patients (n=19) using the same analysis pipeline as in Study I. No respective white matter changes were detected on a network level in PTSD-D. However, subsequent exploratory analyses revealed alterations in two subcortical networks comprising a limbic-thalamic circuit and low-level motor regions, respectively. The limbic-thalamic network is crucial for declarative and spatial mnemonic processes, which according to dual memory models play a crucial role for the development of intrusive memories. We tested the respective memory model in Study III and confirmed for the first time empirically, that spatial-contextual (allocentric) memory ability is negatively associated with severity of intrusive memories in 33 patients with PTSD. The findings of the present work indicate that (1) dissociation in DPD is underpinned by different alterations in structural connectivity than in PTSD-D and (2) dissociative and intrusive memories are associated with aberrations in similar sub-cortical circuits, supporting the notion that in PTSD-D, a lower state of consciousness exacerbates de-contextualization of the traumatic content, resulting in heightened intrusive symptomatology. Clinical implications of our findings are discussed

Age-Related Changes in Human Anatomical and Functional Brain Networks

Thesis (Ph.D.) - Indiana University, Psychological and Brain Sciences, 2015i) The first component characterizes age-related changes in specific connections. We find that functional connections within and between intrinsic connectivity networks (ICNs) follow distinct lifespan trajectories. We further characterize these changes in terms of each ICN’s “modularity” and find that most ICNs become less modular (i.e. less segregated) with age. In anatomical networks we find that hub regions are disproportionately affected by age and become less efficiently connected to the rest of the brain. Finally, we find that, with age stronger functional connections are supported by longer (multi-step) anatomical pathways for communication. ii) The second component is concerned with characterizing age-related changes in the boundaries of ICNs. To this end we used a multi-layer variant of modularity maximization to decompose networks into modules at different organizational scales, which we find exhibit scale-specific trends with age. At coarse scales, for example, we find that modules become more segregated whereas modules defined at finer scales become less segregated. We also find that module composition changes with age, and specific areas associated with memory change their module allegiance with age. iii) In the final component we use generative models to uncover wiring rules for the anatomical brain networks. Modeling network growth as a spatial penalty combined with homophily, we find that we can generate synthetic networks with many of the same properties as real-world brain networks. Fitting this model to individuals, we show that the parameter governing the severity of the spatial penalty weakens monotonically with age and that the overall ability to reproduce realistic connectomes for older individuals suffers. These results suggest that, with age, additional constraints may play an important role in shaping the topology of brain structural networks

Disruption of white matter connectivity in chronic obstructive pulmonary disease.

BACKGROUND: Mild cognitive impairment is a common systemic manifestation of chronic obstructive pulmonary disease (COPD). However, its pathophysiological origins are not understood. Since, cognitive function relies on efficient communication between distributed cortical and subcortical regions, we investigated whether people with COPD have disruption in white matter connectivity. METHODS: Structural networks were constructed for 30 COPD patients (aged 54-84 years, 57% male, FEV1 52.5% pred.) and 23 controls (aged 51-81 years, 48% Male). Networks comprised 90 grey matter regions (nodes) interconnected by white mater fibre tracts traced using deterministic tractography (edges). Edges were weighted by the number of streamlines adjusted for a) streamline length and b) end-node volume. White matter connectivity was quantified using global and nodal graph metrics which characterised the networks connection density, connection strength, segregation, integration, nodal influence and small-worldness. Between-group differences in white matter connectivity and within-group associations with cognitive function and disease severity were tested. RESULTS: COPD patients' brain networks had significantly lower global connection strength (p = 0.03) and connection density (p = 0.04). There was a trend towards COPD patients having a reduction in nodal connection density and connection strength across the majority of network nodes but this only reached significance for connection density in the right superior temporal gyrus (p = 0.02) and did not survive correction for end-node volume. There were no other significant global or nodal network differences or within-group associations with disease severity or cognitive function. CONCLUSION: COPD brain networks show evidence of damage compared to controls with a reduced number and strength of connections. This loss of connectivity was not sufficient to disrupt the overall efficiency of network organisation, suggesting that it has redundant capacity that makes it resilient to damage, which may explain why cognitive dysfunction is not severe. This might also explain why no direct relationships could be found with cognitive measures. Smoking and hypertension are known to have deleterious effects on the brain. These confounding effects could not be excluded

Individual Differences in White Matter Microstructure Predict Mathematical Achievement

The current study uses diffusion tensor imaging to test whether individual differences in white matter predict performance on the math subtest of the preliminary Scholastic Aptitude Test (PSAT). Grade 10 and 11 PSAT scores were obtained from 30 young adults (ages 17- 18) with wide-ranging math achievement levels. Tract based spatial statistics was used to examine the correlation between PSAT math scores, fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD). FA in left parietal white matter was positively correlated with math PSAT scores (specifically in the left superior longitudinal fasciculus, left superior corona radiata, and left corticospinal tract). Furthermore, RD, but not AD, was correlated with PSAT math scores in these white matter microstructures. The negative correlation with RD suggests increased myelination in participants with higher PSAT math scores. Individual differences in FA and RD may reflect variability in experience dependent plasticity over the course of learning and development

Dissociable roles of the inferior longitudinal fasciculus and fornix in face and place perception

We tested a novel hypothesis, generated from representational accounts of medial temporal lobe (MTL) function, that the major white matter tracts converging on perirhinal cortex (PrC) and hippocampus (HC) would be differentially involved in face and scene perception, respectively. Diffusion tensor imaging was applied in healthy participants alongside an odd-one-out paradigm sensitive to PrC and HC lesions in animals and humans. Microstructure of inferior longitudinal fasciculus (ILF, connecting occipital and ventro-anterior temporal lobe, including PrC) and fornix (the main HC input/output pathway) correlated with accuracy on odd-one-out judgements involving faces and scenes, respectively. Similarly, blood oxygen level-dependent (BOLD) response in PrC and HC, elicited during oddity judgements, was correlated with face and scene oddity performance, respectively. We also observed associations between ILF and fornix microstructure and category-selective BOLD response in PrC and HC, respectively. These striking three-way associations highlight functionally dissociable, structurally instantiated MTL neurocognitive networks for complex face and scene perception

Pitfalls in fMRI

Several different techniques allow a functional assessment of neuronal activations by magnetic resonance imaging (fMRI). The by far most influential fMRI technique is based on a local T2*-sensitive hemodynamic response to neuronal activation, also known as the blood oxygenation level dependent or BOLD effect. Consequently, the term ‘fMRI' is often used synonymously with BOLD imaging. Because interpretations of fMRI brain activation maps often appear intuitive and compelling, the reader might be tempted not to critically question the fundamental processes and assumptions. We review some essential processes and assumptions of BOLD fMRI and discuss related confounds and pitfalls in fMRI - from the underlying physiological effect, to data acquisition, data analysis and the interpretation of the results including clinical fMRI. A background framework is provided for the systematic and critical interpretation of fMRI result

White matter changes following chronic restraint stress and neuromodulation: A diffusion magnetic resonance imaging study in young male rats

Background Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation technique, is an effective treatment for depression. However, few studies have used diffusion magnetic resonance imaging to investigate the longitudinal effects of rTMS on the abnormal brain white matter (WM) described in depression. Methods In this study, we acquired diffusion magnetic resonance imaging from young adult male Sprague Dawley rats to investigate 1) the longitudinal effects of 10- and 1-Hz low-intensity rTMS (LI-rTMS) in healthy animals; 2) the effect of chronic restraint stress (CRS), an animal model of depression; and 3) the effect of 10 Hz LI-rTMS in CRS animals. Diffusion magnetic resonance imaging data were analyzed using tract-based spatial statistics and fixel-based analysis. Results Similar changes in diffusion and kurtosis fractional anisotropy were induced by 10- and 1-Hz stimulation in healthy animals, although changes induced by 10-Hz stimulation were detected earlier than those following 1-Hz stimulation. Additionally, 10-Hz stimulation increased axial and mean kurtosis within the external capsule, suggesting that the two protocols may act via different underlying mechanisms. Brain maturation–related changes in WM, such as increased corpus callosum, fimbria, and external and internal capsule fiber cross-section, were compromised in CRS animals compared with healthy control animals and were rescued by 10-Hz LI-rTMS. Immunohistochemistry revealed increased myelination within the corpus callosum in LI-rTMS–treated CRS animals compared with those that received sham or no stimulation. Conclusions Overall, decreased WM connectivity and integrity in the CRS model corroborate findings in patients experiencing depression with high anxiety, and the observed LI-rTMS–induced effects on WM structure suggest that LI-rTMS might rescue abnormal WM by increasing myelination