Ultra-high field proton magnetic resonance spectroscopy (1HMRS) offers a unique opportunity to measure the concentration of neurometabolites implicated in psychosis (PSY). The extant 7 T 1HMRS ...literature measuring glutamate-associated neurometabolites in the brain in PSY in vivo is small, but a comprehensive, quantitative summary of these data can offer insight and guidance to this emerging field. This meta-analysis examines proton spectroscopy (1HMRS) measures of glutamate (Glu), glutamine (Gln), glutamate+glutamine (Glx), gamma aminobutyric acid (GABA), and glutathione (GSH) across 255 individuals with PSY (121 first episode) and 293 healthy comparison participants (HC). While all five neurometabolites were lower in PSY as compared to HC, only Glu (Cohen's d = −0.18) and GSH (Cohen's d = −0.21) concentrations were significantly lower in PSY, whereas concentrations of Gln, Glx, and GABA did not significantly differ between groups. Notably, 1HMRS methodological choices and sample demographic characteristics did not impact study-specific effect sizes for PSY-related Glu or GSH differences. This review thus provides further evidence of neurometabolite dysfunction in first episode and chronic PSY, and thereby suggests that Glu and GSH abnormalities may additionally play a role in more incipient stages of the disorder: in clinical high risk stages. Additional 7 T neurochemical imaging studies in larger, longitudinal, and unmedicated samples and in youth at risk for developing psychosis are needed. Such studies will be critical for elucidating the neurodevelopmental and clinical time course of PSY-related neurometabolite alterations, and for assessing the potential for implicated metabolites to serve as druggable targets for decreasing PSY risk.
Understanding the neuropathological underpinnings of mental disorders such as schizophrenia, major depression, and bipolar disorder is an essential step towards the development of targeted ...treatments. Diffusion MRI studies utilizing the diffusion tensor imaging (DTI) model have been extremely successful to date in identifying microstructural brain abnormalities in individuals suffering from mental illness, especially in regions of white matter, although identified abnormalities have been biologically non-specific. Building on DTI's success, in recent years more advanced diffusion MRI methods have been developed and applied to the study of psychiatric populations, with the aim of offering increased sensitivity to subtle neurological abnormalities, as well as improved specificity to candidate pathologies such as demyelination and neuroinflammation. These advanced methods, however, usually come at the cost of prolonged imaging sequences or reduced signal to noise, and they are more difficult to evaluate compared with the more simplified approach taken by the now common DTI model. To date, a limited number of advanced diffusion MRI methods have been employed to study schizophrenia, major depression and bipolar disorder populations. In this review we survey these studies, compare findings across diverse methods, discuss the main benefits and limitations of the different methods, and assess the extent to which the application of more advanced diffusion imaging approaches has led to novel and transformative information with regards to our ability to better understand the etiology and pathology of mental disorders.
The human brain undergoes a prolonged period of cortical development that spans multiple decades. During childhood and adolescence, cortical development progresses from lower-order, primary and ...unimodal cortices with sensory and motor functions to higher-order, transmodal association cortices subserving executive, socioemotional, and mentalizing functions. The spatiotemporal patterning of cortical maturation thus proceeds in a hierarchical manner, conforming to an evolutionarily rooted, sensorimotor-to-association axis of cortical organization. This developmental program has been characterized by data derived from multimodal human neuroimaging and is linked to the hierarchical unfolding of plasticity-related neurobiological events. Critically, this developmental program serves to enhance feature variation between lower-order and higher-order regions, thus endowing the brain’s association cortices with unique functional properties. However, accumulating evidence suggests that protracted plasticity within late-maturing association cortices, which represents a defining feature of the human developmental program, also confers risk for diverse developmental psychopathologies.
Sydnor et al. review how human brain maturation progresses along an evolutionarily rooted, sensorimotor-to-association axis of cortical organization. This spatiotemporal developmental program endows association cortices with a protracted period of plasticity, unique neurobiological properties, and heightened maturational variability linked to psychopathology.
In this perspective, we describe how developmental improvements in youth executive function (EF) are supported by hierarchically organized maturational changes in functional brain systems. We first ...highlight evidence that functional brain systems are embedded within a hierarchical sensorimotor-association axis of cortical organization. We then review data showing that functional system developmental profiles vary along this axis: systems near the associative end become more functionally segregated, while those in the middle become more integrative. Developmental changes that strengthen the hierarchical organization of the cortex may support EF by facilitating top-down information flow and balancing within- and between-system communication. We propose a central role for attention and frontoparietal control systems in the maturation of healthy EF and suggest that reduced functional system differentiation across the sensorimotor-association axis contributes to transdiagnostic EF deficits.
Executive function relies on both specialized processing within functional systems and flexible communication between functional systems.Functional systems exhibit graded differences in connectivity profiles that are embedded within a sensorimotor-association axis, a hierarchical axis of cortical organization.Functional systems at the top of this hierarchical axis tend to become more functionally segregated during development, while regions in middle-axis systems become more integrated; this balance may support healthy executive function.Integrative attention and control systems may drive large-scale functional connectome reorganization during late childhood and adolescence, facilitating hierarchical information flow and multisystem coordination.Abnormal functional system development in youth may lead to executive dysfunction, thereby increasing risk for psychopathology.
Glutamate (Glu) is a key molecule in cellular metabolism, the most abundant excitatory neurotransmitter in the brain, and the principal neurotransmitter of cortical efferents. Glutamate dysfunction, ...on the other hand, is common in neurodegenerative disorders, and likely contributes to age-related declines in behavioral and cognitive functioning. Nonetheless, the extant literature measuring age-related changes in brain glutamate in vivo has yet to be comprehensively and quantitatively summarized. This meta-analysis examines proton spectroscopy (1HMRS) measures of Glu-related brain metabolites across 589 healthy young and older adults. Glu (Cohen's d = −0.82) and Glu+glutamine (Cohen's d = −0.51) concentrations were significantly lower in older compared with younger adults, whereas the concentration of glutamine (d = 0.43) was significantly higher in older individuals. Notably, 1HMRS methodological choices impacted effect sizes for age-related Glu differences. Glu metabolite change appears to be a robust marker of aging-related neurological change; however, additional studies are needed to elucidate age-related trajectories of glutamatergic alterations and their relationship to cognitive phenotypes.
•Meta-analysis demonstrates reductions in glutamate metabolite levels in older adults.•Methodological heterogeneity across study accounts for sizable variation of effect size.•Brain glutamate may serve as a biomarker for delineating typical and atypical aging.
Diffusion magnetic resonance imaging (dMRI) is an important method for studying white matter connectivity in the brain in vivo in both healthy and clinical populations. Improvements in dMRI ...tractography algorithms, which reconstruct macroscopic three-dimensional white matter fiber pathways, have allowed for methodological advances in the study of white matter; however, insufficient attention has been paid to comparing post-tractography methods that extract white matter fiber tracts of interest from whole-brain tractography. Here we conduct a comparison of three representative and conceptually distinct approaches to fiber tract delineation: 1) a manual multiple region of interest-based approach, 2) an atlas-based approach, and 3) a groupwise fiber clustering approach, by employing methods that exemplify these approaches to delineate the arcuate fasciculus, the middle longitudinal fasciculus, and the uncinate fasciculus in 10 healthy male subjects. We enable qualitative comparisons across methods, conduct quantitative evaluations of tract volume, tract length, mean fractional anisotropy, and true positive and true negative rates, and report measures of intra-method and inter-method agreement. We discuss methodological similarities and differences between the three approaches and the major advantages and drawbacks of each, and review research and clinical contexts for which each method may be most apposite. Emphasis is given to the means by which different white matter fiber tract delineation approaches may systematically produce variable results, despite utilizing the same input tractography and reliance on similar anatomical knowledge.
There is substantial variation between healthy individuals in the number of retinal ganglion cells (RGC) in the eye, with commensurate variation in the number of axons in the optic tracts. ...Fixel-based analysis of diffusion MR produces estimates of fiber density (FD) and cross section (FC). Using these fixel measurements along with retinal imaging, we asked if individual differences in RGC tissue volume are correlated with individual differences in FD and FC measurements obtained from the optic tracts, and subsequent structures along the cortical visual pathway. We find that RGC endowment is correlated with optic tract FC, but not with FD. RGC volume had a decreasing relationship with measurements from subsequent regions of the visual system (LGN volume, optic radiation FC/FD, and V1 surface area). However, we also found that the variations in each visual area were correlated with the variations in its immediately adjacent visual structure. We only observed these serial correlations when FC is used as the measure of interest for the optic tract and radiations, but no significant relationship was found when FD represented these white matter structures. From these results, we conclude that the variations in RGC endowment, LGN volume, and V1 surface area are better predicted by the overall cross section of the optic tract and optic radiations as compared to the intra-axonal restricted signal component of these white matter pathways. Additionally, the presence of significant correlations between adjacent, but not distant, anatomical structures suggests that there are multiple, local sources of anatomical variation along the visual pathway.
The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derive personalized functional ...networks across 29 scales in a large sample of youths (n = 693, ages 8-23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling reflect and strengthen a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks are dissociably related to the emergence of executive function. These results suggest that the development of functional brain networks align with and refine a hierarchy linked to cognition.
Individual differences in cognition during childhood are associated with important social, physical, and mental health outcomes in adolescence and adulthood. Given that cortical surface arealization ...during development reflects the brain's functional prioritization, quantifying variation in the topography of functional brain networks across the developing cortex may provide insight regarding individual differences in cognition. We test this idea by defining personalized functional networks (PFNs) that account for interindividual heterogeneity in functional brain network topography in 9-10 year olds from the Adolescent Brain Cognitive Development℠ Study. Across matched discovery (n = 3525) and replication (n = 3447) samples, the total cortical representation of fronto-parietal PFNs positively correlates with general cognition. Cross-validated ridge regressions trained on PFN topography predict cognition in unseen data across domains, with prediction accuracy increasing along the cortex's sensorimotor-association organizational axis. These results establish that functional network topography heterogeneity is associated with individual differences in cognition before the critical transition into adolescence.
Human neuroimaging studies have demonstrated that brain development progresses hierarchically along an S–A axis in which areas of association cortex are the last to mature.Animal models delineate a ...hierarchical progression of critical periods of elevated experience-dependent plasticity across sensory systems which is governed by a conserved set of neurobiological mechanisms.We propose that hierarchical development along the S–A axis in humans is driven by a cascade of critical periods that culminate in association cortices during adolescence.We highlight advances in in vivo neuroimaging and computational approaches, including pharmacological functional magnetic resonance imaging (fMRI), chemogenetic fMRI, and biophysical modeling, that can provide insights into the development of critical period mechanisms along the S–A axis in humans.
To understand human brain development it is necessary to describe not only the spatiotemporal patterns of neurodevelopment but also the neurobiological mechanisms that underlie them. Human neuroimaging studies have provided evidence for a hierarchical sensorimotor-to-association (S–A) axis of cortical neurodevelopment. Understanding the biological mechanisms that underlie this program of development using traditional neuroimaging approaches has been challenging. Animal models have been used to identify periods of enhanced experience-dependent plasticity – 'critical periods' – that progress along cortical hierarchies and are governed by a conserved set of neurobiological mechanisms that promote and then restrict plasticity. In this review we hypothesize that the S–A axis of cortical development in humans is partly driven by the cascading maturation of critical period plasticity mechanisms. We then describe how recent advances in in vivo neuroimaging approaches provide a promising path toward testing this hypothesis by linking signals derived from non-invasive imaging to critical period mechanisms.
To understand human brain development it is necessary to describe not only the spatiotemporal patterns of neurodevelopment but also the neurobiological mechanisms that underlie them. Human neuroimaging studies have provided evidence for a hierarchical sensorimotor-to-association (S–A) axis of cortical neurodevelopment. Understanding the biological mechanisms that underlie this program of development using traditional neuroimaging approaches has been challenging. Animal models have been used to identify periods of enhanced experience-dependent plasticity – 'critical periods' – that progress along cortical hierarchies and are governed by a conserved set of neurobiological mechanisms that promote and then restrict plasticity. In this review we hypothesize that the S–A axis of cortical development in humans is partly driven by the cascading maturation of critical period plasticity mechanisms. We then describe how recent advances in in vivo neuroimaging approaches provide a promising path toward testing this hypothesis by linking signals derived from non-invasive imaging to critical period mechanisms.
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