White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis

White-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge’s g = 0.38, 95% confidence interval (CI) 0.07–0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females (z = −2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.

Poorer white matter microstructure predicts slower and more variable reaction time performance: evidence for the neural noise hypothesis in a large lifespan cohort

Most prior research in the neural and behavioral sciences has been focused on characterizing averages in cognition, brain characteristics, or behavior, and attempting to predict differences in these averages among individuals. However, this overwhelming focus on mean levels may leave us with an incomplete picture of what drives individual differences in behavioral phenotypes by ignoring the variability of behavior around an individual’s mean. In particular, better white matter (WM) structural microstructure has been hypothesized to support consistent behavioral performance by decreasing gaussian noise in signal transfer. In contrast, lower indices of white matter microstructure have been associated with greater within-subject variance in the ability to deploy performance-related resources, especially in clinical samples. We tested this ‘neural noise’ hypothesis in a large adult lifespan cohort (Cam-CAN) with over 2500 individuals in a (2681 behavioral sessions with 708 scans in adults aged 18–102) using measures of WM tract microstructure to predict mean levels and variability in reaction time performance on a simple behavioral task using a dynamic structural equation model (DSEM). We found broad support for neural noise hypothesis, such that lower WM microstructure predicted individual differences in separable components of behavioral performance estimated using DSEM, including slower mean responses and increased variability. These effects were robust when including age in the model, suggesting consistent effects of WM microstructure across the adult lifespan above and beyond concurrent effects of ageing. Crucially, these results demonstrate the utility of DSEM for modeling and predicting behavioral variability directly, and the promise of studying variability for understanding cognitive processes.

White Matter Brain Structure Predicts Language Performance and Learning Success

Individual differences in the ability to deal with language have long been discussed. The neural basis of these, however, is yet unknown. Here we investigated the relationship between long-range white matter connectivity of the brain, as revealed by diffusion tractography, and the ability to process syntactically complex sentences in the participants' native language as well as the improvement thereof by multi-day training. We identified specific network motifs that indeed related white matter tractography to individual language processing performance. First, for two such motifs, one in the left and one in the right hemisphere, their individual prevalence significantly predicted the individual language performance suggesting a predisposition for the individual ability to process syntactically complex sentences, which manifests itself in the white matter brain structure. Both motifs comprise a number of cortical regions, but seem to be dominated by areas known for the involvement in working memory rather than the classical language network itself. Second, we identified another left hemispheric network motif, whose change of prevalence over the training period significantly correlated with the individual change in performance, thus reflecting training induced white matter plasticity. This motif comprises diverse cortical areas including regions known for their involvement in language processing, working memory and motor functions. The present findings suggest that individual differences in language processing and learning can be explained, in part, by individual differences in the brain's white matter structure. Brain structure may be a crucial factor to be considered when discussing variations in human cognitive performance, more generally.

Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at least in isolation) to draw strong reverse inferences about white matter microstructure, but based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users. Therefore, this paper will briefly discuss the complex biophysical underpinnings of these measures in the context of crossing fibers, provide some intuitive “thought experiments” to highlight how conventional interpretations can lead to incorrect conclusions, and suggest that future studies refrain from using (over-interpreting) FA, AD, and RD values as standalone biomarkers of cerebral white matter microstructure.

Cerebral White Matter Mediation of Age-Related Differences in Picture Naming Across Adulthood

As people age, one of the most common complaints is difficulty with word retrieval. A wealth of behavioral research confirms such age-related language production deficits, yet the structural neural differences that relate to age-related language production deficits remains an open area of exploration. Therefore, the present study used a large sample of healthy adults across adulthood to investigate how age-related white matter differences in three key left-hemisphere language tracts may contribute to age-related differences in language ability. Specifically, we used diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and radial diffusivity (RD) which are indicators of white matter structure. We then used a series of path models to test whether white matter from the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the frontal aslant tract (FAT) mediated age-related differences in one form of language production, picture naming. We found that FA, as well as RD from the SLF and FAT mediated the relation between age and picture naming performance, whereas a control tract (corticospinal; CST) was not a mediator. Moreover, differences between mediation of picture naming and a control naming condition suggest that left SLF has a greater role in higher-order aspects of naming, such as semantic and lexical selection whereas left FAT is more sensitive to sensorimotor aspects of fluency or speech motor planning. These results suggest that dorsal white matter contributes to age-related differences in generating speech and may be particularly important in supporting word retrieval across adulthood.

Investigation of Posture/Balance Disorder and Pd-related Pain by Using Diffusion Tensor Imaging and Transcranial Doppler

Background: Posture/balance disorder and pain are both present in Parkinson's patients, but their neural basis remain unclear. To investigate the central mechanism of posture/balance disorder and PD-related pain in Parkinson's disease by using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), combined with Transcranial Doppler (TCD). Results: It was found that the dose of levodopa, UPDRSⅡ and UPDRSⅢ were higher value in the group with higher score of posture/balance. In the more severe posture/balance disorder group, the fiber bundles of the prefrontal cortex, anterior cingulate cortex and basal ganglia were more likely to be affected. In addition, the DTI parameter values of the three brain regions had a significant correlation with the parameter values of the corresponding arteries. In the analysis of PD-related pain, the white matter fiber bundles from the midbrain to the basal ganglia increased in patients with PD-related pain. There were no statistic difference in prevalence of PD-related pain was found between different groups according to posture/balance. Conclusions: Posture and balance in PD were correlated with the severity of the disease and the dosage of compound levodopa. Posture and balance in PD were related to changes in the white matter integrity of the prefrontal cortex, anterior cingulate cortex and basal ganglia. The function of cerebral arteries had contributions to white matter integrity of these area and posture/balance. PD-related pain was positively correlated with sleep score. Patients with PD-related pain had an increase in the fiber projection from the midbrain to the basal ganglia. No relation was found between posture/balance disorder with PD-related pain.

Impact of 25-Hydroxy Vitamin D on White Matter Hyperintensity in Elderly Patients: A Systematic Review and Meta-Analysis

Some studies show that low serum vitamin D levels are associated with white matter hyperintensity (WMH), while other studies report no association. This meta-analysis aimed to investigate the presence of an association between serum 25-hydroxy vitamin D [25(OH)D] levels and WMH. PubMed, Embase, the Cochrane Library, CNKI, WANFANG, and VIP were searched for available papers published up to December 2020. The outcomes were the odds ratios (ORs) with 95% confidence intervals (CIs) for the association between different vitamin D statuses and WMH. All meta-analyses were performed using a random-effects model. Five studies (4393 patients) were included. Compared with sufficient 25(OH)D levels, 25(OH)D deficiency was not associated with WMH (OR = 1.67, 95%CI: 0.92–3.04; I2 = 70.2%, Pheterogeneity = 0.009), nor was 25(OH)D insufficiency (OR = 1.21, 95%CI: 0.89–1.65; I2 = 48.1%, Pheterogeneity = 0.103). A decrease of 25 nmol/L in 25(OH)D levels was associated with WMH (OR = 1.83, 95%CI: 1.34-2.49; I2 = 0%, Pheterogeneity= 0.512). The sensitivity analyses showed that the results were robust. 25(OH)D deficiency and insufficiency are not associated with WMH. A decrease of 25 nmol/L in 25(OH)D levels was associated with WMH, but this result will have to be confirmed. Prospective trials, both cross-sectional and longitudinal, are necessary to examine the association between 25(OH)D levels and WMH.