Role Of White Matter Integrity Research Articles

Mental flexibility depends on a largely distributed white matter network: Causal evidence from connectome-based lesion-symptom mapping

Mental flexibility (MF) refers to the capacity to dynamically switch from one task to another. Current neurocognitive models suggest that since this function requires interactions between multiple remote brain areas, the integrity of the anatomic tracts connecting these brain areas is necessary to maintain performance.We tested this hypothesis by assessing with a connectome-based lesion-symptom mapping approach the effects of white matter lesions on the brain’s structural connectome and their association with performance on the trail making test, a neuropsychological test of MF, in a sample of 167 first unilateral stroke patients.We found associations between MF deficits and damage of i) left lateralized fronto-temporo-parietal connections and interhemispheric connections between left temporo-parietal and right parietal areas; ii) left cortico-basal connections; and iii) left cortico-pontine connections. We further identified a relationship between MF and white matter disconnections within cortical areas composing the cognitive control, default mode and attention functional networks.These results for a central role of white matter integrity in MF extend current literature by providing causal evidence for a functional interdependence among the regional cortical and subcortical structures composing the MF network. Our results further emphasize the necessity to consider connectomics in lesion-symptom mapping analyses to establish comprehensive neurocognitive models of high-order cognitive functions.

Age-related decline in interhemispheric transfer of tactile information: The fingertip cross-localization task

According to the disconnection hypothesis of cognitive aging, cognitive deficits associated with brain aging could be a result of damage to connective fibres. It has been suggested that the age-related decline in cognitive abilities is accompanied by age-related changes in interhemispheric communication ensured by commissural fibres. This study aimed to contribute to this topic by investigating the effects of aging on the efficiency of interhemispheric transfer of tactile information. A total of 168 right-handed subjects, aged 20–90 years, have been tested using the fingertip cross-localization task: the subject must respond to a tactile stimulus presented to one hand using the ipsilateral (uncrossed condition) or contralateral hand (crossed condition). Because the crossed task requires interhemispheric transfer of information, the value of the difference between the uncrossed and crossed conditions (CUD) can be deemed to be a reliable measure of the efficiency of the interhemispheric interactions. The uncrossed condition was more accurate than the crossed condition for all ages. However, the degree of the CUD was significantly age-dependent. The effectiveness of the interhemispheric transfer of tactile information decreased significantly with age and may indicate the occurrence of age-related changes of the corpus callosum. Considerably, performance appears to decline around the seventh decade of life with the fastest decline in the subsequent decades. The results suggest a relationship between brain aging and the efficiency of the interhemispheric transfer of tactile information. The findings are discussed in relation to the strategic role of white matter integrity in preserving behavioural performances.

T154. WHITE MATTER INTEGRITY, DURATION OF UNTREATED PSYCHOSIS, AND ANTIPSYCHOTIC TREATMENT RESPONSE IN MEDICATION-NAïVE FIRST EPISODE PSYCHOSIS PATIENTS

BackgroundIt is becoming increasingly clear that longer duration of untreated psychosis (DUP) is associated with adverse clinical outcomes in patients with psychosis spectrum disorders. Especially because this association is often cited when justifying early intervention efforts, it is imperative to better understand underlying biological mechanisms.MethodsWe recruited 74 antipsychotic-naïve first episode psychosis (FEP) patients and 45 matched healthy controls in this trial. At baseline, we used a human connectome style diffusion weighted imaging (DWI) sequence to quantify white matter integrity in both groups. Patients then received 16 weeks of treatment with risperidone. DWI scans were acquired with opposite phase encoding directions [TR/TE: 3230ms/ 89.20ms; multiband acceleration factor 4, Flip angle: 84°; slice thickness 1.5mm, 92 slices, voxel size 1.5mm3, 92 diffusion weighted images distributed equally over 2 shells with b-values of ~ 1500s/mm2 and ~ 3000s/mm2, as well as 7 interspersed b= ~ 0s/mm2 images]). Preprocessing of DWI images was performed in TORTOISE (version 3.1.2). This included correction for thermal noise, Gibbs-ringing, high b-value based bulk motion and eddy-current distortions using a MAP-MRI model, resampling of images to 1mm3, and rotation of gradient tables independently for each DWI phase encoding direction. Then, DR-BUDDI was used to correct EPI distortions with input from the anatomical image and to combine the two datasets using geometric averaging to generate the final corrected dataset. Tensors were computed with DIFF_CALC using a linear fitting algorithm. To spatially normalize images to the Illinois Institute of Technology atlas (IIT4) space, we implemented an optimized non-linear image registration procedure using a modified version of 3dQwarp in AFNI. We compared whole brain fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD) and radial diffusivity between groups. To test if structural white matter integrity mediates the relationship between longer DUP and poorer treatment response, we fit a mediator model and estimated indirect effects.ResultsGroups did not differ in age (FEP: 23.83+/-6.21 years; HC: 24.78+/-6.24 years), sex (FEP: 65.2% male; HC: 64.4% male), or parental socioeconomic status (FEP: 5.95+/-4.83; HC: 4.22+/-4.06). We found decreased whole brain FA and AD in medication-naive FEP compared to controls. In patients, lower FA was correlated with longer DUP (r= -0.32; p= 0.03) and poorer subsequent response to antipsychotic treatment (r= 0.40; p= 0.01). Importantly, we found a significant mediation effect for FA (indirect effect: -2.70; p= 0.03), indicating that DUP exerts its effects on treatment response through affecting white matter integrity.DiscussionTo our knowledge, this is the first study to examine a putative role of white matter integrity in the observed association between DUP and clinical outcomes in first episode psychosis. Our data provide empirical support to the idea the DUP may have fundamental pathogenic effects on the natural history of psychosis, suggest a biological mechanism underlying this phenomenon, and underscore the importance of early intervention efforts in this disabling neuropsychiatric syndrome.

Acute pediatric traumatic brain injury severity predicts long-term verbal memory performance through suppression by white matter integrity on diffusion tensor imaging.

Mediation analysis was used to investigate the role of white matter integrity in the relationship between injury severity and verbal memory performance in participants with chronic pediatric traumatic brain injury (TBI). DTI tractography was used to measure fractional anisotropy (FA) within the corpus callosum, fornix, cingulum bundles, perforant pathways, and uncinate fasciculi. Injury severity was indexed using Glasgow Coma Scale (GCS) scores obtained at the time of the injury. Verbal memory was measured by performance on the long-delay free recall (LDFR) trial of the California Verbal Learning Test-Children's version. Participants were between the ages of 10-18 and included 21 children with TBI (injured before age 9) and 19 typically-developing children (TDC). Children with TBI showed lower FA across all pathways and poorer LDFR performance relative to TDC. Within the TBI group, mediation analysis revealed neither a significant total effect of GCS on LDFR nor significant direct effects of GCS on LDFR across pathways; however, the indirect effects of GCS on LDFR through FA of the corpus callosum, left perforant pathway, and left uncinate fasciculus were significant and opposite in sign to their respective direct effects. These results suggests that the predictive validity of GCS for LDFR is initially suppressed by the substantial variance accounted for by FA, which is uncorrelated with GCS, and the predictive validity of GCS increases only when FA is considered, and the opposing path is controlled. These findings illustrate the complex associations between acute injury severity, white matter pathways, and verbal memory several years following pediatric TBI.

A Preliminary Diffusion Tensor Imaging Study: Analysis of Whole Brain according to the Affected Side in Tinnitus

Aim: To investigate the role of white matter integrity in the pathophysiology of tinnitus, and also to analyze the whole brain for white matter changes quantitatively by comparing tinnitus patients with healthy controls based on the affected side of the tinnitus using Tract Based Spatial Statistics (TBSS).Methods: Total of 41 right-handed tinnitus patients and 35 age-matched right-handed healthy controls were initially examined non-invasively in resting-state using the 3.0T MRI scanner. We obtained the estimated Fractional anisotropy (FA), mean diffusivity (MD), Axial Diffusivity (AD), Radial Diffusivity (RD), and Mode of Anisotropy (MO) data for each subject. TBSS was used to perform group statistical analysis of DTI data from each group.Results: Compared to controls in right-sided tinnitus patients, FA and MO were decreased, and MD was normal with decreased AD and increased RD. FA and AD showed similar decreased values (t>1.5, FWEcorrected P<0.05) in the right corticospinal tract, right superior longitudinal fasciculus, and right inferior fronto-occipital fasciculus. Compared to controls with left-sided tinnitus patients, FA and MO were decreased, and MD was also increased with decreased AD with increased RD in patients. MO showed significantly decreased values (t>1.5, FWEcorrected P<0.05) of MO in Forceps major, bilateral cingulum (especially the left), and bilateral anterior thalamic radiation. Bilaterally affected tinnitus patients showed no difference when compared to controls.Conclusion: After analyzing the whole brain for white matter changes quantitatively using TBSS, changes were observed in unilaterally affected tinnitus patients compared to controls. Our findings indicated cross-modal plasticity could have caused changes in somatosensory, audio-visual, limbic, and attention pathways.Nepal Journal of Radiology Vol.5(1-2) 2015: 1-12

No Evidence That Short-Term Cognitive or Physical Training Programs or Lifestyles Are Related to Changes in White Matter Integrity in Older Adults at Risk of Dementia.

Cognitive and physical activities can benefit cognition. However, knowledge about the neurobiological mechanisms underlying these activity-induced cognitive benefits is still limited, especially with regard to the role of white matter integrity (WMI), which is affected in cognitive aging and Alzheimer’s disease. To address this knowledge gap, we investigated the immediate and long-term effects of cognitive or physical training on WMI, as well as the association between cognitive and physical lifestyles and changes in WMI over a 6-month period. Additionally, we explored whether changes in WMI underlie activity-related cognitive changes, and estimated the potential of both trainings to improve WMI by correlating training outcomes with WMI. In an observational and interventional pretest, posttest, 3-month follow-up design, we assigned 47 community-dwelling older adults at risk of dementia to 50 sessions of auditory processing and working memory training (n = 13), 50 sessions of cardiovascular, strength, coordination, balance and flexibility exercises (n = 14), or a control group (n = 20). We measured lifestyles trough self-reports, cognitive training skills through training performance, functional physical fitness through the Senior Fitness Test, and global cognition through a cognitive test battery. WMI was assessed via a composite score of diffusion tensor imaging-based fractional anisotropy (FA) of three regions of interest shown to be affected in aging and Alzheimer’s disease: the genu of corpus callosum, the fornix, and the hippocampal cingulum. Effects for training interventions on FA outcomes, as well as associations between lifestyles and changes in FA outcomes were not significant. Additional analyses did show associations between cognitive lifestyle and global cognitive changes at the posttest and the 3-month follow-up (β ≥ 0.40, p ≤ 0.02) and accounting for changes in WMI did not affect these relationships. The targeted training outcomes were related to FA scores at baseline (cognitive training skills and FA composite score, rs = 0.68, p = 0.05; functional physical fitness and fornix FA, r = 0.35, p = 0.03). Overall, we found no evidence of a link between short-term physical or cognitive activities and WMI changes, despite activity-related cognitive changes in older adults at risk of dementia. However, we found positive associations between the two targeted training outcomes and WMI, hinting at a potential of long-term activities to affect WMI.

Individual differences in reasoning and visuospatial attention are associated with prefrontal and parietal white matter tracts in healthy older adults.

Although reasoning and attention are 2 cognitive processes necessary for ensuring the efficiency of many everyday activities in older adults, the role of white matter integrity in these processes has been little studied. This is an important question due to the role of white matter integrity as a neural substrate of cognitive aging. Here, we sought to examine the white matter tracts subserving reasoning and visuospatial attention in healthy older adults. Sixty-one adults ages 60 and older completed a battery of cognitive tests to assess reasoning and visuospatial attention. In addition, diffusion tensor images were collected to assess fractional anisotropy (FA), a measure of white matter integrity. A principle components analysis of the test scores yielded 2 components: reasoning and visuospatial attention. Whole-brain correlations between FA and the cognitive components were submitted to probabilistic tractography analyses for visualization of cortical targets of tracts. For reasoning, bilateral thalamo-anterior prefrontal, anterior corpus callosum, and corpus callosum body tracts interconnecting the superior frontal cortices and right cingulum bundle were found. For visuospatial attention, a right inferior fronto-parietal tract and bilateral parietal and temporal connections were found. We conclude that in older adults, prefrontal cortex white matter tracts and interhemispheric communication are important in higher order cognitive functioning. On the other hand, right-sided fronto-parietal tracts appear to be critical for supporting control of cognitive processes, such as redirecting attention. Researchers may use our results to develop neuroscience-based interventions for older adults targeting brain mechanisms involved in cognitive plasticity. (PsycINFO Database Record

White matter integrity as a mediator in the relationship between dietary nutrients and cognition in the elderly

We examined the association of nutrient intake with microstructural white matter integrity, and the role of white matter integrity in the association between nutrient consumption and cognition. This cross-sectional analysis included 239 elderly (age ≥ 65 years) participants of a multiethnic cohort. White matter integrity was measured with fractional anisotropy (FA) from diffusion tensor magnetic resonance imaging. Nutrient patterns were derived from principal component analysis based on energy-adjusted intake of 24 selected nutrients. Generalized linear models were used to assess the association between nutrient patterns and mean FA of 26 white matter tracts. Mediation analysis was used to determine whether FA mediates the nutrient-cognition relationship. All models were adjusted for age at time of scan, gender, ethnicity, education, caloric intake, and apolipoprotein genotype. Among the identified 6 nutrient patterns, 1 (nutrient pattern 6, characterized by high intakes of Ω-3 and Ω-6 polyunsaturated fatty acids and vitamin E) was positively associated with FA. Those with the highest tertile of nutrient pattern 6 score had a mean of 0.01 (p = 0.01) higher FA value than those with the lowest tertile, similar to the effect of a 10-year decrease in age (b for age = -0.001, p = 0.01). FA mediated the relationship between nutrient pattern 6 and memory, language, visuospatial and speed/executive function, and mean cognitive scores. Our study suggests that older adults consuming more polyunsaturated fatty acids and vitamin E rich foods had better white matter integrity, and that maintaining white matter microstructural integrity might be a mechanism for the beneficial role of diet on cognition. Ann Neurol 2016;79:1014-1025.

Decreased White Matter Integrity in Neuropsychologically Defined Mild Cognitive Impairment Is Independent of Cortical Thinning

Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer’s disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for corticalthic kness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes.

White matter integrity and reaction time intraindividual variability in healthy aging and early-stage Alzheimer disease

Aging and early-stage Alzheimer disease (AD) have been shown to be associated with increased RT intraindividual variability (IIV, as reflected by the coefficient of variation) and an exaggeration of the slow tail of the reaction time (RT) distribution in attentional control tasks, based on ex-Gaussian analyses. The current study examined associations between white matter volume, IIV, and ex-Gaussian RT distribution parameters in cognitively normal aging and early-stage AD. Three RT attention tasks (Stroop, Simon, and a consonant-vowel odd-even switching task) in conjunction with MRI-based measures of cerebral and regional white matter volume were obtained in 133 cognitively normal and 33 early-stage AD individuals. Larger volumes were associated with less IIV and less slowing in the tail of the RT distribution, and larger cerebral and inferior parietal white matter volumes were associated with faster modal reaction time. Collectively, these results support a role of white matter integrity in IIV and distributional skewing, and are consistent with the hypothesis that IIV and RT distributional skewing are sensitive to breakdowns in executive control processes in normal and pathological aging.

Diffusion tensor imaging in the study of language and aphasia

Background: Diffusion tensor imaging (DTI) is an emerging research technique that is used to map and characterise white matter tracts in the healthy and damaged brain. Aims: The aim of this paper is to familiarise the readers with DTI while giving the tools to understand and evaluate recent developments in aphasia research that use DTI methodology. Main Contribution: Principles of DTI technology as well as its main caveats are described. An overview of studies that used DTI to explore the language system and aphasia is given. Future directions and the potential contribution of DTI to the understanding of aphasia diagnosis and recovery are highlighted. Conclusions: DTI is an emerging technology, increasingly being applied to further our understanding of aphasia and its recovery. So far it has contributed to our knowledge in four areas of research. In the area of brain anatomy it is used to redefine the borders between various parts of the cortex based on their structural connectivity, to acquire a more accurate map of the tracts connecting the various parts of the language system, and to measure hemispheric asymmetry. Future studies might be able to further our understanding of language anatomy and relate hemispheric asymmetry to recovery potential. Second, DTI can help in relating structure to function. So far many studies focused on repetition deficits and conduction aphasia. Future studies can explore the anatomy of other language deficits. Third, DTI has been used in the study of brain damage and recovery. Studies have documented the damage that occurs to white matter following stroke and other insults, and the spontaneous reorganisation that follows. In the future DTI might contribute to the debate about the role of the right hemisphere in recovery from aphasia. Lastly, in the area of aphasia rehabilitation there is great lack of data. The studies reviewed here have shown that rehabilitation potential is dependent on white matter integrity and that white matter changes can occur as a result of therapy. Future studies should further our understanding of the role of white matter integrity in recovery, therefore contributing to the question of why some patients show good recovery while others do not. Future studies should also try and map white matter changes that are associated with successful versus unsuccessful rehabilitation, and with different stages of recovery.

Aging Effects on Recollection and Familiarity: The Role of White Matter Hyperintensities

ABSTRACT Previous studies have indicated that aging is associated with declines in recollection whereas familiarity-based recognition is left largely unaffected. The brain changes underlying these recollection declines are yet not well understood. In the current study we examined the role of white matter integrity as measured by white matter hyperintensities (WMH) on age-related changes in recollection and familiarity. Recognition was measured using a remember/know procedure (Experiment 1) and a source-memory process-dissociation procedure (Experiment 2). Robust age related declines in recollection were observed, but there was no evidence that white matter damage was related to the observed memory declines. Although future studies with larger samples will be necessary to fully characterize the role of WMH in normal age-related declines in different types of memory, the results suggest that declines in recollection are not strongly related to the brain changes indexed by WMHs.

Some guidelines for structural equation modelling in cognitive neuroscience: The case of Charlton et al.’s study on white matter integrity and cognitive ageing

Charlton et al. (2008) (Charlton, R.A., Landua, S., Schiavone, F., Barrick, T.R., Clark, C.A., Markus, H.S., Morris, R.G.A., 2008. Structural equation modelling investigation of age-related variance in executive function and DTI-measured white matter change. Neurobiol. Aging 29, 1547-1555) presented a model that suggests a specific age-related effect of white matter integrity on working memory. We illustrate potential pitfalls of structural equation modelling by criticizing their model for (a) its neglect of latent variables, (b) its complexity, (c) its questionable causal assumptions, (d) the use of empirical model reduction, (e) the mix-up of theoretical perspectives, and (f) the failure to compare alternative models. We show that a more parsimonious model, based solely on the well-established general factor of cognitive ability, fits their data at least as well. Importantly, when modelled this way there is no support for a role of white matter integrity in cognitive aging in this sample, indicating that their conclusion is strongly dependent on how the data are analysed. We suggest that evidence from more conclusive study designs is needed.

Cerebral White Matter Integrity and Cognitive Aging: Contributions from Diffusion Tensor Imaging

The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior-posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.

Cerebral White Matter Integrity Mediates Adult Age Differences in Cognitive Performance

Previous research has established that age-related decline occurs in measures of cerebral white matter integrity, but the role of this decline in age-related cognitive changes is not clear. To conclude that white matter integrity has a mediating (causal) contribution, it is necessary to demonstrate that statistical control of the white matter-cognition relation reduces the magnitude of age-cognition relation. In this research, we tested the mediating role of white matter integrity, in the context of a task-switching paradigm involving word categorization. Participants were 20 healthy, community-dwelling older adults (60-85 years), and 20 younger adults (18-27 years). From diffusion tensor imaging tractography, we obtained fractional anisotropy (FA) as an index of white matter integrity in the genu and splenium of the corpus callosum and the superior longitudinal fasciculus (SLF). Mean FA values exhibited age-related decline consistent with a decrease in white matter integrity. From a model of reaction time distributions, we obtained independent estimates of the decisional and nondecisional (perceptual-motor) components of task performance. Age-related decline was evident in both components. Critically, age differences in task performance were mediated by FA in two regions: the central portion of the genu, and splenium-parietal fibers in the right hemisphere. This relation held only for the decisional component and was not evident in the nondecisional component. This result is the first demonstration that the integrity of specific white matter tracts is a mediator of age-related changes in cognitive performance.