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Though youth living in disadvantaged neighborhoods experience greater risk for poor behavioral and mental health outcomes, many go on to show resilience in the face of adversity. A few recent studies have identified neural markers of resilience in cognitive and affective brain networks, yet the broader network organization supporting resilience in youth remains unknown, particularly in relation to neighborhood disadvantage. Moreover, most studies have defined resilience as the absence of psychopathology, which does not consider growing evidence that resilience also includes positive outcomes across multiple domains (e.g., social, academic). We examined associations between brain network organization and multiple resilience domains in a sample of 708 twins (7-19 years old) recruited from neighborhoods with above-average poverty levels. Graph analysis on functional connectivity data from resting-state and task-based functional magnetic resonance imaging was used to characterize features of intrinsic whole-brain and network-level organization, from which we explored associations with resilience in three domains: psychological, social, and academic. Fewer connections between a brain network involved in self-referential processing (i.e., default mode network) and the subcortical system were associated with greater social resilience. Further, greater whole-brain functional integration (i.e., efficiency) was associated with better psychological resilience among youth with relatively lower levels of cumulative adversity exposure. Alternatively, lower whole-brain efficiency and higher whole-brain robustness to disruption (i.e., assortativity) were associated with greater psychological and social resilience among youth with relatively higher levels of cumulative adversity. These findings advance support for multidimensional resilience models and reveal distinct neural mechanisms supporting resilience to neighborhood disadvantage across specific domains in youth. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

While cognitive theory has advanced several candidate frameworks to explain attentional entrainment, the neural basis for the temporal allocation of attention is unknown. Here we present a new model of attentional entrainment guided by empirical evidence obtained using a cohort of 50 artificial brains. These brains were evolved in silico to perform a duration judgment task similar to one where human subjects perform duration judgments in auditory oddball paradigms. We found that the artificial brains display psychometric characteristics remarkably similar to those of human listeners and exhibit similar patterns of distortions of perception when presented with out-of-rhythm oddballs. A detailed analysis of mechanisms behind the duration distortion suggests that attention peaks at the end of the tone, which is inconsistent with previous attentional entrainment models. Instead, the new model of entrainment emphasizes increased attention to those aspects of the stimulus that the brain expects to be highly informative., (© 2024 Massachusetts Institute of Technology.)

Turner syndrome, caused by complete or partial loss of an X-chromosome, is often accompanied by specific cognitive challenges. Magnetic resonance imaging studies of adults and children with Turner syndrome suggest these deficits reflect differences in anatomical and functional connectivity. However, no imaging studies have explored connectivity in infants with Turner syndrome. Consequently, it is unclear when in development connectivity differences emerge. To address this gap, we compared functional connectivity and white matter microstructure of 1-year-old infants with Turner syndrome to typically developing 1-year-old boys and girls. We examined functional connectivity between the right precentral gyrus and five regions that show reduced volume in 1-year old infants with Turner syndrome compared to controls and found no differences. However, exploratory analyses suggested infants with Turner syndrome have altered connectivity between right supramarginal gyrus and left insula and right putamen. To assess anatomical connectivity, we examined diffusivity indices along the superior longitudinal fasciculus and found no differences. However, an exploratory analysis of 46 additional white matter tracts revealed significant group differences in nine tracts. Results suggest that the first year of life is a window in which interventions might prevent connectivity differences observed at later ages, and by extension, some of the cognitive challenges associated with Turner syndrome., (© The Author(s) 2024. Published by Oxford University Press.)

Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brain vascular tracing shows an overall ~10% decrease in vascular length and branching density with ~7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling reveals increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities show selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We find increased blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice demonstrates reduced baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging., (© 2024. The Author(s).)

Mate choice plays a fundamental role in speciation, yet we know little about the molecular mechanisms that underpin this crucial decision-making process. Stickleback fish differentially adapted to limnetic and benthic habitats are reproductively isolated and females of each species use different male traits to evaluate prospective partners and reject heterospecific males. Here, we integrate behavioural data from a mate choice experiment with gene expression profiles from the brains of females actively deciding whether to mate. We find substantial gene expression variation between limnetic and benthic females, regardless of behavioural context, suggesting general divergence in constitutive gene expression patterns, corresponding to their genetic differentiation. Intriguingly, female gene co-expression modules covary with male display traits but in opposing directions for sympatric populations of the two species, suggesting male displays elicit a dynamic neurogenomic response that reflects known differences in female preferences. Furthermore, we confirm the role of numerous candidate genes previously implicated in female mate choice in other species, suggesting evolutionary tinkering with these conserved molecular processes to generate divergent mate preferences. Taken together, our study adds important new insights to our understanding of the molecular processes underlying female decision-making critical for generating sexual isolation and speciation.

Implantable neurotechnology enables monitoring and stimulating of the brain signals responsible for performing cognitive, motor, and sensory tasks. Electrode arrays implanted in the brain are increasingly used in the clinic to treat a variety of sources of neurological diseases and injuries. However, the implantation of a foreign body typically initiates a tissue response characterized by physical disruption of vasculature and the neuropil as well as the initiation of inflammation and the induction of reactive glial states. Likewise, electrical stimulation can induce damage to the surrounding tissue depending on the intensity and waveform parameters of the applied stimulus. These phenomena, in turn, are likely influenced by the surface chemistry and characteristics of the materials employed, but further information is needed to effectively link the biological responses observed to specific aspects of device design. In order to inform improved design of implantable neurotechnology, we are investigating the basic science principles governing device-tissue integration. We are employing multiple techniques to characterize the structural, functional, and genetic changes that occur in the cells surrounding implanted electrodes. First, we have developed a new "device-in-slice" technique to capture chronically implanted electrodes within thick slices of live rat brain tissue for interrogation with single-cell electrophysiology and two-photon imaging techniques. Our data revealed several new observations of tissue remodeling surrounding devices: (a) there was significant disruption of dendritic arbors in neurons near implants, where losses were driven asymmetrically on the implant-facing side. (b) There was a significant loss of dendritic spine densities in neurons near implants, with a shift toward more immature (nonfunctional) morphologies. (c) There was a reduction in excitatory neurotransmission surrounding implants, as evidenced by a reduction in the frequency of excitatory postsynaptic currents (EPSCs). Lastly, (d) there were changes in the electrophysiological underpinnings of neuronal spiking regularity. In parallel, we initiated new studies to explore changes in gene expression surrounding devices through spatial transcriptomics, which we applied to both recording and stimulating arrays. We found that (a) device implantation is associated with the induction of hundreds of genes associated with neuroinflammation, glial reactivity, oligodendrocyte function, and cellular metabolism and (b) electrical stimulation induces gene expression associated with damage or plasticity in a manner dependent upon the intensity of the applied stimulus. We are currently developing computational analysis tools to distill biomarkers of device-tissue interactions from large transcriptomics data sets. These results improve the current understanding of the biological response to electrodes implanted in the brain while producing new biomarkers for benchmarking the effects of novel electrode designs on responses. As the next generation of neurotechnology is developed, it will be increasingly important to understand the influence of novel materials, surface chemistries, and implant architectures on device performance as well as the relationship with the induction of specific cellular signaling pathways.

Introduction: Dementia risk may be elevated in socioeconomically disadvantaged neighborhoods. Reasons for this remain unclear, and this elevation has yet to be shown at a national population level., Methods: We tested whether dementia was more prevalent in disadvantaged neighborhoods across the New Zealand population (N = 1.41 million analytic sample) over a 20-year observation. We then tested whether premorbid dementia risk factors and MRI-measured brain-structure antecedents were more prevalent among midlife residents of disadvantaged neighborhoods in a population-representative NZ-birth-cohort (N = 938 analytic sample)., Results: People residing in disadvantaged neighborhoods were at greater risk of dementia (HR per-quintile-disadvantage-increase = 1.09, 95% confidence interval [CI]:1.08-1.10) and, decades before clinical endpoints typically emerge, evidenced elevated dementia-risk scores (CAIDE, LIBRA, Lancet, ANU-ADRI, DunedinARB; β's 0.31-0.39) and displayed dementia-associated brain structural deficits and cognitive difficulties/decline., Discussion: Disadvantaged neighborhoods have more residents with dementia, and decades before dementia is diagnosed, residents have more dementia-risk factors and brain-structure antecedents. Whether or not neighborhoods causally influence risk, they may offer scalable opportunities for primary dementia prevention., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Sex differences exist in numerous parameters of the brain. Yet, sex-related factors are part of a large set of variables that interact to affect many aspects of brain structure and function. This raises questions regarding how to interpret findings of sex differences at the level of single brain measures and the brain as a whole. In the present study, we reanalyzed two datasets consisting of measures of oxytocin, vasopressin V1a, and mu opioid receptor binding densities in multiple brain regions in rats. At the level of single brain measures, we found that sex differences were rarely dimorphic and were largely persistent across estrous stage and parental status but not across age or context. At the level of aggregates of brain measures showing sex differences, we tested whether individual brains are 'mosaics' of female-typical and male-typical measures or are internally consistent, having either only female-typical or only male-typical measures. We found mosaicism for measures showing overlap between females and males. Mosaicism was higher a) with a larger number of measures, b) with smaller effect sizes of the sex difference in these measures, and c) in rats with more diverse life experiences. Together, these results highlight the limitations of the binary framework for interpreting sex effects on the brain and suggest two complementary pathways to studying the contribution of sex to brain function: (1) focusing on measures showing dimorphic and persistent sex differences and (2) exploring the relations between specific brain mosaics and specific endpoints., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Youth self-reports are a mainstay of delinquency assessment; however, making valid inferences about delinquency using these assessments requires equivalent measurement across groups of theoretical interest. We examined whether a brief 10-item delinquency measure exhibited measurement invariance across non-Hispanic White ( n = 6,064) and Black ( n = 1,666) youth (ages 10-11 years old) in the Adolescent Brain Cognitive Development sm Study (ABCD Study®). We detected differential item functioning (DIF) in two items. Black youth were more likely to report being arrested or picked up by police than White youth with the same score on the latent delinquency trait. Although multiple covariates (income, urgency, and callous-unemotional traits) reduced mean-level difference in overall delinquency, they were generally unrelated to the DIF in the Arrest item. However, the DIF in the Arrest item was reduced in size and no longer significant after adjusting for neighborhood safety. Results illustrate the importance of considering measurement invariance when using self-reported delinquency scores to draw inferences about group differences, and the utility of measurement invariance analyses for helping to identify mechanisms that contribute to group differences generally., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Family poverty has been associated with altered brain structure, function, and connectivity in youth. However, few studies have examined how disadvantage within the broader neighborhood may influence functional brain network organization. The present study leveraged a longitudinal community sample of 538 twins living in low-income neighborhoods to evaluate the prospective association between exposure to neighborhood poverty during childhood (6-10 y) with functional network architecture during adolescence (8-19 y). Using resting-state and task-based fMRI, we generated two latent measures that captured intrinsic brain organization across the whole-brain and network levels - network segregation and network segregation-integration balance. While age was positively associated with network segregation and network balance overall across the sample, these associations were moderated by exposure to neighborhood poverty. Specifically, these positive associations were observed only in youth from more, but not less, disadvantaged neighborhoods. Moreover, greater exposure to neighborhood poverty predicted reduced network segregation and network balance in early, but not middle or late, adolescence. These effects were detected both across the whole-brain system as well as specific functional networks, including fronto-parietal, default mode, salience, and subcortical systems. These findings indicate that where children live may exert long-reaching effects on the organization and development of the adolescent brain., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Functional connectivity networks of the human brain are commonly studied using tools from complex network theory. Existing methods focus on functional connectivity within a single frequency band. However, it is well-known that higher order brain functions rely on the integration of information across oscillations at different frequencies. Therefore, there is a need to study these cross-frequency interactions. In this paper, we use multilayer networks to model functional connectivity across multiple frequencies, where each layer corresponds to a different frequency band. We then introduce the multilayer modularity metric to develop a multilayer community detection algorithm. The proposed approach is applied to electroencephalogram (EEG) data collected during a study of error monitoring in the human brain. The differences between the community structures within and across different frequency bands for two response types, i.e. error and correct, are studied. The results indicate that following an error response, the brain organizes itself to form communities across frequencies, in particular between theta and gamma bands while a similar cross-frequency community formation is not observed following the correct response., (© 2023. The Author(s).)

Imaging genetics provides an opportunity to discern associations between genetic variants and brain imaging phenotypes. Historically, the field has focused on adults and adolescents; very few imaging genetics studies have focused on brain development in infancy and early childhood (from birth to age 6 years). This is an important knowledge gap because developmental changes in the brain during the prenatal and early postnatal period are regulated by dynamic gene expression patterns that likely play an important role in establishing an individual's risk for later psychiatric illness and neurodevelopmental disabilities. In this review, we summarize findings from imaging genetics studies spanning from early infancy to early childhood, with a focus on studies examining genetic risk for neuropsychiatric disorders. We also introduce the Organization for Imaging Genomics in Infancy (ORIGINs), a working group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium, which was established to facilitate large-scale imaging genetics studies in infancy and early childhood., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Functional magnetic resonance imaging has been used to identify complex brain networks by examining the correlation of blood-oxygen-level-dependent signals between brain regions during the resting state. Many of the brain networks identified in adults are detectable at birth, but genetic and environmental influences governing connectivity within and between these networks in early infancy have yet to be explored. We investigated genetic influences on neonatal resting-state connectivity phenotypes by generating intraclass correlations and performing mixed effects modeling to estimate narrow-sense heritability on measures of within network and between-network connectivity in a large cohort of neonate twins. We also used backwards elimination regression and mixed linear modeling to identify specific demographic and medical history variables influencing within and between network connectivity in a large cohort of typically developing twins and singletons. Of the 36 connectivity phenotypes examined, only 6 showed narrow-sense heritability estimates greater than 0.10, with none being statistically significant. Demographic and obstetric history variables contributed to between- and within-network connectivity. Our results suggest that in early infancy, genetic factors minimally influence brain connectivity. However, specific demographic and medical history variables, such as gestational age at birth and maternal psychiatric history, may influence resting-state connectivity measures., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding the mechanical behaviors and properties of brain tissue are crucial to study the mechanisms of traumatic brain injury (TBI). Such injury may be associated with high rate loading conditions and the large deformation of brain tissue. Thus, constitutive models that consider the rate dependent large deformation of brain tissue and its possible damage initiation and evolution may help uncover the related mechanisms of TBI. Motivated from this, in this paper we present a fully three-dimensional large strain viscohyperelastic-damage model with the purpose of reproducing the experimentally observed rate sensitive elastic and damage-induced stress softening behaviors of brain tissue. The parameters of the proposed model can be identified using the experimental data from simple monotonic tests such as uniaxial tension, compression and simple shear. The proposed model is validated by comparing its prediction with experimental data. Good agreement between predictive results and experimental data is achieved indicating the potential of the proposed model in characterizing the mechanical behaviors of brain tissue considering rate dependence and damage effect., 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 © 2023 Elsevier Ltd. All rights reserved.)

Seasonal changes in peripheral inflammation are well documented in both humans and animal models, but seasonal changes in neuroinflammation, especially the impact of seasonal lighting environment on neuroinflammation remain unclear. To address this question, the present study examined the effects of environmental lighting conditions on neuroinflammation in a diurnal rodent model, Nile grass rats (Arvicanthis niloticus). Male and female grass rats were housed in either bright (brLD) or dim (dimLD) light during the day to simulate a summer or winter light condition, respectively. After 4 weeks, microglia markers Iba-1 and CD11b, as well as pro-inflammatory cytokines TNF-α and IL-6, were examined in the anterior cingulate cortex (ACC), basolateral amygdala (BLA), and dorsal hippocampus (dHipp). The results revealed that winter-like dim light during the day leads to indicators of increased neuroinflammation in a brain site- and sex-specific manner. Specifically, relatively few changes in the neuroinflammatory markers were observed in the ACC, while numerous changes were found in the BLA and dHipp. In the BLA, winter-like dimLD resulted in hyper-ramified microglia morphology and increased expression of the pro-inflammatory cytokine IL-6, but only in males. In the dHipp, dimLD led to a higher number and hyper-ramified morphology of microglia as well as increased expression of CD11b and TNF-α, but only in females. Neuroinflammatory state is thus influenced by environmental light, differently in males and females, and could play a role in sex differences in the prevalence and symptoms of psychiatric or neurological disorders that are influenced by season or other environmental light conditions. Diurnal Nile grass rats were housed under bright or dim light during the day for 4 weeks, simulating seasonal fluctuations in daytime lighting environment. Dim light housing resulted in hyper-ramified morphology of microglia (scale bar, 15 μm) and altered expression of pro-inflammatory cytokines (TNF-α) in a sex- and brain region-specific manner., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Laterality indices (LIs) quantify the left-right asymmetry of brain and behavioural variables and provide a measure that is statistically convenient and seemingly easy to interpret. Substantial variability in how structural and functional asymmetries are recorded, calculated, and reported, however, suggest little agreement on the conditions required for its valid assessment. The present study aimed for consensus on general aspects in this context of laterality research, and more specifically within a particular method or technique (i.e., dichotic listening, visual half-field technique, performance asymmetries, preference bias reports, electrophysiological recording, functional MRI, structural MRI, and functional transcranial Doppler sonography). Experts in laterality research were invited to participate in an online Delphi survey to evaluate consensus and stimulate discussion. In Round 0, 106 experts generated 453 statements on what they considered good practice in their field of expertise. Statements were organised into a 295-statement survey that the experts then were asked, in Round 1, to independently assess for importance and support, which further reduced the survey to 241 statements that were presented again to the experts in Round 2. Based on the Round 2 input, we present a set of critically reviewed key recommendations to record, assess, and report laterality research for various methods.

The song circuit in passerine birds is an outstanding model system for understanding the relationship between brain morphology and behavior, in part due to varying degrees of sex differences in structure and function across species. House wrens (Troglodytes aedon) offer a unique opportunity to advance our understanding of this relationship. Intermediate sex differences in song rate and complexity exist in this species compared to other passerines, and, among individual females, song complexity varies dramatically. Acoustic complexity in wild house wrens was quantified using a new machine learning approach. Volume, cell number, cell density, and neuron soma size were then measured for three song circuit regions, Area X, HVC (used as a proper name), and the robust nucleus of the arcopallium (RA), and one control region, the nucleus rotundus (Rt). For each song control area, males had a larger volume with more cells, larger somas, and lower cell density. Male songs had greater acoustic complexity than female songs, but these distributions overlapped. In females, increased acoustic complexity was correlated with larger volumes of and more cells in Area X and RA, as well as larger soma size in RA. In males, song complexity was unrelated to morphology, although our methods may underestimate male song complexity. This is the first study to identify song control regions in house wrens and one of few examining individual variation in both sexes. Parallels between morphology and the striking variability in female song in this species provide a new model for understanding relationships between neural structure and function., (© 2023 S. Karger AG, Basel.)

Magnetoencephalography, the extracranial detection of tiny magnetic fields emanating from intracranial electrical activity of neurons, and its source modeling relation, magnetic source imaging, represent a powerful functional neuroimaging technique, able to detect and localize both spontaneous and evoked activity of the brain in health and disease. Recent years have seen an increased utilization of this technique for both clinical practice and research, in the United States and worldwide. This report summarizes current thinking, presents recommendations for clinical implementation, and offers an outlook for emerging new clinical indications., (© 2022 by American Journal of Neuroradiology.)

Two-dimensional mesoscale finite element analysis (FEA) of a multilayered brain tissue was performed to calculate the damage-related average stress triaxiality and local maximum von Mises strain in the brain. The FEA was integrated with rate-dependent hyperelastic and internal state variable (ISV) models, respectively, describing the behaviors of wet and dry brain tissues. Using the finite element results, a statistical method of design of experiments (DOE) was utilized to independently screen the relative influences of seven parameters related to brain morphology (sulcal width/depth, gray matter (GM) thickness, cerebrospinal fluid (CSF) thickness and brain lobe) and loading/environment conditions (strain rate and humidity) with respect to the potential damage growth/coalescence in the brain tissue. The results of the parametric study illustrated that the GM thickness and humidity were the two most crucial parameters affecting average stress triaxiality. For the local maximum von Mises strain at the depth of brain sulci, the brain lobe/region was the most influential factor. The conclusion of this investigation gives insight for the future development and refinement of a macroscale brain damage model incorporating information from lower length scale., (Copyright © 2022 by ASME.)

Neurotransmitters play essential roles in regulating neural circuit dynamics both in the central nervous system as well as at the peripheral, including the gastrointestinal tract 1-3 . Their real-time monitoring will offer critical information for understanding neural function and diagnosing disease 1-3 . However, bioelectronic tools to monitor the dynamics of neurotransmitters in vivo, especially in the enteric nervous systems, are underdeveloped. This is mainly owing to the limited availability of biosensing tools that are capable of examining soft, complex and actively moving organs. Here we introduce a tissue-mimicking, stretchable, neurochemical biological interface termed NeuroString, which is prepared by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer. NeuroString sensors allow chronic in vivo real-time, multichannel and multiplexed monoamine sensing in the brain of behaving mouse, as well as measuring serotonin dynamics in the gut without undesired stimulations and perturbing peristaltic movements. The described elastic and conformable biosensing interface has broad potential for studying the impact of neurotransmitters on gut microbes, brain-gut communication and may ultimately be extended to biomolecular sensing in other soft organs across the body., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Deep learning (primarily using backpropagation) and neuroevolution are the preeminent methods of optimizing artificial neural networks. However, they often create black boxes that are as hard to understand as the natural brains they seek to mimic. Previous work has identified an information-theoretic tool, referred to as R, which allows us to quantify and identify mental representations in artificial cognitive systems. The use of such measures has allowed us to make previous black boxes more transparent. Here we extend R to not only identify where complex computational systems store memory about their environment but also to differentiate between different time points in the past. We show how this extended measure can identify the location of memory related to past experiences in neural networks optimized by deep learning as well as a genetic algorithm., (© 2022 Massachusetts Institute of Technology.)

Despite extensive efforts to increase the signal-to-noise ratio (SNR) of fMRI images for brain-wide mapping, technical advances of focal brain signal enhancement are lacking, in particular, for animal brain imaging. Emerging studies have combined fMRI with fiber optic-based optogenetics to decipher circuit-specific neuromodulation from meso to macroscales. High-resolution fMRI is needed to integrate hemodynamic responses into cross-scale functional dynamics, but the SNR remains a limiting factor given the complex implantation setup of animal brains. Here, we developed a multimodal fMRI imaging platform with an implanted inductive coil detector. This detector boosts the tSNR of MRI images, showing a 2-3-fold sensitivity gain over conventional coil configuration. In contrast to the cryoprobe or array coils with limited spaces for implanted brain interface, this setup offers a unique advantage to study brain circuit connectivity with optogenetic stimulation and can be further extended to other multimodal fMRI mapping schemes., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Neurophysiological measurements suggest that human information processing is evinced by neuronal activity. However, the quantitative relationship between the activity of a brain region and its information processing capacity remains unclear. We introduce and validate a mathematical model of the information processing capacity of a brain region in terms of neuronal activity, input storage capacity, and the arrival rate of afferent information. We applied the model to fMRI data obtained from a flanker paradigm in young and old subjects. Our analysis showed that-for a given cognitive task and subject-higher information processing capacity leads to lower neuronal activity and faster responses. Crucially, processing capacity-as estimated from fMRI data-predicted task and age-related differences in reaction times, speaking to the model's predictive validity. This model offers a framework for modelling of brain dynamics in terms of information processing capacity, and may be exploited for studies of predictive coding and Bayes-optimal decision-making., (© 2022. The Author(s).)

Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2-100) and used normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision-making., Competing Interests: SR, CF, RD, SK, TW, MZ, PB, AW, SV, DA, LH, JB, PD, PM, RM, AS, CS, IT, ED, SC, BP, MH, SB, LH, DA, CW, LW, RZ, AM No competing interests declared, OA is a consultant for HealthLytix and received speaker's honorarium from Lundbeck and Sunovion, HR received speaker's honorarium from Lundbeck and Janssen, CB is director and shareholder of SBGNeuro Ltd, (© 2022, Rutherford et al.)

EFhd2 is a conserved calcium-binding protein that is highly expressed in the central nervous system. We have shown that EFhd2 interacts with tau protein, a key pathological hallmark in Alzheimer's disease and related dementias. However, EFhd2's physiological and pathological functions in the brain are still poorly understood. To gain insights into its physiological function, we identified proteins that co-immunoprecipitated with EFhd2 from mouse forebrain and hindbrain, using tandem mass spectrometry (MS). In addition, quantitative mass spectrometry was used to detect protein abundance changes due to the deletion of the Efhd2 gene in mouse forebrain and hindbrain regions. Our data show that mouse EFhd2 is associated with cytoskeleton components, vesicle trafficking modulators, cellular stress response-regulating proteins, and metabolic proteins. Moreover, proteins associated with the cytoskeleton, vesicular transport, calcium signaling, stress response, and metabolic pathways showed differential abundance in Efhd2 (-/-) mice. This study presents, for the first time, an EFhd2 brain interactome that it is associated with different cellular and molecular processes. These findings will help prioritize further studies to investigate the mechanisms by which EFhd2 modulates these processes in physiological and pathological conditions of the nervous system., (© 2021 International Society for Neurochemistry.)

Enhancers are cis -regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type-specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in the brain., Competing Interests: JL, LS, KC, TW, IZ, YW, KL, JH, SM, CC, TS, EC, VH, SM, HP, DQ, DS, DV, LB, AN No competing interests declared, (© 2021, Lambert et al.)

Competing Interests: The authors report no conflicts of interest.

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear., Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites., Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data., Study Selection: In total, 45 1H-MRS studies contributed data., Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor., Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL)., Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose., Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Background: Mood and metabolic disorders are interrelated and may share common pathological processes. Autonomic neurons link the brain with the gastrointestinal tract and constitute a likely pathway for peripheral metabolic challenges to affect behaviors controlled by the brain. The activities of neurons along these pathways are regulated by glia, which exhibit phenotypic shifts in response to changes in their microenvironment. How glial changes might contribute to the behavioral effects of consuming a high-fat diet (HFD) is uncertain. Here, we tested the hypothesis that anxiogenic and depressive-like behaviors driven by consuming a HFD involve compromised duodenal barrier integrity and subsequent phenotypic changes to glia and neurons along the gut-brain axis., Methods: C57Bl/6 male mice were exposed to a standard diet or HFD for 20 weeks. Bodyweight was monitored weekly and correlated with mucosa histological damage and duodenal expression of tight junction proteins ZO-1 and occludin at 0, 6, and 20 weeks. The expression of GFAP, TLR-4, BDNF, and DCX were investigated in duodenal myenteric plexus, nodose ganglia, and dentate gyrus of the hippocampus at the same time points. Dendritic spine number was measured in cultured neurons isolated from duodenal myenteric plexuses and hippocampi at weeks 0, 6, and 20. Depressive and anxiety behaviors were also assessed by tail suspension, forced swimming, and open field tests., Results: HFD mice exhibited duodenal mucosa damage with marked infiltration of immune cells and decreased expression of ZO-1 and occludin that coincided with increasing body weight. Glial expression of GFAP and TLR4 increased in parallel in the duodenal myenteric plexuses, nodose ganglia, and hippocampus in a time-dependent manner. Glial changes were associated with a progressive decrease in BDNF, and DCX expression, fewer neuronal dendritic spines, and anxiogenic/depressive symptoms in HFD-treated mice. Fluorocitrate (FC), a glial metabolic poison, abolished these effects both in the enteric and central nervous systems and prevented behavioral alterations at week 20., Conclusions: HFD impairs duodenal barrier integrity and produces behavioral changes consistent with depressive and anxiety phenotypes. HFD-driven changes in both peripheral and central nervous systems are glial-dependent, suggesting a potential glial role in the alteration of the gut-brain signaling that occurs during metabolic disorders and psychiatric co-morbidity.

Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer's disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 ( Arg1 ) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells' inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness., Competing Interests: 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 © 2021 Ma, Hunt, Kovalenko, Liang, Selenica, Orr, Zhang, Gensel, Feola, Gordon, Morgan, Bickford and Lee.)

The small peptide neurotensin (Nts) is implicated in myriad processes including analgesia, thermoregulation, reward, arousal, blood pressure, and modulation of feeding and body weight. Alterations in Nts have recently been described in individuals with obesity or eating disorders, suggesting that disrupted Nts signaling may contribute to body weight disturbance. Curiously, Nts mediates seemingly opposing regulation of body weight via different tissues. Peripherally acting Nts promotes fat absorption and weight gain, whereas central Nts signaling suppresses feeding and weight gain. Thus, because Nts is pleiotropic, a location-based approach must be used to understand its contributions to disordered body weight and whether the Nts system might be leveraged to improve metabolic health. Here we review the role of Nts signaling in the brain to understand the sites, receptors, and mechanisms by which Nts can promote behaviors that modify body weight. New techniques permitting site-specific modulation of Nts and Nts receptor-expressing cells suggest that, even in the brain, not all Nts circuitry exerts the same function. Intriguingly, there may be dedicated brain regions and circuits via which Nts specifically suppresses feeding behavior and weight gain vs other Nts-attributed physiology. Defining the central mechanisms by which Nts signaling modifies body weight may suggest strategies to correct disrupted energy balance, as needed to address overweight, obesity, and eating disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

In most vertebrates, camera-style eyes contain retinal ganglion cell neurons that project to visual centers on both sides of the brain. However, in fish, ganglion cells were thought to innervate only the contralateral side, suggesting that bilateral visual projections appeared in tetrapods. Here we show that bilateral visual projections exist in non-teleost fishes and that the appearance of ipsilateral projections does not correlate with terrestrial transition or predatory behavior. We also report that the developmental program that specifies visual system laterality differs between fishes and mammals, as the Zic2 transcription factor, which specifies ipsilateral retinal ganglion cells in tetrapods, appears to be absent from fish ganglion cells. However, overexpression of human ZIC2 induces ipsilateral visual projections in zebrafish. Therefore, the existence of bilateral visual projections likely preceded the emergence of binocular vision in tetrapods., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation., Competing Interests: The authors have declared that no competing interests exist.

Context: Fear has been cited as the primary barrier to return to sport (RTS) by athletes after anterior cruciate ligament reconstruction (ACLR). Understanding the neural factors that contribute to fear after ACLR may help us to identify interventions for this population., Objective: To characterize the underlying neural substrate of injury-related fear in patients after ACLR versus healthy matched control individuals during a picture imagination task (PIT) consisting of sport-specific images and images of activities of daily living (ADL)., Design: Case-control study., Setting: Research laboratory., Patients or Other Participants: A total of 24 right-hand-dominant participants (12 with left-sided ACLR and 12 control individuals) were enrolled. Participants underwent full-brain functional magnetic resonance imaging., Main Outcome Measure(s): Functional data were acquired using blood oxygen level-dependent (BOLD) echoplanar imaging. Independent t tests were conducted to identify between-groups differences in BOLD signal changes during all images of the PIT. Paired t tests were computed to examine differences in BOLD signal change between sport-specific and ADL images in the ACLR group., Results: Increased activation in the inferior parietal lobule and the mediodorsal thalamus was observed during PIT in the ACLR group. An inability to suppress the default mode network in the ACLR group was noted. The ACLR group exhibited increased activation in the cerebellum and inferior occipital regions during the sport-specific images versus the ADL images, but no other regions of interest demonstrated differences., Conclusion: After ACLR, patients may be more predisposed to fear, anxiety, and pain during sport-specific activities and ADLs. Psychosocial interventions may be warranted after ACLR to reduce injury-related fear and mitigate potentially maladaptive neuroplasticity., (© by the National Athletic Trainers' Association, Inc.)

Ornithine decarboxylase 1 ( ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC&#95;000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

Parkinson's disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding α-synuclein (aSyn) protein, either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent preformed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA-targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the nonhuman primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that, by inhibiting production of aSyn, it may be possible to reverse established pathology; thus, these data support the development of SNCA ASOs as a potential disease-modifying therapy for PD and related synucleinopathies.

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time-course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by 6 hr following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA., Competing Interests: CC, ME, KC, KA, JA, SC, KP, LS, IZ, EK, EC, JS, JG, KF, TS, Dv, LH, JV, DV, AM, AN No competing interests declared, (© 2021, Canales et al.)

Key Points: The cerebral fluid response to exercise, including the arterial and venous cerebral blood flow (CBF) and cerebrospinal fluid (CSF), currently remains unknown. We used time-resolved phase-contrast magnetic resonance imaging to assess changes in CBF and CSF flow dynamics during moderate-intensity rhythmic handgrip (RHG) exercise in young healthy men and women. Our data demonstrated that RHG increases the cerebral arterial inflow and venous outflow while decreasing the pulsatile CSF flow during RHG. Furthermore, changes in blood stroke volume at the measured arteries, veins, and sinuses and CSF stroke volume at the cerebral aqueduct were positively correlated with each other during RHG. Male and female participants exhibited distinct blood pressure responses to RHG, but their cerebral fluid responses were similar. These results collectively suggest that RHG influences both CBF and CSF flow dynamics in a way that is consistent with the Monro-Kellie hypothesis to maintain intracranial volume-pressure homeostasis in young healthy adults., Abstract: Cerebral blood flow (CBF) increases during exercise, but its impact on cerebrospinal fluid (CSF) flow remains unknown. This study investigated CBF and CSF flow dynamics during moderate-intensity rhythmic handgrip (RHG) exercise in young healthy men and women. Twenty-six participants (12 women) underwent the RHG and resting control conditions in random order. Participants performed 3 sets of RHG, during which cine phase-contrast magnetic resonance imaging (PC-MRI) was performed to measure blood stroke volume (SV) and flow rate in the internal carotid (ICA) and vertebral (VA) arteries, the internal jugular vein (IJV), the superior sagittal (SSS) and straight sinuses (SRS), and CSF SV and flow rate in the cerebral aqueduct of Sylvius. Blood pressure, end-tidal CO 2 (EtCO 2 ), heart rate (HR), and respiratory rate were simultaneously measured during cine PC-MRI scans. Compared with control conditions, RHG showed significant elevations of HR, mean arterial pressure, and respiratory rate with a mild reduction of EtCO 2 (all P < 0.05). RHG decreased blood SV in the measured arteries, veins, and sinuses and CSF SV in the aqueduct (all P < 0.05). Conversely, RHG increased blood flow in the ICA, VA, and IJV (all P < 0.05). At the aqueduct, RHG decreased the absolute CSF flow rate (P = 0.0307), which was calculated as a sum of the caudal and cranial CSF flow rates. Change in the ICA SV was positively correlated with changes in the IJV, SSS, SRS, and aqueductal SV during RHG (all P < 0.05). These findings demonstrate a close coupling between the CBF and CSF flow dynamics during RHG in young healthy adults., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Adolescence is a transitional period between childhood and adulthood characterized by significant changes in global and regional brain tissue volumes. It is also a period of increasing vulnerability to psychiatric illness. The relationship between these patterns and increased levels of circulating sex steroids during adolescence remains unclear. The objective of the current study was to determine whether gonadectomy, prior to puberty, alters adolescent brain development in male rhesus macaques. Ninety-six structural MRI scans were acquired from 12 male rhesus macaques (8 time points per animal over a two-year period). Six animals underwent gonadectomy and 6 animals underwent a sham operation at 29 months of age. Mixed-effects models were used to determine whether gonadectomy altered developmental trajectories of global and regional brain tissue volumes. We observed a significant effect of gonadectomy on the developmental trajectory of prefrontal gray matter (GM), with intact males showing peak volumes around 3.5 years of age with a subsequent decline. In contrast, prefrontal GM volumes continued to increase in gonadectomized males until the end of the study. We did not observe a significant effect of gonadectomy on prefrontal white matter or on any other global or regional brain tissue volumes, though we cannot rule out that effects might be detected in a larger sample. Results suggest that the prefrontal cortex is more vulnerable to gonadectomy than other brain regions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: An objective, reliable indicator of the presence and severity of concussive brain injury and of the readiness for the return to activity has the potential to reduce concussion-related disability., Objective: To validate the classification accuracy of a previously derived, machine learning, multimodal, brain electrical activity-based Concussion Index in an independent cohort of athletes with concussion., Design, Setting, and Participants: This prospective diagnostic cohort study was conducted at 10 clinical sites (ie, US universities and high schools) between February 4, 2017, and March 20, 2019. A cohort comprising a consecutive sample of 207 athletes aged 13 to 25 years with concussion and 373 matched athlete controls without concussion were assessed with electroencephalography, cognitive testing, and symptom inventories within 72 hours of injury, at return to play, and 45 days after return to play. Variables from the multimodal assessment were used to generate a Concussion Index at each time point. Athletes with concussion had experienced a witnessed head impact, were removed from play for 5 days or more, and had an initial Glasgow Coma Scale score of 13 to 15. Participants were excluded for known neurologic disease or history within the last year of traumatic brain injury. Athlete controls were matched to athletes with concussion for age, sex, and type of sport played., Main Outcomes and Measures: Classification accuracy of the Concussion Index at time of injury using a prespecified cutoff of 70 or less (total range, 0-100, where ≤70 indicates it is likely the individual has a concussion and >70 indicates it is likely the individual does not have a concussion)., Results: Of 580 eligible participants with analyzable data, 207 had concussion (124 male participants [59.9%]; mean [SD] age, 19.4 [2.5] years), and 373 were athlete controls (187 male participants [50.1%]; mean [SD] age, 19.6 [2.2] years). The Concussion Index had a sensitivity of 86.0% (95% CI, 80.5%-90.4%), specificity of 70.8% (95% CI, 65.9%-75.4%), negative predictive value of 90.1% (95% CI, 86.1%-93.3%), positive predictive value of 62.0% (95% CI, 56.1%-67.7%), and area under receiver operator characteristic curve of 0.89. At day 0, the mean (SD) Concussion Index among athletes with concussion was significantly lower than among athletes without concussion (75.0 [14.0] vs 32.7 [27.2]; P < .001). Among athletes with concussion, there was a significant increase in the Concussion Index between day 0 and return to play, with a mean (SD) paired difference between these time points of -41.2 (27.0) (P < .001)., Conclusions and Relevance: These results suggest that the multimodal brain activity-based Concussion Index has high classification accuracy for identification of the likelihood of concussion at time of injury and may be associated with the return to control values at the time of recovery. The Concussion Index has the potential to aid in the clinical diagnosis of concussion and in the assessment of athletes' readiness to return to play.

Lower midlife physical activity is associated with higher risk of neurodegenerative disease in late life. However, it remains unknown whether physical exercise and fitness are associated with brain structural integrity during midlife. The purpose of this study was to compare brain structures between middle-aged aerobically trained adults (MA), middle-aged sedentary (MS), and young sedentary (YS) adults. Thirty MA (54±4 years), 30 MS (54±4 years), and 30 YS (32±6 years) participants (50% women) underwent measurements of brain volume, cortical thickness, and white matter (WM) fiber integrity using MRI. MA participants had aerobic training for 24.8±9.6 years and the highest cardiorespiratory fitness level (i.e., peak oxygen uptake: VO 2peak ) among all groups. Global WM integrity, as assessed with fractional anisotropy (FA) from diffusion tensor imaging, was lower in the MS compared with the YS group. However, global FA in the MA group was significantly higher than that in the MS group (P<0.05) and at a similar level to the YS group. Furthermore, tract-based spatial statistical analysis demonstrated that FA in the anterior, superior, and limbic WM tracts (e.g., the genu of the corpus callosum, superior longitudinal fasciculus, uncinate fasciculus) was higher in the MA compared with MS groups, and positively associated with VO 2peak , independently from age and sex. From cortical thickness analysis, MS and MA participants showed thinner prefrontal and parieto-temporal areas than the YS group. On the other hand, the MA group exhibited thicker precentral, postcentral, pericalcarine, and lateral occipital cortices than the MS and YS groups. But, the insula and right superior frontal gyrus showed thinner cortical thickness in the MA compared with the MS groups. Collectively, these findings suggest that midlife aerobic exercise is associated with higher WM integrity and greater primary motor and somatosensory cortical thickness., Competing Interests: Declaration of Completing Interest The authors have no actual or potential conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Gulf War Illness (GWI) is a chronic multisymptom illness that includes gastrointestinal disorders. Although the exact etiology of GWI is unknown, exposure to the drug pyridostigmine bromide (PB) is considered a major factor. Exposure to PB drives enteric neuroinflammation, promotes immunosuppression, and alters physiological functions of the colon in the short term but whether exposure to PB is sufficient to promote long term dysfunction is not known. Here, we tested whether exposure to PB is sufficient to drive long term changes that reflect GWI, and whether the endogenous anti-inflammatory mediator palmitoylethanolamide (PEA) is sufficient to reduce the detrimental effects of PB in the gut and brain of mice. Exposure to PB alone was not sufficient to cause major changes in neuromuscular transmission but did drive major changes by altering the effects of PEA. Calcium imaging data show that the mechanisms responsible include a shift in receptor signaling mediated by TRPV1, endocannabinoids, and peroxisome proliferator-activated receptors alpha (PPARα). Additional mechanisms include the development of glial reactivity and changes in enteric neurochemical coding and survival. PB and PEA caused major shifts in pro-inflammatory cytokines/chemokines in the brain and colon that persisted up to 5 months following exposure. Many of the effects of PB and PEA exhibit significant sex differences. Together, these results highlight novel mechanisms whereby PB promotes long-lasting changes in nervous system and immune function by inducing occult neuroplasticity that is revealed by subsequent exposure to unrelated drugs in a sex dependent manner., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Twenty million Americans suffer from peripheral nerve injury. These patients often develop chronic pain and sensory dysfunctions. In the past decade, neuroimaging studies showed that these changes are associated with altered cortical excitation-inhibition balance and maladaptive plasticity. We tested if neuromodulation of the deprived sensory cortex could restore the cortical balance, and whether it would be effective in alleviating sensory complications., Objective: We tested if non-invasive repetitive transcranial magnetic stimulation (rTMS) which induces neuronal excitability, and cell-specific magnetic activation via the Electromagnetic-perceptive gene (EPG) which is a novel gene that was identified and cloned from glass catfish and demonstrated to evoke neural responses when magnetically stimulated, can restore cortical excitability., Methods: A rat model of forepaw denervation was used. rTMS was delivered every other day for 30 days, starting at the acute or at the chronic post-injury phase. A minimally-invasive neuromodulation via EPG was performed every day for 30 days starting at the chronic phase. A battery of behavioral tests was performed in the days and weeks following limb denervation in EPG-treated rats, and behavioral tests, fMRI and immunochemistry were performed in rTMS-treated rats., Results: The results demonstrate that neuromodulation significantly improved long-term mobility, decreased anxiety and enhanced neuroplasticity. The results identify that both acute and delayed rTMS intervention facilitated rehabilitation. Moreover, the results implicate EPG as an effective cell-specific neuromodulation approach., Conclusion: Together, these results reinforce the growing amount of evidence from human and animal studies that are establishing neuromodulation as an effective strategy to promote plasticity and rehabilitation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Where is human language processed in the brain independent of its form? We addressed this issue by analyzing the cortical responses to spoken, written and signed sentences at the level of individual subjects. By applying a novel fingerprinting method based on the distributed pattern of brain activity, we identified a left-lateralized network composed by the superior temporal gyrus/sulcus (STG/STS), inferior frontal gyrus (IFG), precentral gyrus/sulcus (PCG/PCS), and supplementary motor area (SMA). In these regions, the local distributed activity pattern induced by any of the three language modalities can predict the activity pattern induced by the other two modalities, and such cross-modal prediction is individual-specific. The prediction is successful for speech-sign bilinguals across all possible modality pairs, but fails for monolinguals across sign-involved pairs. In comparison, conventional group-mean focused analysis detects shared cortical activations across modalities only in the STG, PCG/PCS and SMA, and the shared activations were found in both groups. This study reveals the core language system in the brain that is shared by spoken, written and signed language, and demonstrates that it is possible and desirable to utilize the information of individual differences for functional brain mapping., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Mass media messaging is central for health communication. The success of these efforts, however, depends on whether health messages resonate with their target audiences. Here, we used electroencephalography (EEG) to capture brain responses of young adults - an important target group for alcohol prevention - while they viewed real-life video messages of varying perceived message effectiveness about risky alcohol use. We found that strong messages, which were rated to be more effective, prompted enhanced inter-subject correlation (ISC). In further analyses, we linked ISC to subsequent drinking behavior change and used time-resolved EEG-ISC to model functional neuroimaging data (fMRI) of an independent audience. The EEG measure was not only related to sensory-perceptual brain regions, but also to regions previously related to successful messaging, i.e., cortical midline regions and the insula. The findings suggest EEG-ISC as a marker for audience engagement and effectiveness of naturalistic health messages, which could quantify the impact of mass communication within the brains of small target audiences., Competing Interests: Declaration of Competing interest The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)