Individual differences in white matter microstructure reflect variation in functional connectivity during action choice.

The relation between brain structure and function is of fundamental importance in neuroscience. Comparisons between behavioral and brain imaging measures suggest that variation in brain structure correlates with the presence of specific skills[1-3]. Behavioral measures, however, reflect the integrated function of multiple brain regions. Rather than behavior, a physiological index of function could be a more sensitive and informative measure with which to compare structural measures. Here, we test for a relationship between a physiological measure of functional connectivity between two brain areas during a simple decision making task and a measure of structural connectivity. Paired-pulse transcranial magnetic stimulation indexed functional connectivity between two regions important for action choices: premotor and motor cortex. Fractional anisotropy (FA), a marker of microstructural integrity, indexed structural connectivity. Individual differences in functional connectivity during action selection show highly specific correlations with FA in localised regions of white matter interconnecting regions including the premotor and motor cortex. Probabilistic tractography[4, 5], a technique for identifying fibre pathways from diffusion-weighted imaging (DWI), reconstructed the anatomical networks linking the component brain regions involved in making decisions. These findings demonstrate a relationship between individual differences in functional and structural connectivity within human brain networks central to action choice

Axon diameters and myelin content modulate microscopic fractional anisotropy at short diffusion times in fixed rat spinal cord

Mapping tissue microstructure accurately and noninvasively is one of the frontiers of biomedical imaging. Diffusion Magnetic Resonance Imaging (MRI) is at the forefront of such efforts, as it is capable of reporting on microscopic structures orders of magnitude smaller than the voxel size by probing restricted diffusion. Double Diffusion Encoding (DDE) and Double Oscillating Diffusion Encoding (DODE) in particular, are highly promising for their ability to report on microscopic fractional anisotropy ({\mu}FA), a measure of the pore anisotropy in its own eigenframe, irrespective of orientation distribution. However, the underlying correlates of {\mu}FA have insofar not been studied. Here, we extract {\mu}FA from DDE and DODE measurements at ultrahigh magnetic field of 16.4T in the aim to probe fixed rat spinal cord microstructure. We further endeavor to correlate {\mu}FA with Myelin Water Fraction (MWF) derived from multiexponential T2 relaxometry, as well as with literature-based spatially varying axonal diameters. In addition, a simple new method is presented for extracting unbiased {\mu}FA from three measurements at different b-values. Our findings reveal strong anticorrelations between {\mu}FA (derived from DODE) and axon diameter in the distinct spinal cord tracts; a moderate correlation was also observed between {\mu}FA derived from DODE and MWF. These findings suggest that axonal membranes strongly modulate {\mu}FA, which - owing to its robustness towards orientation dispersion effects - reflects axon diameter much better than its typical FA counterpart. The {\mu}FA exhibited modulations when measured via oscillating or blocked gradients, suggesting selective probing of different parallel path lengths and providing insight into how those modulate {\mu}FA metrics. Our findings thus shed light into the underlying microstructural correlates of {\mu}FA and are (...

Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia

Diffusion Tensor Imaging Predictors of Episodic Memory Decline in Healthy Elders at Genetic Risk for Alzheimer’s Disease

Objectives: White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer’s disease (AD). Methods: Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1–5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. Results: Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. Conclusions: Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005–1015

Multiple indices of diffusion identifies white matter damage in mild cognitive impairment and Alzheimer's disease

The study of multiple indices of diffusion, including axial (DA), radial (DR) and mean diffusion (MD), as well as fractional anisotropy (FA), enables WM damage in Alzheimer's disease (AD) to be assessed in detail. Here, tract-based spatial statistics (TBSS) were performed on scans of 40 healthy elders, 19 non-amnestic MCI (MCIna) subjects, 14 amnestic MCI (MCIa) subjects and 9 AD patients. Significantly higher DA was found in MCIna subjects compared to healthy elders in the right posterior cingulum/precuneus. Significantly higher DA was also found in MCIa subjects compared to healthy elders in the left prefrontal cortex, particularly in the forceps minor and uncinate fasciculus. In the MCIa versus MCIna comparison, significantly higher DA was found in large areas of the left prefrontal cortex. For AD patients, the overlap of FA and DR changes and the overlap of FA and MD changes were seen in temporal, parietal and frontal lobes, as well as the corpus callosum and fornix. Analysis of differences between the AD versus MCIna, and AD versus MCIa contrasts, highlighted regions that are increasingly compromised in more severe disease stages. Microstructural damage independent of gross tissue loss was widespread in later disease stages. Our findings suggest a scheme where WM damage begins in the core memory network of the temporal lobe, cingulum and prefrontal regions, and spreads beyond these regions in later stages. DA and MD indices were most sensitive at detecting early changes in MCIa

Empirical comparison of diffusion kurtosis imaging and diffusion basis spectrum imaging using the same acquisition in healthy young adults

As diffusion tensor imaging gains widespread use, many researchers have been motivated to go beyond the tensor model and fit more complex diffusion models, to gain a more complete description of white matter microstructure and associated pathology. Two such models are diffusion kurtosis imaging (DKI) and diffusion basis spectrum imaging (DBSI). It is not clear which DKI parameters are most closely related to DBSI parameters, so in the interest of enabling comparisons between DKI and DBSI studies, we conducted an empirical survey of the interrelation of these models in 12 healthy volunteers using the same diffusion acquisition. We found that mean kurtosis is positively associated with the DBSI fiber ratio and negatively associated with the hindered ratio. This was primarily driven by the radial component of kurtosis. The axial component of kurtosis was strongly and specifically correlated with the restricted ratio. The joint spatial distributions of DBSI and DKI parameters are tissue-dependent and stable across healthy individuals. Our contribution is a better understanding of the biological interpretability of the parameters generated by the two models in healthy individuals

Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome.

22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk

Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing-remitting multiple sclerosis

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor maging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with GeneralLinear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities