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.

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.

Microstructural Impairments in a Topologically Distinct Prefrontal-Habenular Connection in Cocaine Addiction

Drug addiction is characterized by neuroadaptations in mesocorticolimbic networks regulating reward and inhibitory control. The habenula (Hb) is central to adaptive reward and aversion-driven behaviors, serving as a hub connecting emotion/cognitive processing regions including the prefrontal cortex (PFC). However, its role in human drug addiction has not been fully explored. Using diffusion tractography, we detailed PFC structural connectivity with three regions, namely the Hb, ventral tegmental area (VTA), and anterior thalamus (AT), and quantified the tract-specific microstructural integrity using diffusion tensor imaging within the anterior limb of the internal capsule (ALIC) in healthy and cocaine-addicted individuals. White matter microstructure in cocaine-addicted individuals was uniquely impaired in PFC-Hb projections in the ALIC, distinguishable from adjacent PFC-VTA and PFC-AT projections, with more pronounced abnormalities in short-term abstinence. These findings extend preclinical evidence of PFC-Hb circuit impairments in addiction and contextualize the plausible existence of a similar PFC-Hb connection in the human brain.

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD). This condition contributes to about 50% of dementias worldwide, a massive health burden in aging. Microstructural alterations in the deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in the superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In this paper, 141 patients with CSVD were studied. Processing speed was assessed by the completion time of the Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (lesion volume on T2-FLAIR) and diffusion MRI, including DTI and free-water (FW) imaging microstructure measures. The results of our study indicate that the superficial white matter may play a particularly important role in cognitive decline in CSVD. SWM imaging measures resulted in a large contribution to processing speed, despite a relatively small WMH burden in the SWM. SWM FW had the strongest association with processing speed among all imaging markers and, unlike the other diffusion MRI measures, significantly increased between two patient subgroups with the lowest WMH burdens (possibly representing early stages of disease). When comparing two patient subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Given significant effects of WMH volume and regional FW on processing speed, we performed a mediation analysis. SWM FW was found to fully mediate the association between WMH volume and processing speed, while no mediation effect of DWM FW was observed. Overall, our findings identify SWM abnormalities in CSVD and suggest that the SWM has an important contribution to processing speed. Results indicate that FW in the SWM is a sensitive marker of microstructural changes associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes in future research.

SYT1 Gene-Wide Analysis on White Matter Microstructure in Adulthood ADHD

The Synaptotagmin-1 encoding gene (SYT1) is a key regulator of neurotransmitter release and is associated with cognitive and psychiatric phenotypes in GWAS, and with ADHD in single-gene studies, raising the need for dissecting possible cross-trait effects on clinical and brain phenotypes. Inferences about white matter microstructure can be made by diffusion-tensor imaging (DTI), which makes this method a promising tool in the understanding of biological changes that underpin cognitive functions and brain disorders. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects multiple functioning domains, highly overlapping with other psychiatric disorders, and known to involve white matter abnormalities and neurotransmission dysfunction. Using a set-based analysis, the present study investigates how genetic variants within SYT1 might affect brain white matter at a cellular level using DTI in adults with ADHD (n = 85). The combined effect of all measured variations in the gene (i.e., 468 variants) was evaluated concerning specific white matter tracts. Set-based analysis was performed in PLINK software and followed by in silico analysis of all variants included in the study. SYT1 gene was nominally associated with white matter changes in two important tracts: forceps major and inferior fronto-occipital fasciculus. In addition, two regions within the SYT1 have more consistent associations with different white matter tracts. These findings endorse the involvement of SYT1 on psychiatric phenotypes and suggest that white matter tracts underlie this complex relationship.

Widespread White Matter Microstructure Alterations Based on Diffusion Tensor Imaging and Diffusion Kurtosis Imaging in Patients With Pontine Infarction

Neurological deficits after stroke are closely related to white matter microstructure damage. However, secondary changes in white matter microstructure after pontine infarction (PI) in the whole brain remain unclear. This study aimed to investigate the correlation of diffusion kurtosis imaging (DKI)-derived diffusion and kurtosis parameters of abnormal white matter tracts with behavioral function in patients with chronic PI. Overall, 60 patients with unilateral chronic PI (33 patients with left PI and 27 patients with right PI) and 30 normal subjects were recruited and underwent DKI scans. Diffusion parameters derived from diffusion tensor imaging (DTI) and DKI and kurtosis parameters derived from DKI were obtained. Between-group differences in multiple parameters were analyzed to assess the changes in abnormal white matter microstructure. Moreover, we also calculated the sensitivities of different diffusion and kurtosis parameters of DTI and DKI for identifying abnormal white matter tracts. Correlations between the DKI-derived parameters in secondary microstructure changes and behavioral scores in the PI were analyzed. Compared with the NC group, both left PI and right PI groups showed more extensive perilesional and remote white matter microstructure changes. The DKI-derived diffusion parameters showed higher sensitivities than did the DTI-derived parameters. Further, DKI-derived diffusion and kurtosis parameters in abnormal white matter regions were correlated with impaired motor and cognitive function in patients with PI. In conclusion, PI could lead to extensive white matter tracts impairment in perilesional and remote regions. Further, the diffusion and kurtosis parameters could be complementary for identifying comprehensive tissue microstructural damage after PI.

Association Study Between White Matter Microstructure and Intelligence Decline in Schizophrenia

Patients with schizophrenia can exhibit intelligence decline, which is an important element of cognitive impairment. Previous magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have altered gray matter structures and functional connectivity associated with intelligence decline defined by a difference between premorbid and current intelligence quotients (IQs). However, it has remained unclear whether white matter microstructures are related to intelligence decline. In the present study, the indices of diffusion tensor imaging (DTI) obtained from 138 patients with schizophrenia and 554 healthy controls were analyzed. The patients were classified into three subgroups based on intelligence decline: deteriorated (94 patients), preserved (42 patients), and compromised IQ (2 patients) groups. Given that the DTI of each subject was acquired using either one of two different MRI scanners, we analyzed DTI indices separately for each scanner group. In the comparison between the deteriorated IQ group and the healthy controls, differences in some DTI indices were noted in three regions of interest irrespective of the MRI scanners, whereas differences in only one region of interest were noted between the preserved IQ group and the healthy controls. However, the comparisons between the deteriorated and preserved IQ groups did not show any reproducible differences. Together with the previous findings, it is thought that gray matter structures and functional connectivity are more promising as markers of intelligence decline in schizophrenia than white matter microstructures.

Segmental Abnormalities of White Matter Microstructure in End-Stage Renal Disease Patients: An Automated Fiber Quantification Tractography Study

Background and Purpose: End-stage renal disease (ESRD) results in extensive white matter abnormalities, but the specific damage segment cannot be identified. This study aimed to determine the segmental abnormalities of white matter microstructure in ESRD and its relationship with cognitive and renal function indicators.Methods: Eighteen ESRD patients and 19 healthy controls (HCs) were prospectively recruited. All participants underwent DTI and clinical assessments. Automatic fiber quantification (AFQ) was applied to generate bundle profiles along 16 main white matter tracts. We compared the DTI parameters between groups. Besides, we used partial correlation and multiple linear regression analyses to explore the associations between white matter integrity and cognitive performance as well as renal function indicators.Results: In the global tract level, compared to HCs, ESRD patients had greater MD, AD, and RD values and lower FA value in several fibers (P < 0.05, FDR correction). In the point-wise level, extensive damage existed in specific locations of different fiber tracts, particularly in the left hemisphere (P < 0.05, FDR correction). Among these tracts, the mean AD values of the left cingulum cingulate correlated negatively with MoCA score. Urea and UA level were independent predictors of the AD value of superior component of the left corticospinal. Besides, urea level was the independent predictors of mean MD value of left anterior thalamic radiation (ATR).Conclusion: White matter fiber tract damage in ESRD patients may be characterized by abnormalities in its specific location, especially in the left hemisphere. Aberrational specific located fibers were related to cognitive impairment and renal dysfunction.