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The ability to communicate with conspecifics is an adaptive behavior important for survival and reproduction, particularly in lineages that evolved enlarged brains and complex social behavior. In humans, language is supported by a robust, left-lateralized white matter fiber tract called the arcuate fasciculus, which links Broca's and Wernicke's areas, the core neocortical language regions located in the frontal and temporal lobes, respectively 1 . This tract is also present in chimpanzees, less substantial than in humans and either weakly leftwardly-asymmetric or not asymmetric 2 . Other mammalian lineages have evolved large brains, complex behavior and social communication in parallel with primates, notably including carnivores. In dogs (Canis familiaris), domestication has almost certainly involved additional selective pressures and environmental factors that have shaped the evolution and development of neural circuits for communication. We report that the dog brain possesses a large, left-lateralized white matter tract that links cortical centers for productive and receptive communication, and that this tract is positively associated with individual variation in receptive vocabulary size., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cognitive control processes enable the suppression of automatic behaviors and the initiation of appropriate responses. The Stroop color naming task serves as a benchmark paradigm for understanding the neurobiological model of verbal cognitive control. Previous research indicates a predominant engagement of the prefrontal and premotor cortex during the Stroop task compared to reading. We aim to further this understanding by creating a dynamic atlas of task-preferential modulations of functional connectivity through white matter. Patients undertook word-reading and Stroop tasks during intracranial EEG recording. We quantified task-related high-gamma amplitude modulations at 547 nonepileptic electrode sites, and a mixed model analysis identified regions and timeframes where these amplitudes differed between tasks. We then visualized white matter pathways with task-preferential functional connectivity enhancements at given moments. Word reading, compared to the Stroop task, exhibited enhanced functional connectivity in inter- and intra-hemispheric white matter pathways from the left occipital-temporal region 350-600 ms before response, including the posterior callosal fibers as well as the left vertical occipital, inferior longitudinal, inferior fronto-occipital, and arcuate fasciculi. The Stroop task showed enhanced functional connectivity in the pathways from the left middle-frontal pre-central gyri, involving the left frontal u-fibers and anterior callosal fibers. Automatic word reading largely utilizes the left occipital-temporal cortices and associated white matter tracts. Verbal cognitive control predominantly involves the left middle frontal and precentral gyri and its connected pathways. Our dynamic tractography atlases may serve as a novel resource providing insights into the unique neural dynamics and pathways of automatic reading and verbal cognitive control., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The processing of auditory stimuli which are structured in time is thought to involve the arcuate fasciculus, the white matter tract which connects the temporal cortex and the inferior frontal gyrus. Research has indicated effects of both musical and language experience on the structural characteristics of the arcuate fasciculus. Here, we investigated in a sample of n = 84 young adults whether continuous conceptualizations of musical and multilingual experience related to structural characteristics of the arcuate fasciculus, measured using diffusion tensor imaging. Probabilistic tractography was used to identify the dorsal and ventral parts of the white matter tract. Linear regressions indicated that different aspects of musical sophistication related to the arcuate fasciculus' volume (emotional engagement with music), volumetric asymmetry (musical training and music perceptual abilities), and fractional anisotropy (music perceptual abilities). Our conceptualization of multilingual experience, accounting for participants' proficiency in reading, writing, understanding, and speaking different languages, was not related to the structural characteristics of the arcuate fasciculus. We discuss our results in the context of other research on hemispheric specializations and a dual-stream model of auditory processing., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

In adults, individual differences in procedural learning (PL) are associated with white matter organization within the basal ganglia-cerebellar circuit. However, no research has examined whether this circuitry is related to individual differences in PL during childhood. Here, 28 children (M age  = 10.00 ± 2.31, 10 female) completed the serial reaction time (SRT) task to measure PL, and underwent structural magnetic resonance imaging (MRI). Fixel-Based Analysis was performed to extract specific measures of white matter fiber density (FD) and fiber cross-section (FC) from the superior cerebellar peduncles (SCP) and the striatal premotor tracts (STPMT), which underlie the fronto-basal ganglia-cerebellar system. These fixel metrics were correlated with the 'rebound effect' from the SRT task - a measure of PL proficiency which compares reaction times associated with generating a sequence, to random trials. While no significant associations were observed at the fixel level, a significant positive association was observed between average FD in the right SCP and the rebound effect, with a similar trend observed in the left SCP. No significant effects were detected in the STPMT. Our results indicate that, like in adults, microstructure of the basal ganglia-cerebellar circuit may explain individual differences in childhood PL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We determined the intersubject association between the rhythmic entrainment abilities of human subjects during a synchronization-continuation tapping task (SCT) and the macro- and microstructural properties of their superficial (SWM) and deep (DWM) white matter. Diffusion-weighted images were obtained from 32 subjects who performed the SCT with auditory or visual metronomes and five tempos ranging from 550 to 950 ms. We developed a method to determine the density of short-range fibers that run underneath the cortical mantle, interconnecting nearby cortical regions (U-fibers). Notably, individual differences in the density of U-fibers in the right audiomotor system were correlated with the degree of phase accuracy between the stimuli and taps across subjects. These correlations were specific to the synchronization epoch with auditory metronomes and tempos around 1.5 Hz. In addition, a significant association was found between phase accuracy and the density and bundle diameter of the corpus callosum (CC), forming an interval-selective map where short and long intervals were behaviorally correlated with the anterior and posterior portions of the CC. These findings suggest that the structural properties of the SWM and DWM in the audiomotor system support the tapping synchronization abilities of subjects, as cortical U-fiber density is linked to the preferred tapping tempo and the bundle properties of the CC define an interval-selective topography., Competing Interests: PG, Cd, FM, LC No competing interests declared, HM Reviewing editor, eLife, (© 2024, Garcia-Saldivar et al.)

Despite the important role of motor imagery (MI) in motor development, our understanding of the contribution of white matter fibre properties to MI performance in childhood remains limited. To provide novel insight into the white matter correlates of MI performance, this study examined the association between white matter fibre properties and motor imagery performance in a sample of typically developing children. High angular diffusion weighted imaging data were collected from 22 typically developing children aged 6-14 years (12 female, M Age = 10.56). Implicit motor imagery performance was assessed using a mental hand rotation paradigm. The cerebellar peduncles and the superior longitudinal fasciculus were reconstructed using TractSeg, a semi-automated method. For each tract, white matter microstructure (fibre density, FD) and morphology (fibre bundle cross-section, FC) were estimated using Fixel-Based Analysis. Permutation-based inference testing and partial correlation analyses demonstrated that higher FC in the middle cerebellar peduncles was associated with better MI performance. Tract-based region of interest analyses showed that higher FC in the middle and superior cerebellar peduncles were associated with better MI performance. Results suggest that white matter connectivity along the cerebellar peduncles may facilitate MI performance in childhood. These findings advance our understanding of the neurobiological systems that underlie MI performance in childhood and provide early evidence for the relevance of white matter sensorimotor pathways to internal action representations., (© 2024. The Author(s).)

Objectives: To investigate potential effects of heading on the neurocognitive performance and the white matter (WM) of the brain in high-level adult male football players., Design: Prospective longitudinal., Methods: Football players engaging in the highest football leagues in Germany were included. Neurocognitive performance tests and diffusion tensor imaging (DTI) were executed before and after the observation period. Video recordings of each training session and each match play during the observation period were analyzed regarding heading exposure and characteristics. Four DTI measures from tract-based spatial statistics (fractional anisotropy, mean, axial, and radial diffusivity) were investigated. Associations between heading variables and DTI and neurocognitive parameters were tested subsequently., Results: 8052 headers of 22 players (19.9 ± 2.7 years) were documented in a median of 16.9 months. The individual total heading number ranged from 57 to 943 (median: 320.5). Header characteristics differed between training sessions and matches. Neurocognitive performance (n = 22) and DTI measures (n = 14) showed no significant differences from pre- to post-test. After correction for multiple comparisons, no significant correlations with the total heading number were found. However, the change in fractional anisotropy in the splenium of the corpus callosum correlated significantly with the total amount of long-distance headers (Pearson's r = -0.884; p < 0.0001)., Conclusions: Over the median observation period of 16.9 months, DTI measures and neurocognitive performance remained unchanged. To elucidate the meaning of the association between individual change in fractional anisotropy and long-distance headers further investigations with larger samples, longer observations, and various cohorts regarding age and level of play are required., Competing Interests: Declaration of interest statement CR receives scientific funding for projects on traumatic brain injuries and heading from the Federal Institute of Sports Sciences (Germany) and the Heinz Nixdorf Westfalian Foundation. He is a member of the medical committee of the German Football association (DFB) and provides counseling on the management of traumatic brain injury to the Union of European Football Associations (UEFA). All other authors declare no conflicting interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Table tennis training has been employed as an exercise treatment to enhance cognitive brain functioning in patients with mental illnesses. However, research on its underlying mechanisms remains limited. In this study, we investigated functional and structural changes in large-scale brain regions between 20 table tennis players (TTPs) and 21 healthy controls (HCs) using 7-Tesla magnetic resonance imaging (MRI) techniques. Compared with those of HCs, TTPs exhibited significantly greater fractional anisotropy (FA) and axial diffusivity (AD) values in multiple fiber tracts. We used the locations with the most significant structural changes in white matter as the seed areas and then compared static and dynamic functional connectivity (sFC and dFC). Brodmann 11, located in the orbitofrontal cortex, showed altered dFC values to large-scale brain regions, such as the occipital lobe, thalamus, and cerebellar hemispheres, in TTPs. Brodmann 48, located in the temporal lobe, showed altered dFC to the parietal lobe, frontal lobe, cerebellum, and occipital lobe. Furthermore, the AD values of the forceps minor (Fmi) and right anterior thalamic radiations (ATRs) were negatively correlated with useful field of view (UFOV) test scores in TTPs. Our results suggest that table tennis players exhibit a unique pattern of dynamic neural activity, this provides evidence for potential mechanisms through which table tennis interventions can enhance attention and other cognitive functions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We aimed to examine the white matter changes associated with lexical production difficulties, beginning in midlife with increased naming latencies. To delay lexical production decline, middle-aged adults may rely on domain-general and language-specific compensatory mechanisms proposed by the LARA model (Lexical Access and Retrieval in Aging). However, the white matter changes supporting these mechanisms remains largely unknown. Using data from the CAMCAN cohort, we employed an unsupervised and data-driven methodology to examine the relationships between diffusion-weighted imaging and lexical production. Our findings indicate that midlife is marked by alterations in brain structure within distributed dorsal, ventral, and anterior cortico-subcortical networks, marking the onset of lexical production decline around ages 53-54. Middle-aged adults may initially adopt a "semantic strategy" to compensate for lexical production challenges, but this strategy seems compromised later (ages 55-60) as semantic control declines. These insights underscore the interplay between domain-general and language-specific processes in the trajectory of lexical production performance in healthy aging and hint at potential biomarkers for language-related neurodegenerative pathologies., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sustained attention is important for maintaining cognitive function and autonomy during ageing, yet older people often show reductions in this domain. The role of the underlying neurobiology is not yet well understood, with most neuroimaging studies primarily focused on fMRI. Here, we utilise sMRI to investigate the relationships between age, structural brain volumes and sustained attention performance. Eighty-nine healthy older adults (50-84 years, M age 65.5 (SD=8.4) years, 74 f) underwent MRI brain scanning and completed two sustained attention tasks: a rapid visual information processing (RVP) task and sustained attention to response task (SART). Independent hierarchical linear regressions demonstrated that greater volumes of white matter hyperintensities (WMH) were associated with worse RVP&#95;A' performance, whereas greater grey matter volumes were associated with better RVP&#95;A' performance. Further, greater cerebral white matter volumes were associated with better SART&#95;d' performance. Importantly, mediation analyses revealed that both grey and white matter volumes completely mediated the relationship between ageing and sustained attention. These results explain disparate attentional findings in older adults, highlighting the intervening role of brain structure., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Human brain gray matter (GM) has usually been clustered into multiple functional networks. The white matter (WM) fiber bundles are known to interconnect these networks simultaneously, engaging in numerous cognitive functions. However, the exact interconnections between GM and WM are still unclear, whether functional signals in WM rewires GM community organization remains to be explored. In this study, we divided brain functional connections into three types by using edge-centric method, including intra-GM, intra-WM and GM-WM connections, and calculated the edge community evaluation indexes for quantifying GM community engagement. The results showed that the involvement of WM significantly enhanced community entropy in the heteromodal system, while the sensory-attention system remained barely changed. In addition, delta community entropy showed a significant correlation with clinical cognitive scale. Our results suggested that WM rewired GM community organization, enhancing the community engagement of brain regions in the heteromodal system. This involvement was observed to be disrupted in disease groups. Our study revealed that considering the functional signals of GM and WM simultaneously could better understand the brain's functional organization., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest relevant to this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The tendency to show the renewal effect of extinction appears as an intra-individually stable, reproducible processing strategy associated with differential patterns of BOLD activation in hippocampus, iFG and vmPFC, as well as differential resting-state functional connectivity between prefrontal regions and the dorsal attention network. Also, pharmacological modulations of the noradrenergic system that influence attentional processing have partially different effects upon individuals with (REN) and without (NoREN) a propensity for renewal. However, it is as yet unknown whether REN and NoREN individuals differ regarding microstructural properties in attention-related white matter (WM) regions, and whether such differences are related to noradrenergic processing. In this diffusion tensor imaging (DTI) analysis we investigated the relation between microstructural properties of attention-related WM tracts and ABA renewal propensity, under conditions of noradrenergic stimulation by means of the noradrenergic reuptake inhibitor atomoxetine, compared to placebo. Fractional anisotropy (FA) was higher in participants with noradrenergic stimulation (ATO) compared to placebo (PLAC), the effect was predominantly left-lateralized and based on the comparison of ATO REN and PLAC REN participants. In REN participants of both treatment groups, FA in several WM tracts showed a positive correlation with the ABA renewal level, suggesting higher renewal levels were associated with higher microstructural integrity. These findings point towards a relation between microstructural properties of attention-related WM tracts and the propensity for renewal that is not specifically dependent on noradrenergic processing., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Learning new motor skills relies on neural plasticity within motor and limbic systems. This study uniquely combined diffusion tensor imaging and multiparametric mapping MRI to detail these neuroplasticity processes. We recruited 18 healthy male participants who underwent 960 min of training on a computer-based motion game, while 14 were scanned without training. Diffusion tensor imaging, which quantifies tissue microstructure by measuring the capacity for, and directionality of, water diffusion, revealed mostly linear changes in white matter across the corticospinal-cerebellar-thalamo-hippocampal circuit. These changes related to performance and reflected different responses to upper- and lower-limb training in brain areas with known somatotopic representations. Conversely, quantitative MRI metrics, sensitive to myelination and iron content, demonstrated mostly quadratic changes in gray matter related to performance and reflecting somatotopic representations within the same brain areas. Furthermore, while myelin and iron-sensitive multiparametric mapping MRI was able to describe time lags between different cortical brain systems, diffusion tensor imaging detected time lags within the white matter of the motor systems. These findings suggest that motor skill learning involves distinct phases of white and gray matter plasticity across the sensorimotor network, with the unique combination of diffusion tensor imaging and multiparametric mapping MRI providing complementary insights into the underlying neuroplastic responses., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The balance between goal-directed and habitual control has been proposed to determine the flexibility of instrumental behaviour, in both humans and animals. This view is supported by neuroscientific studies that have implicated dissociable neural pathways in the ability to flexibly adjust behaviour when outcome values change. A previous Diffusion Tensor Imaging study provided preliminary evidence that flexible instrumental performance depends on the strength of parallel cortico-striatal white-matter pathways previously implicated in goal-directed and habitual control. Specifically, estimated white-matter strength between caudate and ventromedial prefrontal cortex correlated positively with behavioural flexibility, and posterior putamen-premotor cortex connectivity correlated negatively, in line with the notion that these pathways compete for control. However, the sample size of the original study was limited, and so far, there have been no attempts to replicate these findings. In the present study, we aimed to conceptually replicate these findings by testing a large sample of 205 young adults to relate cortico-striatal connectivity to performance on the slips-of-action task. In short, we found only positive neural correlates of goal-directed performance, including striatal connectivity (caudate and anterior putamen) with the dorsolateral prefrontal cortex. However, we failed to provide converging evidence for the existence of a neural habit system that puts limits on the capacity for flexible, goal-directed action. We discuss the implications of our findings for dual-process theories of instrumental action., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The macroscale connectome is the network of physical, white-matter tracts between brain areas. The connections are generally weighted and their values interpreted as measures of communication efficacy. In most applications, weights are either assigned based on imaging features-e.g. diffusion parameters-or inferred using statistical models. In reality, the ground-truth weights are unknown, motivating the exploration of alternative edge weighting schemes. Here, we explore a multi-modal, regression-based model that endows reconstructed fiber tracts with directed and signed weights. We find that the model fits observed data well, outperforming a suite of null models. The estimated weights are subject-specific and highly reliable, even when fit using relatively few training samples, and the networks maintain a number of desirable features. In summary, we offer a simple framework for weighting connectome data, demonstrating both its ease of implementation while benchmarking its utility for typical connectome analyses, including graph theoretic modeling and brain-behavior associations., (© 2024. The Author(s).)

Objective: With a globally aging population, there is a need to better understand how brain structure relates to function in healthy older and younger adults., Methods: 34 healthy participants divided into older (17; Mean = 70.9, SD = 5.4) and younger adults (17; Mean = 28.1, SD = 2.8) underwent diffusion-weighted imaging and neuropsychological assessment, including the California Verbal Learning Test 2nd Edition and the Trail Making Test (TMT-A and TMT-B). Differences in white matter microstructure for older and younger adults and the association between DTI metrics (fractional anisotropy, FA; mean diffusivity, MD) and cognitive performance were analyzed using tract-based spatial statistics (p < 0.05, corrected)., Results: Older adults had significantly lower FA and higher MD than younger adults in widespread brain regions. There was a significant negative correlation between executive function (TMT-B) and MD for older adults in the right superior/anterior corona radiata and the corpus callosum. No significant relationship was detected between DTI metrics and executive function in younger adults or with memory performance in either group., Conclusions: The findings underscore the need to examine brain-behaviour relationships as a function of age. Future studies should include comprehensive assessments in larger lifespan samples to better understand the aging brain., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sheriff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human learning varies greatly among individuals and is related to the microstructure of major white matter tracts in several learning domains, yet the impact of the existing microstructure of white matter tracts on future learning outcomes remains unclear. We employed a machine-learning model selection framework to evaluate whether existing microstructure might predict individual differences in learning a sensorimotor task, and further, if the mapping between tract microstructure and learning was selective for learning outcomes. We used diffusion tractography to measure the mean fractional anisotropy (FA) of white matter tracts in 60 adult participants who then practiced drawing a set of 40 unfamiliar symbols repeatedly using a digital writing tablet. We measured drawing learning as the slope of draw duration over the practice session and measured visual recognition learning for the symbols using an old/new 2-AFC task. Results demonstrated that tract microstructure selectively predicted learning outcomes, with left hemisphere pArc and SLF3 tracts predicting drawing learning and the left hemisphere MDLFspl predicting visual recognition learning. These results were replicated using repeat, held-out data and supported with complementary analyses. Results suggest that individual differences in the microstructure of human white matter tracts may be selectively related to future learning outcomes., (© 2024. The Author(s).)

A variation of the longitudinal relaxation time T 1 in brain regions that differ in their main fiber direction has been occasionally reported, however, with inconsistent results. Goal of the present study was to clarify such inconsistencies, and the origin of potential T 1 orientation dependence, by applying direct sample rotation and comparing the results from different approaches to measure T 1 . A section of fixed porcine spinal cord white matter was investigated at 3 T with variation of the fiber-to-field angle θ FB . The experiments included one-dimensional inversion-recovery, MP2RAGE, and variable flip-angle T 1 measurements at 22 °C and 36 °C as well as magnetization-transfer (MT) and diffusion-weighted acquisitions. Depending on the technique, different degrees of T 1 anisotropy (between 2 and 10%) were observed as well as different dependencies on θ FB (monotonic variation or T 1 maximum at 30-40°). More pronounced anisotropy was obtained with techniques that are more sensitive to MT effects. Furthermore, strong correlations of θ FB -dependent MT saturation and T 1 were found. A comprehensive analysis based on the binary spin-bath model for MT revealed an interplay of several orientation-dependent parameters, including the transverse relaxation times of the macromolecular and the water pool as well as the longitudinal relaxation time of the macromolecular pool., (© 2024. The Author(s).)

Despite the clinical significance of narcissistic personality, its neural bases have not been clarified yet, primarily because of methodological limitations of the previous studies, such as the low sample size, the use of univariate techniques and the focus on only one brain modality. In this study, we employed for the first time a combination of unsupervised and supervised machine learning methods, to identify the joint contributions of grey matter (GM) and white matter (WM) to narcissistic personality traits (NPT). After preprocessing, the brain scans of 135 participants were decomposed into eight independent networks of covarying GM and WM via parallel ICA. Subsequently, stepwise regression and Random Forest were used to predict NPT. We hypothesized that a fronto-temporo parietal network, mainly related to the default mode network, may be involved in NPT and associated WM regions. Results demonstrated a distributed network that included GM alterations in fronto-temporal regions, the insula and the cingulate cortex, along with WM alterations in cerebellar and thalamic regions. To assess the specificity of our findings, we also examined whether the brain network predicting narcissism could also predict other personality traits (i.e., histrionic, paranoid and avoidant personalities). Notably, this network did not predict such personality traits. Additionally, a supervised machine learning model (Random Forest) was used to extract a predictive model for generalization to new cases. Results confirmed that the same network could predict new cases. These findings hold promise for advancing our understanding of personality traits and potentially uncovering brain biomarkers associated with narcissism., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Healthy older adults often exhibit lower performance but increased functional recruitment of the frontoparietal control network during cognitive control tasks. According to the cortical disconnection hypothesis, age-related changes in the microstructural integrity of white matter may disrupt inter-regional neuronal communication, which in turn can impair behavioral performance. Here, we use fMRI and diffusion-weighted imaging to determine whether age-related differences in white matter microstructure contribute to frontoparietal over-recruitment and behavioral performance during a response inhibition (go/no-go) task in an adult life span sample (n = 145). Older and female participants were slower (go RTs) than younger and male participants, respectively. However, participants across all ages were equally accurate on the no-go trials, suggesting some participants may slow down on go trials to achieve high accuracy on no-go trials. Across the life span, functional recruitment of the frontoparietal network within the left and right hemispheres did not vary as a function of age, nor was it related to white matter fractional anisotropy (FA). In fact, only frontal FA and go RTs jointly mediated the association between age and no-go accuracy. Our results therefore suggest that frontal white matter cortical "disconnection" is an underlying driver of age-related differences in cognitive control, and white matter FA may not fully explain functional task-related activation in the frontoparietal network during the go/no-go task. Our findings add to the literature by demonstrating that white matter may be more important for certain cognitive processes in aging than task-related functional activation., (© 2024 Massachusetts Institute of Technology.)

Objective: In tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance., Methods: Patients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts., Results: Elevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76., Conclusions: Optimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways., Significance: This study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We report the reliable detection of reproducible patterns of blood-oxygenation-level-dependent (BOLD) MRI signals within the white matter (WM) of the spinal cord during a task and in a resting state. Previous functional MRI studies have shown that BOLD signals are robustly detectable not only in gray matter (GM) in the brain but also in cerebral WM as well as the GM within the spinal cord, but similar signals in WM of the spinal cord have been overlooked. In this study, we detected BOLD signals in the WM of the spinal cord in squirrel monkeys and studied their relationships with the locations and functions of ascending and descending WM tracts. Tactile sensory stimulus -evoked BOLD signal changes were detected in the ascending tracts of the spinal cord using a general-linear model. Power spectral analysis confirmed that the amplitude at the fundamental frequency of the response to a periodic stimulus was significantly higher in the ascending tracts than the descending ones. Independent component analysis of resting-state signals identified coherent fluctuations from eight WM hubs which correspond closely to the known anatomical locations of the major WM tracts. Resting-state analyses showed that the WM hubs exhibited correlated signal fluctuations across spinal cord segments in reproducible patterns that correspond well with the known neurobiological functions of WM tracts in the spinal cord. Overall, these findings provide evidence of a functional organization of intraspinal WM tracts and confirm that they produce hemodynamic responses similar to GM both at baseline and under stimulus conditions., Competing Interests: Competing interests statement:The authors declare no competing interest.

The global ageing of populations calls for effective, ecologically valid methods to support brain health across adult life. Previous evidence suggests that music can promote white matter (WM) microstructure and grey matter (GM) volume while supporting auditory and cognitive functioning and emotional well-being as well as counteracting age-related cognitive decline. Adding a social component to music training, choir singing is a popular leisure activity among older adults, but a systematic account of its potential to support healthy brain structure, especially with regard to ageing, is currently missing. The present study used quantitative anisotropy (QA)-based diffusion MRI connectometry and voxel-based morphometry to explore the relationship of lifetime choir singing experience and brain structure at the whole-brain level. Cross-sectional multiple regression analyses were carried out in a large, balanced sample (N = 95; age range 21-88) of healthy adults with varying levels of choir singing experience across the whole age range and within subgroups defined by age (young, middle-aged, and older adults). Independent of age, choir singing experience was associated with extensive increases in WM QA in commissural, association, and projection tracts across the brain. Corroborating previous work, these overlapped with language and limbic networks. Enhanced corpus callosum microstructure was associated with choir singing experience across all subgroups. In addition, choir singing experience was selectively associated with enhanced QA in the fornix in older participants. No associations between GM volume and choir singing were found. The present study offers the first systematic account of amateur-level choir singing on brain structure. While no evidence for counteracting GM atrophy was found, the present evidence of enhanced structural connectivity coheres well with age-typical structural changes. Corroborating previous behavioural studies, the present results suggest that regular choir singing holds great promise for supporting brain health across the adult life span., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The generation of new myelin-forming oligodendrocytes in the adult central nervous system is critical for cognitive function and regeneration following injury. Oligodendrogenesis varies between gray and white matter regions, suggesting that local cues drive regional differences in myelination and the capacity for regeneration. However, the layer- and region-specific regulation of oligodendrocyte populations is unclear due to the inability to monitor deep brain structures in vivo. Here we harnessed the superior imaging depth of three-photon microscopy to permit long-term, longitudinal in vivo three-photon imaging of the entire cortical column and subcortical white matter in adult mice. We find that cortical oligodendrocyte populations expand at a higher rate in the adult brain than those of the white matter. Following demyelination, oligodendrocyte replacement is enhanced in the white matter, while the deep cortical layers show deficits in regenerative oligodendrogenesis and the restoration of transcriptional heterogeneity. Together, our findings demonstrate that regional microenvironments regulate oligodendrocyte population dynamics and heterogeneity in the healthy and diseased brain., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Resilient individuals are less likely to develop psychiatric disorders despite extreme psychological distress. This study investigated the multimodal structural neural correlates of dispositional resilience among healthy individuals. Participants included 92 healthy individuals. The Korean version of the Connor-Davidson Resilience Scale and other psychological measures were used. Gray matter volumes (GMVs), cortical thickness, local gyrification index (LGI), and white matter (WM) microstructures were analyzed using voxel-based morphometry, FreeSurfer, and tract-based spatial statistics, respectively. Higher resilient individuals showed significantly higher GMVs in the inferior frontal gyrus (IFG), increased LGI in the insula, and lower fractional anisotropy values in the superior longitudinal fasciculus II (SLF II). These resilience's neural correlates were associated with good quality of life in physical functioning or general health and low levels of depression. Therefore, the GMVs in the IFG, LGI in the insula, and WM microstructures in the SLF II can be associated with resilience that contributes to emotional regulation, empathy, and social cognition., (© 2024. The Author(s).)

The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10 -8 ). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG displayed the most pronounced heritability enrichment in genetic variants within conserved regions. Oligodendrocytes and astrocytes, but not neurons, exhibited notable heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several chronic diseases on brain aging, such as type 2 diabetes on GM-BAG and AD on WM-BAG. Our results provide insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at https://labs.loni.usc.edu/medicine ., (© 2024. The Author(s).)

Patients with bipolar disorder (BD) show higher immuno-inflammatory setpoints, with in vivo alterations in white matter (WM) microstructure and post-mortem infiltration of T cells in the brain. Cytotoxic CD8 + T cells can enter and damage the brain in inflammatory disorders, but little is known in BD. Our study aimed to investigate the relationship between cytotoxic T cells and WM alterations in BD. In a sample of 83 inpatients with BD in an active phase of illness (68 depressive, 15 manic), we performed flow cytometry immunophenotyping to investigate frequencies, activation status, and expression of cytotoxic markers in CD8 + and tested for their association with diffusion tensor imaging (DTI) measures of WM microstructure. Frequencies of naïve and activated CD8 + cell populations expressing Perforin, or both Perforin and Granzyme, negatively associated with WM microstructure. CD8 + Naïve cells negative for Granzyme and Perforin positively associates with indexes of WM integrity, while the frequency of CD8 + memory cells negatively associates with index of WM microstructure, irrespective of toxins expression. The resulting associations involve measures representative of orientational coherence and myelination of the fibers (FA and RD), suggesting disrupted oligodendrocyte-mediated myelination. These findings seems to support the hypothesis that immunosenescence (less naïve, more memory T cells) can detrimentally influence WM microstructure in BD and that peripheral CD8 + T cells may participate in inducing an immune-related WM damage in BD mediated by killer proteins., (© 2023. The Author(s).)

In this study, we propose a novel micromechanical model for the brain white matter, which is described as a heterogeneous material with a complex network of axon fibers embedded in a soft ground matrix. We developed this model in the framework of RVE-based multiscale theories in combination with the finite element method and the embedded element technique for embedding the fibers. Microstructural features such as axon diameter, orientation and tortuosity are incorporated into the model through distributions derived from histological data. The constitutive law of both the fibers and the matrix is described by isotropic one-term Ogden functions. The hyperelastic response of the tissue is derived by homogenizing the microscopic stress fields with multiscale boundary conditions to ensure kinematic compatibility. The macroscale homogenized stress is employed in an inverse parameter identification procedure to determine the hyperelastic constants of axons and ground matrix, based on experiments on human corpus callosum. Our results demonstrate the fundamental effect of axon tortuosity on the mechanical behavior of the brain's white matter. By combining histological information with the multiscale theory, the proposed framework can substantially contribute to the understanding of mechanotransduction phenomena, shed light on the biomechanics of a healthy brain, and potentially provide insights into neurodegenerative processes., (© 2023. The Author(s).)

Recent studies have revealed the production of time-locked blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals throughout the entire brain in response to tasks, challenging the existence of sparse and localized brain functions and highlighting the pervasiveness of potential false negative fMRI findings. "Whole-brain" actually refers to gray matter, the only tissue traditionally studied with fMRI. However, several reports have demonstrated reliable detection of BOLD signals in white matter, which have previously been largely ignored. Using simple tasks and analyses, we demonstrate BOLD signal changes across the whole brain, in both white and gray matters, in similar manner to previous reports of whole brain studies. We investigated whether white matter displays time-locked BOLD signals across multiple structural pathways in response to a stimulus in a similar manner to the cortex. We find that both white and gray matter show time-locked activations across the whole brain, with a majority of both tissue types showing statistically significant signal changes for all task stimuli investigated. We observed a wide range of signal responses to tasks, with different regions showing different BOLD signal changes to the same task. Moreover, we find that each region may display different BOLD responses to different stimuli. Overall, we present compelling evidence that, just like all gray matter, essentially all white matter in the brain shows time-locked BOLD signal changes in response to multiple stimuli, challenging the idea of sparse functional localization and the prevailing wisdom of treating white matter BOLD signals as artifacts to be removed.

Background: Deep brain stimulation of the subcallosal cingulate area (SCC-DBS) is a promising neuromodulatory therapy for treatment-resistant depression (TRD). Biomarkers of optimal target engagement are needed to guide surgical targeting and stimulation parameter selection and to reduce variance in clinical outcome., Objective/hypothesis: We aimed to characterize the relationship between stimulation location, white matter tract engagement, and clinical outcome in a large (n = 60) TRD cohort treated with SCC-DBS. A smaller cohort (n = 22) of SCC-DBS patients with differing primary indications (bipolar disorder/anorexia nervosa) was utilized as an out-of-sample validation cohort., Methods: Volumes of tissue activated (VTAs) were constructed in standard space using high-resolution structural MRI and individual stimulation parameters. VTA-based probabilistic stimulation maps (PSMs) were generated to elucidate voxelwise spatial patterns of efficacious stimulation. A whole-brain tractogram derived from Human Connectome Project diffusion-weighted MRI data was seeded with VTA pairs, and white matter streamlines whose overlap with VTAs related to outcome ('discriminative' streamlines; P uncorrected < 0.05) were identified using t-tests. Linear modelling was used to interrogate the potential clinical relevance of VTA overlap with specific structures., Results: PSMs varied by hemisphere: high-value left-sided voxels were located more anterosuperiorly and squarely in the lateral white matter, while the equivalent right-sided voxels fell more posteroinferiorly and involved a greater proportion of grey matter. Positive discriminative streamlines localized to the bilateral (but primarily left) cingulum bundle, forceps minor/rostrum of corpus callosum, and bilateral uncinate fasciculus. Conversely, negative discriminative streamlines mostly belonged to the right cingulum bundle and bilateral uncinate fasciculus. The best performing linear model, which utilized information about VTA volume overlap with each of the positive discriminative streamline bundles as well as the negative discriminative elements of the right cingulum bundle, explained significant variance in clinical improvement in the primary TRD cohort (R = 0.46, P < 0.001) and survived repeated 10-fold cross-validation (R = 0.50, P = 0.040). This model was also able to predict outcome in the out-of-sample validation cohort (R = 0.43, P = 0.047)., Conclusion(s): These findings reinforce prior indications of the importance of white matter engagement to SCC-DBS treatment success while providing new insights that could inform surgical targeting and stimulation parameter selection decisions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.M.L. is the co-founder of Functional Neuromodulation (a DBS-related company) and is a consultant for Boston Scientific, Medtronic and Abbott (companies that produce DBS hardware). H.S.M., P.G., and S.H.K. are consultants for Abbott. G.J.B.E., A.B., H.S.M, and A.M.L. have intellectual property in the field of DBS. All other authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging is a major risk factor for cognitive impairment. Aerobic exercise benefits brain function and may promote cognitive health in older adults. However, underlying biological mechanisms across cerebral gray and white matter are poorly understood. Selective vulnerability of the white matter to small vessel disease and a link between white matter health and cognitive function suggests a potential role for responses in deep cerebral microcirculation. Here, we tested whether aerobic exercise modulates cerebral microcirculatory changes induced by aging. To this end, we carried out a comprehensive quantitative examination of changes in cerebral microvascular physiology in cortical gray and subcortical white matter in mice (3-6 vs. 19-21 months old), and asked whether and how exercise may rescue age-induced deficits. In the sedentary group, aging caused a more severe decline in cerebral microvascular perfusion and oxygenation in deep (infragranular) cortical layers and subcortical white matter compared with superficial (supragranular) cortical layers. Five months of voluntary aerobic exercise partly renormalized microvascular perfusion and oxygenation in aged mice in a depth-dependent manner, and brought these spatial distributions closer to those of young adult sedentary mice. These microcirculatory effects were accompanied by an improvement in cognitive function. Our work demonstrates the selective vulnerability of the deep cortex and subcortical white matter to aging-induced decline in microcirculation, as well as the responsiveness of these regions to aerobic exercise., Competing Interests: PS, QP, HI, GH, EM, SG, BF, MA, SA, IŞ, BL, CR, SV, CA, EL, KA, AD, SS No competing interests declared, (© 2023, Shin et al.)

In sickle cell disease, the relative importance of reduced hemoglobin (Hb) and peripheral oxygen saturation on brain structure remains uncertain. We applied graph-theoretical analysis to diffusion magnetic resonance imaging data to investigate the effect of structural brain connectivity on cognitive function, alongside the presence or absence, number, and volume of silent cerebral infarction. In patients, we investigated the relationships between network properties, blood oxygenation, and cognition (working memory and processing speed indices). Based on streamline counts and fractional anisotropy, we identified a subnetwork with weakened connectivity in 92 patients with sickle cell disease (91 homozygous for HbS [HbSS], 1 heterozygote with HbSβ0 thalassemia; 49 males; aged 8.0 to 38.8 y), compared with 54 control subjects (22 males; aged 6.7 to 30.6 y). Multiple regression analyses showed a significant effect of Hb on full-network edge density (P < .05) and of peripheral oxygen saturation on streamline-weighted subnetwork efficiency (P < .01). There were effects of fractional anisotropy-weighted full-network and subnetwork efficiency on working memory index (both P < .05), and of streamline-weighted subnetwork efficiency on processing speed index (P = .05). However, there were no effects of presence, number or volume of silent cerebral infarcts. Streamline-weighted efficiency was progressively lower with lower oxygen saturation, with a downstream effect on the processing speed index. In path analysis, indirect relationships between blood oxygenation and cognition, mediated by network properties, were better supported than direct alternatives, with an indirect relationship between low oxygen saturation and processing speed index in patients, mediated by structural connectivity efficiency in a subnetwork of the brain differing from control subjects. Our findings are consistent with the notion that cognitive impairment is primarily mediated by hypoxic-ischemic effects on normal-appearing white matter and highlight the utility of network-based methods in providing biomarkers of cognitive dysfunction in patients with sickle cell disease., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

While functional MRI (fMRI) studies have mainly focused on gray matter, recent studies have consistently found that blood-oxygenation-level-dependent (BOLD) signals can be reliably detected in white matter, and functional connectivity (FC) has been organized into distributed networks in white matter. Nevertheless, it remains unclear whether this white matter FC reflects underlying electrophysiological synchronization. To address this question, we employ intracranial stereotactic-electroencephalography (SEEG) and resting-state fMRI data from a group of 16 patients with drug-resistant epilepsy. We find that BOLD FC is correlated with SEEG FC in white matter, and this result is consistent across a wide range of frequency bands for each participant. By including diffusion spectrum imaging data, we also find that white matter FC from both SEEG and fMRI are correlated with white matter structural connectivity, suggesting that anatomical fiber tracts underlie the functional synchronization in white matter. These results provide evidence for the electrophysiological and structural basis of white matter BOLD FC, which could be a potential biomarker for psychiatric and neurological disorders., (© 2023. The Author(s).)

Most prior research has 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, enhanced white matter (WM) structural microstructure has been hypothesized to support consistent behavioral performance by decreasing Gaussian noise in signal transfer. Conversely, lower indices of WM microstructure are associated with greater within-subject variance in the ability to deploy performance-related resources, especially in clinical populations. We tested a mechanistic account of the "neural noise" hypothesis in a large adult lifespan cohort (Cambridge Centre for Ageing and Neuroscience) with over 2500 adults (ages 18-102; 1508 female; 1173 male; 2681 behavioral sessions; 708 MRI scans) using WM fractional anisotropy to predict mean levels and variability in reaction time performance on a simple behavioral task using a dynamic structural equation model. By modeling robust and reliable individual differences in within-person variability, we found support for a neural noise hypothesis (Kail, 1997), with lower fractional anisotropy predicted individual differences in separable components of behavioral performance estimated using dynamic structural equation model, including slower mean responses and increased variability. These effects remained when including age, suggesting consistent effects of WM microstructure across the adult lifespan unique from concurrent effects of aging. Crucially, we show that variability can be reliably separated from mean performance using advanced modeling tools, enabling tests of distinct hypotheses for each component of performance. SIGNIFICANCE STATEMENT Human cognitive performance is defined not just by the long-run average, but trial-to-trial variability around that average. However, investigations of cognitive abilities and changes during aging have largely ignored this variability component of behavior. We provide evidence that white matter (WM) microstructure predicts individual differences in mean performance and variability in a sample spanning the adult lifespan (18-102). Unlike prior studies of cognitive performance and variability, we modeled variability directly and distinct from mean performance using a dynamic structural equation model, which allows us to decouple variability from mean performance and other complex features of performance (e.g., autoregression). The effects of WM were robust above the effect of age, highlighting the role of WM in promoting fast and consistent performance., (Copyright © 2023 McCormick et al.)

Biomechanical study of brain injuries originated from mechanical damages to white matter tissue requires detailed information on mechanical characteristics of its main components, the axonal fibers and extracellular matrix, which is very limited due to practical difficulties of direct measurement. In this paper, a new theoretical framework was established based on microstructural modeling of brain white matter tissue as a soft composite for bidirectional hyperelastic characterization of its main components. First the tissue was modeled as an Ogden hyperelastic material, and its principal Cauchy stresses were formulated in the axonal and transverse directions under uniaxial and equibiaxial tension using the theory of homogenization. Upon fitting these formulae to the corresponding experimental test data, direction-dependent hyperelastic constants of the tissue were obtained. These directional properties then were used to estimate the strain energy stored in the homogenized model under each loading scenario. A new microstructural composite model of the tissue was also established using principles of composites micromechanics, in which the axonal fibers and surrounding matrix are modeled as different Ogden hyperelastic materials with unknown constants. Upon balancing the strain energies stored in the homogenized and composite models under different loading scenarios, fully coupled nonlinear equations as functions of unknown hyperelastic constants were derived, and their optimum solutions were found in a multi-parametric multi-objective optimization procedure using the response surface methodology. Finally, these solutions were implemented, in a bottom-up approach, into a micromechanical finite element model to reproduce the tissue responses under the same loadings and predict the tissue responses under unseen non-equibiaxial loadings. Results demonstrated a very good agreement between the model predictions and experimental results in both directions under different loadings. Moreover, the axonal fibers with hyperelastic characteristics stiffer than the extracellular matrix were shown to play the dominant role in directional reinforcement of the tissue., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is growing evidence that blood-oxygen-level-dependent (BOLD) activity in the white matter (WM) can be detected by functional magnetic resonance imaging (fMRI). However, the functional relevance and significance of WM BOLD signals remain controversial. Here we investigated whether 7T BOLD fMRI can reveal fine-scale functional organizations of a WM bundle. Population receptive field (pRF) analyses of the 7T retinotopy dataset from the Human Connectome Project revealed clear contralateral retinotopic organizations of two visual WM bundles: the optic radiation (OR) and the vertical occipital fasciculus (VOF). The retinotopic maps of OR are highly consistent with post-mortem dissections and diffusion tractographies, while the VOF maps are compatible with the dorsal and ventral visual areas connected by the WM. Similar to the grey matter (GM) visual areas, both WM bundles show over-representations of the central visual field and increasing pRF size with eccentricity. Hemodynamic response functions of visual WM were slower and wider compared with those of GM areas. These findings clearly demonstrate that WM BOLD at 7 Tesla is closely coupled with neural activity related to axons, encoding highly specific information that can be used to characterize fine-scale functional organizations of a WM bundle., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sleep is an important contributor for neural maturation and emotion regulation during adolescence, with long-term effects on a range of white matter tracts implicated in affective processing in at-risk populations. We investigated the effects of adolescent sleep patterns on longitudinal changes in white matter development and whether this is related to the emergence of emotional (internalizing) problems. Sleep patterns and internalizing problems were assessed using self-report questionnaires in adolescents recruited in the general population followed up from age 14-19 years (N = 111 White matter structure was measured using diffusion tensor imaging (DTI) and estimated using fractional anisotropy (FA). We found that longitudinal increases in time in bed (TIB) on weekends and increases in TIB-variability between weekdays to weekend, were associated with an increase in FA in various interhemispheric and cortico-striatal tracts. Extracted FA values from left superior longitudinal fasciculus mediated the relationship between increases in TIB on weekends and a decrease in internalizing problems. These results imply that while insufficient sleep might have potentially harmful effects on long-term white matter development and internalizing problems, longer sleep duration on weekends (catch-up sleep) might be a natural counteractive and protective strategy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Banaschewski served in an advisory or consultancy role for ADHS digital, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker’s fee by Medice and Takeda. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. He has been involved in clinical trials conducted by Shire & Viforpharma. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. Dr Gowland has received a research grant from Lyndra and an honorarium paid to her employer from GlaxoSmithKline. The present work is unrelated to the above grants and relationships. Competing Interests Dr Banaschewski served in an advisory or consultancy role for ADHS digital, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker’s fee by Medice and Takeda. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. He has been involved in clinical trials conducted by Shire & Viforpharma. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. Dr Gowland has received a research grant from Lyndra and an honorarium paid to her employer from GlaxoSmithKline. The present work is unrelated to the above grants and relationships., (Copyright © 2023. Published by Elsevier Ltd.)

A novel finite element model is proposed to study the mechanical response of axons embedded in extracellular matrix when subjected to tensile loads under purely non-affine kinematic boundary conditions. Ogden hyperelastic material model describes the axons and the extracellular matrix material characterizations. Two axon-glia tethering scenarios in white matter are studied a single oligodendrocyte (single-OL) with multiple connections a multi-oligodendrocyte (multi-OL) one. In the multi-OL tethering configuration, resultant forces are randomly oriented as distributed glial cells arbitrarily wrap around axons in their immediate vicinity. In the single-OL setup, a centrally located oligodendrocyte myelinates multiple axons nearby. Tethering forces are directed towards this oligodendrocyte, resulting in greater directionality and farther-reaching stress distribution. The oligodendrocyte connections to axons are represented by a spring-dashpot model. The material properties of myelin served as the upper limit for the parameterization of the oligodendrocyte stiffness ("K"). The proposed FE models enable realization of connection mechanisms and their influence on axonal stiffness to determine resultant stress states accurately. Root mean square deviation analysis of stress-strain plots of different connection scenarios reveal an increasing axonal stiffness with increasing tethering, indicating the role of oligodendrocytes in stress redistribution. In single-OL submodel, for the same number of connections per axons, RMSD values increased as "K" (the oligodendrocyte spring stiffness) values were set higher. RMSD calculations reveal that for a "K" value, single-OL model yielded slightly stiffer models compared to multi-OL. The current study also addresses the potential geometrical limitations of multi-OL model by randomizing and adding connections to ensure greater responsiveness. Cyclic bending stresses noticed in both submodels suggest the risk of axonal damage accumulation and repeated load failure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Blood oxygenation level-dependent (BOLD) signals in the white matter (WM) have been demonstrated to encode neural activities by showing structure-specific temporal correlations during resting-state and task-specific imaging of fiber pathways with various degrees of correlations in strength and time delay. Previous neuroimaging studies have shown state-dependent functional connectivity and regional amplitude of signal fluctuations in brain gray matter across wakefulness and nonrapid eye movement (NREM) sleep cycles. However, the functional characteristics of WM during sleep remain unknown. Using simultaneous electroencephalography and functional magnetic resonance imaging data during wakefulness and NREM sleep collected from 66 healthy participants, we constructed 10 stable WM functional networks using clustering analysis. Functional connectivity between these WM functional networks and regional amplitude of WM signal fluctuations across multiple low-frequency bands were evaluated. In general, decreased WM functional connectivity between superficial and middle layer WM functional networks was observed from wakefulness to sleep. In addition, functional connectivity between the deep and cerebellar networks was higher during light sleep and lower during both wakefulness and deep sleep. The regional fluctuation amplitude was always higher during light sleep and lower during deep sleep. Importantly, slow-wave activity during deep sleep negatively correlated with functional connectivity between WM functional networks but positively correlated with fluctuation strength in the WM. These observations provide direct physiological evidence that neural activities in the WM are modulated by the sleep-wake cycle. This study provided the initial mapping of functional changes in WM during sleep., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Tractography enables identifying and evaluating the healthy and diseased brain's white matter pathways from diffusion-weighted magnetic resonance imaging data. As previous evaluation studies have reported significant false-positive estimation biases, recent microstructure-informed tractography algorithms have been introduced to improve the trade-off between specificity and sensitivity. However, a major limitation for characterizing the performance of these techniques is the lack of ground truth brain data. In this study, we compared the performance of two relevant microstructure-informed tractography methods, SIFT2 and COMMIT, by assessing the subject specificity and reproducibility of their derived white matter pathways. Specifically, twenty healthy young subjects were scanned at eight different time points at two different sites. Subject specificity and reproducibility were evaluated using the whole-brain connectomes and a subset of 29 white matter bundles. Our results indicate that although the raw tractograms are more vulnerable to the presence of false-positive connections, they are highly reproducible, suggesting that the estimation bias is subject-specific. This high reproducibility was preserved when microstructure-informed tractography algorithms were used to filter the raw tractograms. Moreover, the resulting track-density images depicted a more uniform coverage of streamlines throughout the white matter, suggesting that these techniques could increase the biological meaning of the estimated fascicles. Notably, we observed an increased subject specificity by employing connectivity pre-processing techniques to reduce the underlaying noise and the data dimensionality (using principal component analysis), highlighting the importance of these tools for future studies. Finally, no strong bias from the scanner site or time between measurements was found. The largest intraindividual variance originated from the sole repetition of data measurements (inter-run)., Competing Interests: Conflict of interest G.F.P., T.H., and T.K. are employees of Siemens Healthcare AG, Switzerland., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

A general linear model is widely used for analyzing fMRI data, in which the blood oxygenation-level dependent (BOLD) signals in gray matter (GM) evoked in response to neural stimulation are modeled by convolving the time course of the expected neural activity with a canonical hemodynamic response function (HRF) obtained a priori. The maps of brain activity produced reflect the magnitude of local BOLD responses. However, detecting BOLD signals in white matter (WM) is more challenging as the BOLD signals are weaker and the HRF is different, and may vary more across the brain. Here we propose a model-free approach to detect changes in BOLD signals in WM by measuring task-evoked increases of BOLD signal synchrony in WM fibers. The proposed approach relies on a simple assumption that, in response to a functional task, BOLD signals in relevant fibers are modulated by stimulus-evoked neural activity and thereby show greater synchrony than when measured in a resting state, even if their magnitudes do not change substantially. This approach is implemented in two technical stages. First, for each voxel a fiber-architecture-informed spatial window is created with orientation distribution functions constructed from diffusion imaging data. This provides the basis for defining neighborhoods in WM that share similar local fiber architectures. Second, a modified principal component analysis (PCA) is used to estimate the synchrony of BOLD signals in each spatial window. The proposed approach is validated using a 3T fMRI dataset from the Human Connectome Project (HCP) at a group level. The results demonstrate that neural activity can be reliably detected as increases in fMRI signal synchrony within WM fibers that are engaged in a task with high sensitivities and reproducibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Goal-directed behavior crucially relies on our capacity to suppress impulses and predominant behavioral responses. This ability, called inhibitory control, emerges in early childhood with marked improvements between 3 and 4 years. Here, we ask which brain structures are related to the emergence of this critical ability. Using a multimodal approach, we relate the pronounced behavioral improvements in different facets of 3- and 4-year-olds' ( N = 37, 20 female) inhibitory control to structural indices of maturation in the developing brain assessed with MRI. Our results show that cortical and subcortical structure of core regions in the adult cognitive control network, including the PFC, thalamus, and the inferior parietal cortices, is associated with early inhibitory functioning in preschool children. Probabilistic tractography revealed an association of frontoparietal (i.e., the superior longitudinal fascicle) and thalamocortical connections with early inhibitory control. Notably, these associations to brain structure were distinct for different facets of early inhibitory control, often referred to as motivational ("hot") and cognitive ("cold") inhibitory control. Our findings thus reveal the structural brain networks and connectivity related to the emergence of this core faculty of human cognition. SIGNIFICANCE STATEMENT The capacity to suppress impulses and behavioral responses is crucial for goal-directed behavior. This ability, called inhibitory control, develops between the ages of 3 and 4 years. The factors behind this developmental milestone have been debated intensely for decades; however, the brain structure that underlies the emergence of inhibitory control in early childhood is largely unknown. Here, we relate the pronounced behavioral improvements in inhibitory control between 3 and 4 years with structural brain markers of gray matter and white matter maturation. Using a multimodal approach that combines analyses of cortical surface structure, subcortical structures, and white matter connectivity, our results reveal the structural brain networks and connectivity related to this core faculty of human cognition., (Copyright © 2022 the authors.)

Background: The efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography., Objective: Leverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses., Methods: Evoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression - the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) - in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography., Results: Evoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials., Conclusion: The two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation., Competing Interests: Declaration of competing interest CCM is a paid consultant for Boston Scientific Neuromodulation, receives royalties from Hologram Consultants, Neuros Medical, Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, CereGate, Autonomic Technologies, Cardionomic, Enspire DBS. NP is a consultant for Abbott. SAS is a consultant for Boston Scientific, Zimmer Biomet, Neuropace, Abbott, and Koh Young. MM and RM are employees of Boston Scientific Corporation. KC is a paid full-time employee of Brainlab, Inc. JAA, ET, DO, BAM, RKM, ACW, MER, ABA, AMN, WG, DB, and KRB do not report biomedical financial interests or potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated the white matter correlates of personality profiles predictive of subjective well-being. Using principal component analysis to first determine the possible personality profiles onto which core personality measures would load, we subsequently searched for whole-brain white matter correlations with these profiles. We found three personality profiles that correlated with the integrity of white matter tracts. The correlates of an "optimistic" personality profile suggest (a) an intricate network for self-referential processing that helps regulate negative affect and maintain a positive outlook on life, (b) a sustained capacity for visually tracking rewards in the environment and (c) a motor readiness to act upon the conviction that desired rewards are imminent. The correlates of a "short-term approach behavior" profile was indicative of minimal loss of integrity in white matter tracts supportive of lifting certain behavioral barriers, possibly allowing individuals to act more outgoing and carefree in approaching people and rewards. Lastly, a "long-term approach behavior" profile's association with white matter tracts suggests lowered sensitivity to transient updates of stimulus-based associations of rewards and setbacks, thus facilitating the successful long-term pursuit of goals. Together, our findings yield convincing evidence that subjective well-being has its manifestations in the brain., (© 2022. The Author(s).)

In recent years, mounting evidence from animal models and studies in humans has accumulated for the role of cardiovascular exercise (CE) in improving motor performance and learning. Both CE and motor learning may induce highly dynamic structural and functional brain changes, but how both processes interact to boost learning is presently unclear. Here, we hypothesized that subjects receiving CE would show a different pattern of learning-related brain plasticity compared to non-CE controls, which in turn associates with improved motor learning. To address this issue, we paired CE and motor learning sequentially in a randomized controlled trial with healthy human participants. Specifically, we compared the effects of a 2-week CE intervention against a non-CE control group on subsequent learning of a challenging dynamic balancing task (DBT) over 6 consecutive weeks. Structural and functional MRI measurements were conducted at regular 2-week time intervals to investigate dynamic brain changes during the experiment. The trajectory of learning-related changes in white matter microstructure beneath parieto-occipital and primary sensorimotor areas of the right hemisphere differed between the CE vs. non-CE groups, and these changes correlated with improved learning of the CE group. While group differences in sensorimotor white matter were already present immediately after CE and persisted during DBT learning, parieto-occipital effects gradually emerged during motor learning. Finally, we found that spontaneous neural activity at rest in gray matter spatially adjacent to white matter findings was also altered, therefore indicating a meaningful link between structural and functional plasticity. Collectively, these findings may lead to a better understanding of the neural mechanisms mediating the CE-learning link within the brain., (© 2022. The Author(s).)

Background: In jargonaphasia, speech is fluent but meaningless. While neuropsychological evaluation may distinguish a neologistic component characterised by non-word production and a semantic component where pronounced words are real but speech is senseless, how this relates to the underlying white matter anatomy is debated., Objective: To identify white matter pathways causally involved in jargonaphasia., Methods: We retrospectively screened the intraoperative brain mapping data of 571 awake oncological resections using direct cortico-subcortical electrostimulation. Jargonaphasia was induced in 17 patients (19 sites) during a naming task. Stimulation sites were normalized to the Montreal Neurological Institute template space and used to generate individual disconnectome maps. Non-parametric voxelwise one and two sample t-tests were performed to identify the underlying white matter anatomy., Results: Jargonaphasia was induced only during stimulation of the left hemisphere. No cortical stimulation generated jargonaphasia. Subcortical sites causally associated with jargonaphasia clustered in 3 regions: in the temporal lobe (middle to inferior temporal gyri; n = 12), in the parietal lobe (supramarginal gyrus; n = 3) and in the temporal stem (n = 4). Disconnectome analysis indicated the inferior-fronto-occipital fasciculus (IFOF) was damaged in both neologistic and semantic jargonaphasia, while the involvement of the arcuate fasciculus was specific to neologistic jargonaphasia., Conclusion: For the first time, we show that jargonaphasia is induced by white matter stimulation, hinting at disconnection. As IFOF disconnection unites both variants, these may represent a continuum of disorders distinguished by semantic impairment. Conversely, damage to the arcuate fasciculus in addition to the IFOF is specific to neologistic jargonaphasia, thus suggesting a dual-disconnection syndrome., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Neural oscillations play an important role in the maintenance of brain function by regulating multi-scale neural activity. Characterizing the traveling properties of EEG is helpful for understanding the spatiotemporal dynamics of neural oscillations. However, traveling EEG based on non-invasive approach has little been investigated, and the relationship with brain intrinsic connectivity is not well known. In this study, traveling EEG of different frequency bands on the scalp in terms of the center of mass (EEG-CM) was examined. Then, two quantitative indexes describing the spatiotemporal features of EEG-CM were proposed, i.e., the traveling lateralization and velocity of EEG-CM. Further, based on simultaneous EEG-MRI approach, the relationship between traveling EEG-CM and the resting-state functional networks, as well as the microstructural connectivity of white matter was investigated. The results showed that there was similar spatial distribution of EEG-CM under different frequency bands, while the velocity of rhythmic EEG-CM increased in higher frequency bands. The lateralization of EEG-CM in low frequency bands (< 30 Hz) demonstrated negative relationship with the basal ganglia network (BGN). In addition, the velocity of the traveling EEG-CM was associated with the fractional anisotropy (FA) in corpus callosum and corona radiate. These results provided valid quantitative EEG index for understanding the spatiotemporal characteristics of the scalp EEG, and implied that the EEG dynamics were representations of functional and structural organization of cortical and subcortical structures., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI + DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreER T2 :mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI., (Copyright © 2021. Published by Elsevier Inc.)

The mechanical characterization of brain tissue has been generally analyzed in the frequency and time domain. It is crucial to understand the mechanics of the brain under realistic, dynamic conditions and convert it to enable mathematical modelling in a time domain. In this study, the compressive viscoelastic properties of brain tissue were investigated under time and frequency domains with the same physical conditions and the theory of viscoelasticity was applied to estimate the prediction of viscoelastic response in the time domain based on frequency-dependent mechanical moduli through Finite Element models. Storage and loss modulus were obtained from white and grey matter, of bovine brains, using dynamic mechanical analysis and time domain material functions were derived based on a Prony series representation. The material models were evaluated using brain testing data from stress relaxation and hysteresis in the time dependent analysis. The Finite Element models were able to represent the trend of viscoelastic characterization of brain tissue under both testing domains. The outcomes of this study contribute to a better understanding of brain tissue mechanical behaviour and demonstrate the feasibility of deriving time-domain viscoelastic parameters from frequency-dependent compressive data for biological tissue, as validated by comparing experimental tests with computational simulations., (© 2021. The Author(s).)