Measuring cortical connectivity in Alzheimer's disease as a brain neural network pathology: Toward clinical applications

Objectives: The objective was to review the literature on diffusion tensor imaging as well as resting-state functional magnetic resonance imaging and electroencephalography (EEG) to unveil neuroanatomical and neurophysiological substrates of Alzheimer’s disease (AD) as a brain neural network pathology affecting structural and functional cortical connectivity underlying human cognition. Methods: We reviewed papers registered in PubMed and other scientific repositories on the use of these techniques in amnesic mild cognitive impairment (MCI) and clinically mild AD dementia patients compared to cognitively intact elderly individuals (Controls). Results: Hundreds of peer-reviewed (cross-sectional and longitudinal) papers have shown in patients with MCI and mild AD compared to Controls (1) impairment of callosal (splenium), thalamic, and anterior–posterior white matter bundles; (2) reduced correlation of resting state blood oxygen level-dependent activity across several intrinsic brain circuits including default mode and attention-related networks; and (3) abnormal power and functional coupling of resting state cortical EEG rhythms. Clinical applications of these measures are still limited. Conclusions: Structural and functional (in vivo) cortical connectivity measures represent a reliable marker of cerebral reserve capacity and should be used to predict and monitor the evolution of AD and its relative impact on cognitive domains in pre-clinical, prodromal, and dementia stages of AD. (JINS, 2016, 22, 138–163

Test-retest reliability of structural brain networks from diffusion MRI

Structural brain networks constructed from diffusion MRI (dMRI) and tractography have been demonstrated in healthy volunteers and more recently in various disorders affecting brain connectivity. However, few studies have addressed the reproducibility of the resulting networks. We measured the test–retest properties of such networks by varying several factors affecting network construction using ten healthy volunteers who underwent a dMRI protocol at 1.5 T on two separate occasions. Each T1-weighted brain was parcellated into 84 regions-of-interest and network connections were identified using dMRI and two alternative tractography algorithms, two alternative seeding strategies, a white matter waypoint constraint and three alternative network weightings. In each case, four common graph-theoretic measures were obtained. Network properties were assessed both node-wise and per network in terms of the intraclass correlation coefficient (ICC) and by comparing within- and between-subject differences. Our findings suggest that test–retest performance was improved when: 1) seeding from white matter, rather than grey; and 2) using probabilistic tractography with a two-fibre model and sufficient streamlines, rather than deterministic tensor tractography. In terms of network weighting, a measure of streamline density produced better test–retest performance than tract-averaged diffusion anisotropy, although it remains unclear which is a more accurate representation of the underlying connectivity. For the best performing configuration, the global within-subject differences were between 3.2% and 11.9% with ICCs between 0.62 and 0.76. The mean nodal within-subject differences were between 5.2% and 24.2% with mean ICCs between 0.46 and 0.62. For 83.3% (70/84) of nodes, the within-subject differences were smaller than between-subject differences. Overall, these findings suggest that whilst current techniques produce networks capable of characterising the genuine between-subject differences in connectivity, future work must be undertaken to improve network reliability

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Brain tissue properties differentiate between motor and limbic basal ganglia circuits

Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcom

Using diffusion MRI to discriminate areas of cortical grey matter

Cortical area parcellation is a challenging problem that is often approached by combining structural imaging (e.g., quantitative T1, diffusion-based connectivity) with functional imaging (e.g., task activations, topological mapping, resting state correlations). Diffusion MRI (dMRI) has been widely adopted to analyse white matter microstructure, but scarcely used to distinguish grey matter regions because of the reduced anisotropy there. Nevertheless, differences in the texture of the cortical 'fabric' have long been mapped by histologists to distinguish cortical areas. Reliable area-specific contrast in the dMRI signal has previously been demonstrated in selected occipital and sensorimotor areas. We expand upon these findings by testing several diffusion-based feature sets in a series of classification tasks. Using Human Connectome Project (HCP) 3T datasets and a supervised learning approach, we demonstrate that diffusion MRI is sensitive to architectonic differences between a large number of different cortical areas defined in the HCP parcellation. By employing a surface-based cortical imaging pipeline, which defines diffusion features relative to local cortical surface orientation, we show that we can differentiate areas from their neighbours with higher accuracy than when using only fractional anisotropy or mean diffusivity. The results suggest that grey matter diffusion may provide a new, independent source of information for dividing up the cortex

Mapping hybrid functional-structural connectivity traits in the human connectome

One of the crucial questions in neuroscience is how a rich functional repertoire of brain states relates to its underlying structural organization. How to study the associations between these structural and functional layers is an open problem that involves novel conceptual ways of tackling this question. We here propose an extension of the Connectivity Independent Component Analysis (connICA) framework, to identify joint structural-functional connectivity traits. Here, we extend connICA to integrate structural and functional connectomes by merging them into common hybrid connectivity patterns that represent the connectivity fingerprint of a subject. We test this extended approach on the 100 unrelated subjects from the Human Connectome Project. The method is able to extract main independent structural-functional connectivity patterns from the entire cohort that are sensitive to the realization of different tasks. The hybrid connICA extracted two main task-sensitive hybrid traits. The first, encompassing the within and between connections of dorsal attentional and visual areas, as well as fronto-parietal circuits. The second, mainly encompassing the connectivity between visual, attentional, DMN and subcortical networks. Overall, these findings confirms the potential ofthe hybrid connICA for the compression of structural/functional connectomes into integrated patterns from a set of individual brain networks.Comment: article: 34 pages, 4 figures; supplementary material: 5 pages, 5 figure