•ModelArray is an R package for statistical analysis of fixel-wise data.•ModelArray supports linear and nonlinear modeling and is extensible to more models.•ModelArray is scalable for large-scale ...datasets.•ModelArray facilitates easy statistical analysis of large-scale fixel-wise data.
Diffusion MRI is the dominant non-invasive imaging method used to characterize white matter organization in health and disease. Increasingly, fiber-specific properties within a voxel are analyzed using fixels. While tools for conducting statistical analyses of fixel-wise data exist, currently available tools support only a limited number of statistical models. Here we introduce ModelArray, an R package for mass-univariate statistical analysis of fixel-wise data. At present, ModelArray supports linear models as well as generalized additive models (GAMs), which are particularly useful for studying nonlinear effects in lifespan data. In addition, ModelArray also aims for scalable analysis. With only several lines of code, even large fixel-wise datasets can be analyzed using a standard personal computer. Detailed memory profiling revealed that ModelArray required only limited memory even for large datasets. As an example, we applied ModelArray to fixel-wise data derived from diffusion images acquired as part of the Philadelphia Neurodevelopmental Cohort (n = 938). ModelArray revealed anticipated nonlinear developmental effects in white matter. Moving forward, ModelArray is supported by an open-source software development model that can incorporate additional statistical models and other imaging data types. Taken together, ModelArray provides a flexible and efficient platform for statistical analysis of fixel-wise data.
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Animal studies of neurodevelopment have shown that recordings of intrinsic cortical activity evolve from synchronized and high amplitude to sparse and low amplitude as plasticity declines and the ...cortex matures. Leveraging resting-state functional MRI (fMRI) data from 1,033 youths (ages 8-23 years), we find that this stereotyped refinement of intrinsic activity occurs during human development and provides evidence for a cortical gradient of neurodevelopmental change. Declines in the amplitude of intrinsic fMRI activity were initiated heterochronously across regions and were coupled to the maturation of intracortical myelin, a developmental plasticity regulator. Spatiotemporal variability in regional developmental trajectories was organized along a hierarchical, sensorimotor-association cortical axis from ages 8 to 18. The sensorimotor-association axis furthermore captured variation in associations between youths' neighborhood environments and intrinsic fMRI activity; associations suggest that the effects of environmental disadvantage on the maturing brain diverge most across this axis during midadolescence. These results uncover a hierarchical neurodevelopmental axis and offer insight into the progression of cortical plasticity in humans.
Human cortical maturation has been posited to be organized along the sensorimotor-association axis, a hierarchical axis of brain organization that spans from unimodal sensorimotor cortices to ...transmodal association cortices. Here, we investigate the hypothesis that the development of functional connectivity during childhood through adolescence conforms to the cortical hierarchy defined by the sensorimotor-association axis. We tested this pre-registered hypothesis in four large-scale, independent datasets (total n = 3355; ages 5-23 years): the Philadelphia Neurodevelopmental Cohort (n = 1207), Nathan Kline Institute-Rockland Sample (n = 397), Human Connectome Project: Development (n = 625), and Healthy Brain Network (n = 1126). Across datasets, the development of functional connectivity systematically varied along the sensorimotor-association axis. Connectivity in sensorimotor regions increased, whereas connectivity in association cortices declined, refining and reinforcing the cortical hierarchy. These consistent and generalizable results establish that the sensorimotor-association axis of cortical organization encodes the dominant pattern of functional connectivity development.
Cognitive flexibility exhibits dynamic changes throughout development, with different forms of flexibility showing dissociable developmental trajectories. In this review, we propose that an ...adolescent-specific mode of flexibility in the face of changing environmental contingencies supports the emergence of adolescent-to-adult gains in cognitive shifting efficiency. We first describe how cognitive shifting abilities monotonically improve from childhood to adulthood, accompanied by increases in brain state flexibility, neural variability, and excitatory/inhibitory balance. We next summarize evidence supporting the existence of a dopamine-driven adolescent peak in flexible behavior that results in reward seeking, undirected exploration, and environmental sampling. We propose a neurodevelopmental framework that relates these adolescent behaviors to the refinement of neural phenotypes relevant to mature cognitive flexibility - and thus highlight the importance of the adolescent period in fostering healthy neurocognitive trajectories.
•Different forms of cognitive flexibility show dissociable developmental trajectories.•An adolescent-specific mode of flexibility scaffolds adult-like cognitive shifting.•Maturational shifts in flexibility are supported by multiscale neural variability.•Neural variability may be refined by changes in E/I ratio and dopamine signaling.•Adolescent refinements in neural variability may foster critical brain dynamics.
ABSTRACT
Sports‐related concussion is a serious health challenge, and females are at higher risk of sustaining a sports‐related concussion compared to males. Although there are many studies that ...investigate outcomes following concussion, females remain an understudied population, despite representing a large proportion of the organized sports community. In this review, we provide a summary of studies that investigate sex‐related differences in outcome following sports‐related concussion. Moreover, we provide an introduction to the methods used to study sex‐related differences after sports‐related concussion, including common clinical and cognitive measures, neuroimaging techniques, as well as biomarkers. A literature search inclusive of articles published to March 2020 was performed using PubMed. The studies were reviewed and discussed with regard to the methods used. Findings from these studies remain mixed with regard to the effect of sex on clinical symptoms, concussion‐related alterations in brain structure and function, and recovery trajectories. Nonetheless, there is initial evidence to suggest that sex‐related differences following concussion are important to consider in efforts to develop objective biomarkers for the diagnosis and prognosis of concussion. Additional studies on this topic are, however, clearly needed to improve our understanding of sex‐related differences following concussion, as well as to understand their neurobiological underpinnings. Such studies will help pave the way toward more personalized clinical management and treatment of sports‐related concussion.
During adolescence, the brain undergoes extensive changes in white matter structure that support cognition. Data-driven approaches applied to cortical surface properties have led the field to ...understand brain development as a spatially and temporally coordinated mechanism that follows hierarchically organized gradients of change. Although white matter development also appears asynchronous, previous studies have relied largely on anatomical tract-based atlases, precluding a direct assessment of how white matter structure is spatially and temporally coordinated. Harnessing advances in diffusion modeling and machine learning, we identified 14 data-driven patterns of covarying white matter structure in a large sample of youth. Fiber covariance networks aligned with known major tracts, while also capturing distinct patterns of spatial covariance across distributed white matter locations. Most networks showed age-related increases in fiber network properties, which were also related to developmental changes in executive function. This study delineates data-driven patterns of white matter development that support cognition.
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•We define spatially covarying fiber covariance networks using machine learning•Networks align with major tracts, while also capturing distinct spatial patterns•Most networks show age-related increases in fiber network properties•Fiber covariance networks are linked to developmental changes in executive function
Bagautdinova et al. use machine learning to reveal fiber covariance networks in white matter in a large sample of youth. Most fiber covariance networks show age-related increases in fiber network properties, which are also related to developmental changes in executive function.
•Diffusion MRI measures provide insight into gray matter microstructure in PTSD.•Amygdala-hippocampal and cingulate microstructure is associated with PTSD severity.•Mild TBI may exacerbate the impact ...of limbic microstructure on PTSD severity.•Neural contributors to psychiatric disorder severity may be affected by brain injury.
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships.
Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI.
Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex.
These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.
Ketamine is increasingly being used as a therapeutic for treatment-resistant depression (TRD), yet the effects of ketamine on the human brain remain largely unknown. This pilot study employed ...diffusion magnetic resonance imaging (dMRI) to examine relationships between ketamine treatment and white matter (WM) microstructure, with the aim of increasing the current understanding of ketamine's neural mechanisms of action in humans. Longitudinal dMRI data were acquired from 13 individuals with TRD two hours prior to (pre-infusion), and four hours following (post-infusion), an intravenous ketamine infusion. Free-water imaging was employed to quantify cerebrospinal fluid-corrected mean fractional anisotropy (FA) in 15 WM bundles pre- and post-infusion. Analyses revealed that higher pre-infusion FA in the left cingulum bundle and the left superior longitudinal fasciculus was associated with greater depression symptom improvement 24 h post-ketamine. Moreover, four hours after intravenous administration of ketamine, FA rapidly increased in numerous WM bundles in the brain; this increase was significantly associated with 24 h symptom improvement in select bundles. Overall, the results of this preliminary study suggest that WM properties, as measured by dMRI, may have a potential impact on clinical improvement following ketamine. Ketamine administration additionally appears to be associated with rapid WM diffusivity changes, suggestive of rapid changes in WM microstructure. This study thus points to pre-treatment WM structure as a potential factor associated with ketamine's clinical efficacy, and to post-treatment microstructural changes as a candidate neuroimaging marker of ketamine's cellular mechanisms.
Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar ...gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately reconstructs the position of brain tissue samples, ii) delineates known functional territories, and iii) can model the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical axes differentiating the primary sensory cortex from the association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two nonhuman primate datasets and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well-known transcription factors (e.g., PAX6 and SIX3 ), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.
Functional magnetic resonance imaging (fMRI) is increasingly used to non-invasively study the acute impact of psychedelics on the human brain. While fMRI is a promising tool for measuring brain ...function in response to psychedelics, it also has known methodological challenges. We conducted a systematic review of fMRI studies examining acute responses to experimentally administered psychedelics in order to identify convergent findings and characterize heterogeneity in the literature. We reviewed 91 full-text papers; these studies were notable for substantial heterogeneity in design, task, dosage, drug timing, and statistical approach. Data recycling was common, with 51 unique samples across 91 studies. Fifty-seven studies (54%) did not meet contemporary standards for Type I error correction or control of motion artifact. Psilocybin and LSD were consistently reported to moderate the connectivity architecture of the sensorimotor-association cortical axis. Studies also consistently reported that ketamine administration increased activation in the dorsomedial prefrontal cortex. Moving forward, use of best practices such as pre-registration, standardized image processing and statistical testing, and data sharing will be important in this rapidly developing field.
•Systematic review of studies combining fMRI with acute psychedelic administration.•Great variability in study design and methodology was observed across studies.•Data recycling and methodological limitations are common among studies.•LSD and psilocybin impact connectivity between sensory and association systems.•Ketamine increases functional activation in the medial prefrontal cortex.
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