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Mutations that impair a protein-folding chaperone can lead to brain malformations.

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of "TRiCopathies."

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management., (© 2024. Springer Nature Limited.)

Mitochondrial bioenergetics in females and males is different. However, whether mitochondria from male and female brains display differences in enzymes of oxidative phosphorylation remains unknown. Therefore, we characterized mitochondrial complexes from the brains of male and female macaques (Macaca mulatta). Cerebral tissue from male macaques exhibits elevated content and activity of mitochondrial complex I (NADH:ubiquinone oxidoreductase) and higher activity of complex II (succinate dehydrogenase) compared to females. No significant differences between sexes were found in the content of α-ketoglutarate dehydrogenase or in the activities of cytochrome c oxidase and F 1 F o ATPase. Our results underscore the need for further investigations to elucidate sex-related mitochondrial differences in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Deleterious Ca 2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca 2+ are retarded in hypoxia-tolerant naked mole-rat brain. We hypothesized that naked mole-rat brain mitochondria have an enhanced capacity to buffer exogenous Ca 2+ and examined Ca 2+ handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca 2+ than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC 50 ) at which Ca 2+ inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca 2+ uptake is the mitochondrial membrane potential (Δψ m ), and the IC 50 at which Ca 2+ decreases Δψ m is ∼4-fold higher in naked mole-rat than mouse brain. The ability of naked mole-rat brain mitochondria to safely retain large volumes of Ca 2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca 2+ in mitochondria. Specifically, and relative to mouse brain, naked mole-rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca 2+ management. We propose that excessive Ca 2+ influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca 2+ overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca 2+ influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca 2+ influx into naked mole-rat brain is markedly reduced relative to mice. This is important because naked mole-rat brain is robustly tolerant against in vitro hypoxia, and because Ca 2+ is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole-rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca 2+ stress. This is due to mitochondrial buffering of exogenous Ca 2+ and is driven by a mitochondrial membrane potential-dependant mechanism. The unique ultrastructure of naked mole-rat brain mitochondria, as a large physical storage space, may support increased Ca 2+ buffering and thus hypoxia-tolerance., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Rationale: Brain pericytes can acquire multipotency to produce multi-lineage cells following injury. However, pericytes are a heterogenous population and it remains unknown whether there are different potencies from different subsets of pericytes in response to injury. Methods: We used an ischemic stroke model combined with pericyte lineage tracing animal models to investigate brain pericyte heterogeneity under both naïve and brain injury conditions via single-cell RNA-sequencing and immunohistochemistry analysis. In addition, we developed an NG2 + pericyte neural reprogramming culture model from both murine and humans to unveil the role of energy sensor, AMP-dependent kinase (AMPK), activity in modulating the reprogramming/differentiation process to convert pericytes to functional neurons by targeting a Ser 436 phosphorylation on CREB-binding protein (CBP), a histone acetyltransferase. Results: We showed that two distinct pericyte subpopulations, marked by NG2 + and Tbx18 + , had different potency following brain injury. NG2 + pericytes expressed dominant neural reprogramming potential to produce newborn neurons, while Tbx18 + pericytes displayed dominant multipotency to produce endothelial cells, fibroblasts, and microglia following ischemic stroke. In addition, we discovered that AMPK modulators facilitated pericyte-to-neuron conversion by modulating Ser436 phosphorylation status of CBP, to coordinate an acetylation shift between Sox2 and histone H2B, and to regulate Sox2 nuclear-cytoplasmic trafficking during the reprogramming/differentiation process. Finally, we showed that sequential treatment of compound C (CpdC) and metformin, AMPK inhibitor and activator respectively, robustly facilitated the conversion of human pericytes into functional neurons. Conclusion: We revealed that two distinct subtypes of pericytes possess different reprogramming potencies in response to physical and ischemic injuries. We also developed a genomic integration-free methodology to reprogram human pericytes into functional neurons by targeting NG2 + pericytes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Recent studies have reported significant advances in modeling the biological basis of heterogeneity in major depressive disorder, but investigators have also identified important technical challenges, including scanner-related artifacts, a propensity for multivariate models to overfit, and a need for larger samples with more extensive clinical phenotyping. The goals of the current study were to evaluate dimensional and categorical solutions to parsing heterogeneity in depression that are stable and generalizable in a large, single-site sample., Methods: We used regularized canonical correlation analysis to identify data-driven brain-behavior dimensions that explain individual differences in depression symptom domains in a large, single-site dataset comprising clinical assessments and resting-state functional magnetic resonance imaging data for 328 patients with major depressive disorder and 461 healthy control participants. We examined the stability of clinical loadings and model performance in held-out data. Finally, hierarchical clustering on these dimensions was used to identify categorical depression subtypes., Results: The optimal regularized canonical correlation analysis model yielded 3 robust and generalizable brain-behavior dimensions that explained individual differences in depressed mood and anxiety, anhedonia, and insomnia. Hierarchical clustering identified 4 depression subtypes, each with distinct clinical symptom profiles, abnormal resting-state functional connectivity patterns, and antidepressant responsiveness to repetitive transcranial magnetic stimulation., Conclusions: Our results define dimensional and categorical solutions to parsing neurobiological heterogeneity in major depressive disorder that are stable, generalizable, and capable of predicting treatment outcomes, each with distinct advantages in different contexts. They also provide additional evidence that regularized canonical correlation analysis and hierarchical clustering are effective tools for investigating associations between functional connectivity and clinical symptoms., (Copyright © 2024. Published by Elsevier Inc.)

Different kinds of traumatic experiences like natural catastrophes vs. relational traumatic experiences (e.g., sex/physical abuse, interpersonal partner violence) are involved in the development of the self and PTSD psychopathological manifestations. Looking at a neuroscience approach, it has been proposed a nested hierarchical model of self, which identifies three neural-mental networks: (i) interoceptive; (ii) exteroceptive; (iii) mental. However, it is still unclear how the self and its related brain networks might be affected by non-relational vs relational traumatic experiences. Departing from this background, the current study aims at conducting a meta-analytic review of task-dependent fMRI studies (i.e., emotional processing task) among patients with PTSD due to non-relational (PTSD-NR) and relational (PTSD-R) traumatic experiences using two approaches: (i) a Bayesian network meta-analysis for a region-of-interest-based approach; (ii) a coordinated-based meta-analysis. Our findings suggested that the PTSD-NR mainly recruited areas ascribed to the mental self to process emotional stimuli. Whereas, the PTSD-R mainly activated regions associated with the intero-exteroceptive self. Accordingly, the PTSD-R compared to the PTSD-NR might not reach a higher symbolic capacity to process stimuli with an emotional valence. These results are also clinically relevant in support of the development of differential treatment approaches for non-relational vs. relational PTSD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Meditation encompasses a range of practices employing diverse induction techniques, each characterized by a distinct attentional focus. In Mantra meditation, for instance, practitioners direct their attention narrowly to a given sentence that is recursively repeated, while other forms of meditation such as Shoonya meditation are induced by a wider attentional focus. Here we aimed to identify the neural underpinnings and correlates associated with this spectrum of distinct attentional foci. To accomplish this, we used EEG data to estimate the brain's intrinsic neural timescales (INTs), that is, its temporal windows of activity, by calculating the Autocorrelation Window (ACW) of the EEG signal. The autocorrelation function measures the similarity of a timeseries with a time-lagged version of itself by correlating the signal with itself on different time lags, consequently providing an estimation of INTs length. Therefore, through using the ACW metric, our objective was to explore whether there is a correspondence between the length of the brain's temporal windows of activity and the width of the attentional scope during various meditation techniques. This was performed on three groups of highly proficient practitioners belonging to different meditation traditions, as well as a meditation-naïve control group. Our results indicated that practices with a wider attentional focus, like Shoonya meditation, exhibit longer ACW durations compared to practices requiring a narrower attentional focus, such as Mantra meditation or body-scanning Vipassana meditation. Together, we demonstrated that distinct meditation techniques with varying widths of attentional foci exhibit unique durations in their brain's INTs. This may suggest that the width of the attentional scope during meditation relates and corresponds to the width of the brain's temporal windows in its neural activity. SIGNIFICANCE STATEMENT: Our research uncovered the neural mechanisms that underpin the attentional foci in various meditation techniques. We revealed that distinct meditation induction techniques, featured by their range of attentional widths, are characterized by varying lengths of intrinsic neural timescales (INTs) within the brain, as measured by the Autocorrelation Window function. This finding may bridge the gap between the width of attentional windows (subjective) and the width of the temporal windows in the brain's neural activity (objective) during different meditation techniques, offering a new understanding of how cognitive and neural processes are related to each other. This work holds significant implications, especially in the context of the increasing use of meditation in mental health and well-being interventions. By elucidating the distinct neural foundations of different meditation techniques, our research aims to pave the way for developing more tailored and effective meditation-based treatments., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is a general consensus that schizophrenia (SZ) is characterized by major changes in the sense of self. Phenomenological studies suggest that these changes in the sense of self stem from a basic disturbance, hence the term 'basic self-disturbance'. While imaging studies demonstrate changes in various regions during self-focused tasks, the exact neural correlates of such basic self-disturbances remain unclear. If the self-disturbance is indeed basic and thereby underlies all other symptoms, one would expect it to be related to more global rather than local changes in the brain. Testing this hypothesis, we conducted a systematic review of fMRI studies on self in SZ. Our main findings are 1. Abnormal activity related to the self can be observed in a variety of different regions ranging from higher-order transmodal to lower-order unimodal regions, 2. These findings hold true across different tasks including self-reflection, self-referentiality, and self-agency, and 3. The global neural abnormalities related to the self in SZ correspond to all layers of the self, predominantly the mental and exteroceptive self. Such global neural disturbance of self converges well with the basic self-disturbance as described in phenomenology., Competing Interests: Declaration of competing interest There are no conflicts of interest to report. G.N. is supported by Canadian Institutes of Health Research, Social Sciences and Humanities Research Council, Natural Sciences and Engineering Research Council, New Frontiers in Research Fund, and the UK-Canada AI grant which he holds together with Karl Friston. The funding sources had no involvement in neither the collection, analysis and interpretation of data, nor in the writing of the article nor in the decision to submit the article for publication., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

As spaceflight becomes more common with commercial crews, blood-based measures of crew health can guide both astronaut biomedicine and countermeasures. By profiling plasma proteins, metabolites, and extracellular vesicles/particles (EVPs) from the SpaceX Inspiration4 crew, we generated "spaceflight secretome profiles," which showed significant differences in coagulation, oxidative stress, and brain-enriched proteins. While >93% of differentially abundant proteins (DAPs) in vesicles and metabolites recovered within six months, the majority (73%) of plasma DAPs were still perturbed post-flight. Moreover, these proteomic alterations correlated better with peripheral blood mononuclear cells than whole blood, suggesting that immune cells contribute more DAPs than erythrocytes. Finally, to discern possible mechanisms leading to brain-enriched protein detection and blood-brain barrier (BBB) disruption, we examined protein changes in dissected brains of spaceflight mice, which showed increases in PECAM-1, a marker of BBB integrity. These data highlight how even short-duration spaceflight can disrupt human and murine physiology and identify spaceflight biomarkers that can guide countermeasure development., (© 2024. The Author(s).)

RNA isoforms influence cell identity and function. However, a comprehensive brain isoform map was lacking. We analyze single-cell RNA isoforms across brain regions, cell subtypes, developmental time points and species. For 72% of genes, full-length isoform expression varies along one or more axes. Splicing, transcription start and polyadenylation sites vary strongly between cell types, influence protein architecture and associate with disease-linked variation. Additionally, neurotransmitter transport and synapse turnover genes harbor cell-type variability across anatomical regions. Regulation of cell-type-specific splicing is pronounced in the postnatal day 21-to-postnatal day 28 adolescent transition. Developmental isoform regulation is stronger than regional regulation for the same cell type. Cell-type-specific isoform regulation in mice is mostly maintained in the human hippocampus, allowing extrapolation to the human brain. Conversely, the human brain harbors additional cell-type specificity, suggesting gain-of-function isoforms. Together, this detailed single-cell atlas of full-length isoform regulation across development, anatomical regions and species reveals an unappreciated degree of isoform variability across multiple axes., (© 2024. The Author(s).)

CD46 is a complementary regulatory protein ubiquitously expressed in human cells, controlling complement system activation. CD46 has further been identified to have several other functions including regulatory T cell induction and intestinal epithelial (IEC) barrier regulation. Activation of CD46 in the IEC can impact intestinal barrier permeability and immune system functioning. CD46 has only been identified in the spermatozoa and retina of mice. In other murine cells, the homologue CRRY is identified to function as the complementary regulator. Due to the identification of CRRY across other wild-type mouse cells and the development of mouse strains transgenic for human CD46, no recent research has been conducted to determine if CD46 is present in non-transgenic mouse strains. Therefore, the current study investigated if CD46 is expressed in the substantia nigra (SN) and caudate putamen (CP) of pubescent CD1 mice and examined the acute effects of pubertal antimicrobial and lipopolysaccharide (LPS) treatment on CD46 expression in the brain. As of 5 weeks of age, mice were administered mixed antimicrobial solution or water with oral gavage twice daily for 7 days. At 6 weeks of age, mice received an intraperitoneal injection of LPS or saline. Mice were euthanized 8 h post-injection and brain samples were collected. Our results indicate that pubescent CD-1 mice express CD46 in the SN and CP. However, LPS-treated mice displayed significantly less CD46 expression in the SN in comparison to saline-treated mice. Furthermore, males displayed more CD46 in the CP compared to females, regardless of LPS and antimicrobial treatments. Our data suggest CD46 is present in CD1 mice and that LPS and antimicrobial treatments impact CD46 protein expression in a sex-dependent manner. These results have important implications for the expression of CD46 in the mouse brain and the understanding of its role in immune system regulation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Functional magnetic resonance imaging (fMRI) studies have demonstrated that intrinsic neuronal timescales (INT) undergo modulation by external stimulation during consciousness. It remains unclear if INT keep the ability for significant stimulus-induced modulation during primary unconscious states, such as sleep. This fMRI analysis addresses this question via a dataset that comprises an awake resting-state plus rest and stimulus states during sleep. We analyzed INT measured via temporal autocorrelation supported by median frequency (MF) in the frequency-domain. Our results were replicated using a biophysical model. There were two main findings: (1) INT prolonged while MF decreased from the awake resting-state to the N2 resting-state, and (2) INT shortened while MF increased during the auditory stimulus in sleep. The biophysical model supported these results by demonstrating prolonged INT in slowed neuronal populations that simulate the sleep resting-state compared to an awake state. Conversely, under sine wave input simulating the stimulus state during sleep, the model's regions yielded shortened INT that returned to the awake resting-state level. Our results highlight that INT preserve reactivity to stimuli in states of unconsciousness like sleep, enhancing our understanding of unconscious brain dynamics and their reactivity to stimuli., (© 2023. The Author(s).)

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AR is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and, until 31 July 2020, was a scientific advisory board member of Thermo Fisher Scientific, Syros Pharmaceuticals, Asimov, and Neogene Therapeutics. From 1 August 2020, AR is an employee of Genentech and has equity in Roche. AR is a named inventor on multiple patents related to single cell and spatial genomics filed by or issued to the Broad Institute., (Copyright: © 2023 Hawrylycz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brain-injured patients in a state of cognitive motor dissociation (CMD) exhibit a lack of command following using conventional neurobehavioral examination tools but a high level of awareness and language processing when assessed using advanced imaging and electrophysiology techniques. Because of their behavioral unresponsiveness, patients with CMD may seem clinically indistinguishable from those with a true disorder of consciousness that affects awareness on a substantial level (coma, vegetative state/unresponsive wakefulness state, or minimally conscious state minus). Yet, by expanding the range of motor testing across limb, facial, and ocular motricity, we may detect subtle, purposeful movements even in the subset of patients classified as vegetative state/unresponsive wakefulness state. We propose the term of clinical CMD to describe patients showing these slight but determined motor responses and exhibiting a characteristic akinetic motor behavior as opposed to a pyramidal motor system behavior. These patients may harbor hidden cognitive capabilities and significant potential for a good long-term outcome. Indeed, we envision CMD as ranging from complete (no motor response) to partial (subtle clinical motor response) forms, falling within a spectrum of progressively better motor output in patients with considerable cognitive capabilities. In addition to providing a decisional flowchart, we present this novel approach to classification as a graphical model that illustrates the range of clinical manifestations and recovery trajectories fundamentally differentiating true disorders of consciousness from the spectrum of CMD., (© 2023 American Academy of Neurology.)

Dreams are one of the most bizarre and least understood states of consciousness. Bridging the gap between brain and phenomenology of (un)conscious experience, we propose the Topographic-dynamic Re-organization model of Dreams (TRoD). Topographically, dreams are characterized by a shift towards increased activity and connectivity in the default-mode network (DMN) while they are reduced in the central executive network, including the dorsolateral prefrontal cortex (except in lucid dreaming). This topographic re-organization is accompanied by dynamic changes; a shift towards slower frequencies and longer timescales. This puts dreams dynamically in an intermediate position between awake state and NREM 2/SWS sleep. TRoD proposes that the shift towards DMN and slower frequencies leads to an abnormal spatiotemporal framing of input processing including both internally- and externally-generated inputs (from body and environment). In dreams, a shift away from temporal segregation to temporal integration of inputs results in the often bizarre and highly self-centric mental contents as well as hallucinatory-like states. We conclude that topography and temporal dynamics are core features of the TroD, which may provide the connection of neural and mental activity, e.g., brain and experience during dreams as their "common currency"., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Recent evidence implicates cranial border immune compartments in the meninges, choroid plexus, circumventricular organs, and skull bone marrow in several neuroinflammatory and neoplastic diseases. Their pathogenic importance has also been described for cardiovascular diseases such as hypertension and stroke. In this review, we will examine the cellular composition of these cranial border immune niches, the potential pathways through which they might interact, and the evidence linking them to cardiovascular disease., (© 2023. The Author(s).)

The human brain's cerebral cortex exhibits a topographic division into higher-order transmodal core and lower-order unimodal periphery regions. While timescales between the core and periphery region diverge, features of their power spectra, especially scale-free dynamics during resting-state and their mdulation in task states, remain unclear. To answer this question, we investigated the ~1/f-like pink noise manifestation of scale-free dynamics in the core-periphery topography during rest and task states applying infra-slow inter-trial intervals up to 1 min falling inside the BOLD's infra-slow frequency band. The results demonstrate (1) higher resting-state power-law exponent (PLE) in the core compared to the periphery region; (2) significant PLE increases in task across the core and periphery regions; and (3) task-related PLE increases likely followed the task's atypically low event rates, namely the task's periodicity (inter-trial interval = 52-60 s; 0.016-0.019 Hz). A computational model and a replication dataset that used similar infra-slow inter-trial intervals provide further support for our main findings. Altogether, the results show that scale-free dynamics differentiate core and periphery regions in the resting-state and mediate task-related effects., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: The new 2023 Canadian Brain-Based Definition of Death Clinical Practice Guideline provides a new definition of death as well as clear procedures for the determination of death (i.e., when that definition is met). Since physicians must practice in accordance with existing laws, this legal analysis describes the existing legal definitions of death in Canada and considers whether the new Guideline is consistent with those definitions. It also considers how religious freedom and equality in the Canadian Charter of Rights and Freedoms might apply to the diagnosis of brain death., Method: We performed a legal analysis in accordance with standard procedures of legal research and analysis-including reviews of statutory law, case law, and secondary legal literature. The draft paper was discussed by the Legal-Ethical Working Subgroup and presented to the larger Guideline project team for comment., Results and Conclusion: There are some differences between the wording of the new Guideline and existing legal definitions. To reduce confusion, these should be addressed through revising the legal definitions. In addition, future challenges to brain death based on the Charter of Rights and Freedoms can be anticipated. Facilities should consider and adopt policies that identify what types of accommodation of religious objection and what limits to accommodation are reasonable and well-justified., (© 2023. The Author(s).)

Background: In the cerebral cortex, disinhibited activity is characterized by propagating waves that spread across neural tissue. In this pathological state, a widely reported form of activity are spiral waves that travel in a circular pattern around a fixed spatial locus termed the center of mass. Spiral waves exhibit stereotypical activity and involve broad patterns of co-fluctuations, suggesting that they may be of lower complexity than healthy activity., Results: To evaluate this hypothesis, we performed dense multi-electrode recordings of cortical networks where disinhibition was induced by perfusing a pro-epileptiform solution containing 4-Aminopyridine as well as increased potassium and decreased magnesium. Spiral waves were identified based on a spatially delimited center of mass and a broad distribution of instantaneous phases across electrodes. Individual waves were decomposed into "snapshots" that captured instantaneous neural activation across the entire network. The complexity of these snapshots was examined using a measure termed the participation ratio. Contrary to our expectations, an eigenspectrum analysis of these snapshots revealed a broad distribution of eigenvalues and an increase in complexity compared to baseline networks. A deep generative adversarial network was trained to generate novel exemplars of snapshots that closely captured cortical spiral waves. These synthetic waves replicated key features of experimental data including a tight center of mass, a broad eigenvalue distribution, spatially-dependent correlations, and a high complexity. By adjusting the input to the model, new samples were generated that deviated in systematic ways from the experimental data, thus allowing the exploration of a broad range of states from healthy to pathologically disinhibited neural networks., Conclusions: Together, results show that the complexity of population activity serves as a marker along a continuum from healthy to disinhibited brain states. The proposed generative adversarial network opens avenues for replicating the dynamics of cortical seizures and accelerating the design of optimal neurostimulation aimed at suppressing pathological brain activity., (© 2023. The Author(s).)

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Improper or aberrant protein-protein interactions can lead to severe human diseases including cancer. Here, we describe an adapted proximity ligation assay (PLA) protocol for the assessment of galectin-1-HOXA5 interaction in brain tumor stem cells (BTSCs). We detail the steps for culturing and preparation of BTSCs followed by PLA and detection of protein interactions in situ using fluorescent microscopy. This PLA protocol is optimized specifically for BTSCs and includes key controls for effective result analysis. For complete details on the use and execution of this protocol, please refer to Sharanek et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Single-nuclei RNA sequencing characterizes cell types at the gene level. However, compared to single-cell approaches, many single-nuclei cDNAs are purely intronic, lack barcodes and hinder the study of isoforms. Here we present single-nuclei isoform RNA sequencing (SnISOr-Seq). Using microfluidics, PCR-based artifact removal, target enrichment and long-read sequencing, SnISOr-Seq increased barcoded, exon-spanning long reads 7.5-fold compared to naive long-read single-nuclei sequencing. We applied SnISOr-Seq to adult human frontal cortex and found that exons associated with autism exhibit coordinated and highly cell-type-specific inclusion. We found two distinct combination patterns: those distinguishing neural cell types, enriched in TSS-exon, exon-polyadenylation-site and non-adjacent exon pairs, and those with multiple configurations within one cell type, enriched in adjacent exon pairs. Finally, we observed that human-specific exons are almost as tightly coordinated as conserved exons, implying that coordination can be rapidly established during evolution. SnISOr-Seq enables cell-type-specific long-read isoform analysis in human brain and in any frozen or hard-to-dissociate sample., (© 2022. The Author(s).)

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., (© 2022. The Author(s).)

Previous experiments charted the development of behavioral arousal in postnatal mice. From Postnatal Day 3 (P3) to Postnatal Day 6 (P6) mice (a) become significantly more active, "arousable"; and (b) in large reticular neurons, nucleus gigantocellularis (NGC), patch clamp recordings reveal a significantly increased ability to fire high frequency trains of action potentials as are associated with elevated cortical arousal. These action potential trains depend on delayed rectifiers such as Kv2.1. Here we report tracking the development of expression of a delayed rectifier, Kv2.1 in NGC neurons crucial for initiating CNS arousal. In tissue sections, light microscope immunohistochemistry revealed that expression of Kv2.1 in NGC neurons is greater at day P6 than at P3. Electron microscope immunohistochemistry revealed Kv2.1 labeling on the plasmalemmal surface of soma and dendrites, greater on P6 than P3. In brainstem reticular neuron cell culture, Kv2.1 immunocytochemistry increased monotonically from Days-In-Vitro 3-10, paralleling the ability of such neurons to fire action potential trains. The increase of Kv2.1 expression from P3 to P6, perhaps in conjunction with other delayed rectifier currents, could permit the ability to fire action potential trains in NGC neurons. Further work with genetically identified NGC neurons is indicated., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Impairments in mitochondrial energy metabolism have been implicated in human genetic diseases associated with mitochondrial and nuclear DNA mutations, neurodegenerative and cardiovascular disorders, diabetes, and aging. Alteration in mitochondrial complex I structure and activity has been shown to play a key role in Parkinson's disease and ischemia/reperfusion tissue injury, but significant difficulty remains in assessing the content of this enzyme complex in a given sample. The present study introduces a new method utilizing native polyacrylamide gel electrophoresis in combination with flavin fluorescence scanning to measure the absolute content of complex I, as well as α-ketoglutarate dehydrogenase complex, in any preparation. We show that complex I content is 19 ± 1 pmol/mg of protein in the brain mitochondria, whereas varies up to 10-fold in different mouse tissues. Together with the measurements of NADH-dependent specific activity, our method also allows accurate determination of complex I catalytic turnover, which was calculated as 10 4 min -1 for NADH:ubiquinone reductase in mouse brain mitochondrial preparations. α-ketoglutarate dehydrogenase complex content was determined to be 65 ± 5 and 123 ± 9 pmol/mg protein for mouse brain and bovine heart mitochondria, respectively. Our approach can also be extended to cultured cells, and we demonstrated that about 90 × 10 3 complex I molecules are present in a single human embryonic kidney 293 cell. The ability to determine complex I content should provide a valuable tool to investigate the enzyme status in samples after in vivo treatment in mutant organisms, cells in culture, or human biopsies., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021. Published by Elsevier Inc.)

Neural responses to the same stimulus show significant variability over trials, with this variability typically reduced (quenched) after a stimulus is presented. This trial-to-trial variability (TTV) has been much studied, however how this neural variability quenching is influenced by the ongoing dynamics of the prestimulus period is unknown. Utilizing a human intracranial stereo-electroencephalography (sEEG) data set, we investigate how prestimulus dynamics, as operationalized by standard deviation (SD), shapes poststimulus activity through trial-to-trial variability (TTV). We first observed greater poststimulus variability quenching in those real trials exhibiting high prestimulus variability as observed in all frequency bands. Next, we found that the relative effect of the stimulus was higher in the later (300-600ms) than the earlier (0-300ms) poststimulus period. Lastly, we replicate our findings in a separate EEG dataset and extend them by finding that trials with high prestimulus variability in the theta and alpha bands had faster reaction times. Together, our results demonstrate that stimulus-related activity, including its variability, is a blend of two factors: 1) the effects of the external stimulus itself, and 2) the effects of the ongoing dynamics spilling over from the prestimulus period - the state at stimulus onset - with the second dwarfing the influence of the first., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

The brain is supplied by an elaborate vascular network that originates extracranially and reaches deep into the brain. The concept of the neurovascular unit provides a useful framework to investigate how neuronal signals regulate nearby microvessels to support the metabolic needs of the brain, but it does not consider the role of larger cerebral arteries and systemic vasoactive signals. Furthermore, the recently emerged molecular heterogeneity of cerebrovascular cells indicates that there is no prototypical neurovascular unit replicated at all levels of the vascular network. Here, we examine the cellular and molecular diversity of the cerebrovascular tree and the relative contribution of systemic and brain-intrinsic factors to neurovascular function. Evidence supports the concept of a 'neurovascular complex' composed of segmentally diverse functional modules that implement coordinated vascular responses to central and peripheral signals to maintain homeostasis of the brain. This concept has major implications for neurovascular regulation in health and disease and for brain imaging., (© 2021. Springer Nature America, Inc.)

SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel's distal intracellular C-terminal domain, and we analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in WT and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function, and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.

Objective: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer., Methods: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests., Results: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005)., Interpretation: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169., (© 2021 American Neurological Association.)

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.)

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14 + monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E 2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE 2 , which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The COVID-19 crisis is affecting our sense of self and touches upon our existential fears. This extends to the self-other relationship, as there is both being infected and infecting the other. What does this pandemic crisis tell us about our self and relatedness, its cultural differences, and how these are rooted in the brain's relation to the world? First, we discuss the psychological and neuronal features of self and self-other relation and how they are rooted in a deeper layer of the brain's neural activity complementing its cognitive surface layer. Second, we demonstrate cultural differences of Eastern and Western concepts of the self (i.e., independency and interdependency) and how these reflect the manifestation of the brain's neuro-social and neuro-ecological alignment. Finally, we highlight the intersubjective and cultural nature of the self and its surface in the COVID-19 crisis. Discussing various lines of empirical data showing the brain's intimate alignment to both social and ecological environmental contexts, our results support the assumption of the brain's deep layer features by laying bare a continuum of different degrees of neuro-social and neuro-ecological alignment. This entails a two-stage model of self with neuro-social-ecological and psychological levels that extends the previously suggested basis model of self-specificity. We conclude that the current pandemic shows the importance of the deeper intersubjective and cultural layers of both the self and brain; their neglect can be life-threatening for the self and others and, paradoxically, might reduce, rather than enlarge, the self's sense of freedom and independence., (© 2020 The Authors Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology.)

Phosphatidylinositol-4,5-bisphosphate (PI-4,5-P 2 ) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. PI-4,5-P 2 can be generated by two families of kinases: type 1 phosphatidylinositol-4-phosphate 5-kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol-5-phosphate 4-kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kβ, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kβ is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kβ is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co-localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kβ co-localizes with the neuronal marker, NeuN. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunoperoxidase analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kβ. These results highlight the diverse cell-autonomous expression of PI5P4Kα and PI5P4Kβ and support further exploration into their role in synaptic function in the brain., (© 2020 Wiley Periodicals LLC.)

Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and neuronal death, all key processes in the pathogenesis of Parkinson's disease (PD). Polyunsaturated fatty acids (PUFAs) are important constituents of the synaptic and mitochondrial membranes and are often the first molecular targets attacked by reactive oxygen species (ROS). The rate-limiting step of the chain reaction of ROS-initiated PUFAs autoxidation involves hydrogen abstraction at bis-allylic sites, which can be slowed down if hydrogens are replaced with deuteriums. In this study, we show that targeted overexpression of human A53T α-syn using an AAV vector unilaterally in the rat substantia nigra reproduces some of pathological features seen in PD patients. Chronic dietary supplementation with deuterated PUFAs (D-PUFAs), specifically 0.8% D-linoleic and 0.3% H-linolenic, produced significant disease-modifying beneficial effects against α-syn-induced motor deficits, synaptic pathology, oxidative damage, mitochondrial dysfunction, disrupted trafficking along axons, inflammation and DA neuronal loss. These findings support the clinical evaluation of D-PUFAs as a neuroprotective therapy for PD.

Purpose of Review: Sleep is important in the evaluation of patients with disorders of consciousness (DOC). However, it remains unclear whether reconstitution of sleep could enable consciousness or vice versa. Here we synthesize recent evidence on natural recovery of sleep in DOC, and sleep-promoting therapeutic interventions for recovery of consciousness., Recent Findings: In subacute DOC, physiological sleep--wake cycles and complex sleep patterns are related to better outcomes. Moreover, structured rapid-eye-movement (REM), non-REM (NREM) stages, and presence of sleep spindles correlate with full or partial recovery. In chronic DOC, sleep organization may reflect both integrity of consciousness-supporting brain networks and engagement of those networks during wakefulness. Therapeutic strategies have integrated improvement of sleep and sleep--wake cycles in DOC patients; use of bright light stimulation or drugs enhancing sleep and/or vigilance, treatment of sleep apneas, and neuromodulatory stimulations are promising tools to promote healthy sleep architecture and wakeful recovery., Summary: Sleep features and sleep--wake cycles are important prognostic markers in subacute DOC and can provide insight into covert recovery in chronic DOC. Although large-scale studies are needed, preliminary studies in limited patients suggest that therapeutic options restoring sleep and/or sleep--wake cycles may improve cognitive function and outcomes in DOC.

Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Resting state functional connectivity magnetic resonance imaging (fMRI) is a tool for investigating human brain organization. Here we identify, visually and algorithmically, two prevalent influences on fMRI signals during 440 h of resting state scans in 440 healthy young adults, both caused by deviations from normal breathing which we term deep breaths and bursts. The two respiratory patterns have distinct influences on fMRI signals and signal covariance, distinct timescales, distinct cardiovascular correlates, and distinct tendencies to manifest by sex. Deep breaths are not sex-biased. Bursts, which are serial taperings of respiratory depth typically spanning minutes at a time, are more common in males. Bursts share features of chemoreflex-driven clinical breathing patterns that also occur primarily in males, with notable neurological, psychiatric, medical, and lifespan associations. These results identify common breathing patterns in healthy young adults with distinct influences on functional connectivity and an ability to differentially influence resting state fMRI studies.

Microglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglia rely on CSF1R signaling for survival. However, a small subset of microglia in mouse brains can survive without CSF1R signaling and reestablish the microglial homeostatic population after CSF1R signaling returns. Using single-cell transcriptomic analysis, we characterized the heterogeneous microglial populations under CSF1R inhibition, including microglia with reduced homeostatic markers and elevated markers of inflammatory chemokines and proliferation. Importantly, MAC2/ Lgals3 was upregulated under CSF1R inhibition, and shared striking similarities with microglial progenitors in the yolk sac and immature microglia in early embryos. Lineage-tracing studies revealed that these MAC2+ cells were of microglial origin. MAC2+ microglia were also present in non-treated adult mouse brains and exhibited immature transcriptomic signatures indistinguishable from those that survived CSF1R inhibition, supporting the notion that MAC2+ progenitor-like cells are present among adult microglia., Competing Interests: LZ, LF, LK, PS, MW, GM, YZ, YL No competing interests declared, LG Li Gan is a founder of Aeton Therapeutics, Inc., (© 2020, Zhan et al.)

Previous neuroimaging studies have examined the association between changes in brain structure and gastrointestinal symptoms (GIS), seen in disorders such as Irritable Bowel Syndrome and Irritable Bowel Disease. Studies in adults have found changes in white and grey matter volume (GMV) in patients with various gastrointestinal disorders. However, it is unclear whether GIS-related structural changes in the brain are limited to adults or could be present throughout the lifespan. Given that gastrointestinal disorders are typically diagnosed between 4 and 18 years old, we investigated GIS-induced morphological changes in pre-adolescents (8-10), adolescents (12-16 years) and young adults (17-21 years). Using a voxel-based morphometry (VBM) analysis, we compared regional grey matter volume (GMV) between participants with GIS and controls, using structural brain images from the Philadelphia Neurodevelopmental Cohort (PNC) database. A total of 211 participants (107 participants with GISs and 104 control participants) who had undergone structural magnetic resonance imaging were analysed. VBM analysis was used to objectively analyse GMV across the whole brain and compare between participants with GIS and controls. Participants experiencing GIS showed smaller GMV in regions within the limbic system/basal ganglia (bilateral caudate, bilateral ventral hippocampus, bilateral amygdala and bilateral superior orbital frontal cortex), and larger GMV in regions within the pain-matrix (thalamus, bilateral putamen, right mid-frontal gyrus) compared to controls. These differences were most prominent in the adolescent and young adult groups compared to pre-adolescents. In conclusion, the structural differences found in participants with GIS support the need for further research into the neurophysiological impact of these symptoms., (© 2020 International Society for Developmental Neuroscience.)

This article advances two parallel lines of argument about resting-state functional magnetic resonance imaging (fMRI) signals, one empirical and one conceptual. The empirical line creates a four-part organization of the text: (1) head motion and respiration commonly cause distinct, major, unwanted influences (artifacts) in fMRI signals; (2) head motion and respiratory changes are, confoundingly, both related to psychological and clinical and biological variables of interest; (3) many fMRI denoising strategies fail to identify and remove one or the other kind of artifact; and (4) unremoved artifact, due to correlations of artifacts with variables of interest, renders studies susceptible to identifying variance of noninterest as variance of interest. Arising from these empirical observations is a conceptual argument: that an event-related approach to task-free scans, targeting common behaviors during scanning, enables fundamental distinctions among the kinds of signals present in the data, information which is vital to understanding the effects of denoising procedures. This event-related perspective permits statements like "Event X is associated with signals A, B, and C, each with particular spatial, temporal, and signal decay properties". Denoising approaches can then be tailored, via performance in known events, to permit or suppress certain kinds of signals based on their desirability., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Hypertension is a leading cause of stroke and dementia, effects attributed to disrupting delivery of blood flow to the brain. Hypertension also alters the blood-brain barrier (BBB), a critical component of brain health. Although endothelial cells are ultimately responsible for the BBB, the development and maintenance of the barrier properties depend on the interaction with other vascular-associated cells. However, it remains unclear if BBB disruption in hypertension requires cooperative interaction with other cells. Perivascular macrophages (PVM), innate immune cells closely associated with cerebral microvessels, have emerged as major contributors to neurovascular dysfunction. Using 2-photon microscopy in vivo and electron microscopy in a mouse model of Ang II (angiotensin II) hypertension, we found that the vascular segments most susceptible to increased BBB permeability are arterioles and venules >10 µm and not capillaries. Brain macrophage depletion with clodronate attenuates, but does not abolish, the increased BBB permeability in these arterioles where PVM are located. Deletion of AT1R (Ang II type-1 receptors) in PVM using bone marrow chimeras partially attenuated the BBB dysfunction through the free radical-producing enzyme Nox2. In contrast, downregulation of AT1R in cerebral endothelial cells using a viral gene transfer-based approach prevented the BBB disruption completely. The results indicate that while endothelial AT1R, mainly in arterioles and venules, initiate the BBB disruption in hypertension, PVM are required for the full expression of the dysfunction. The findings unveil a previously unappreciated contribution of resident brain macrophages to increased BBB permeability of hypertension and identify PVM as a putative therapeutic target in diseases associated with BBB dysfunction.

Heavy ions refer to charged particles with a mass greater than four (i.e., alpha particles). The heavy ion irradiation used in radiotherapy or that astronauts suffer in space flight missions induces toxicity in normal tissue and leads to short-term and long-term damage in both the structure and function of the brain. However, the underlying molecular alterations caused by heavy ion radiation have yet to be completely elucidated. Herein, untargeted and targeted lipidomic profiling of the whole brain tissue and blood plasma 7 days after the administration of the 15 Gy (260 MeV, low linear energy (LET) = 13.9 KeV/μm) plateau irradiation of disposable 12 C 6+ heavy ions on the whole heads of rats was explored to study the lipid damage induced by heavy ion radiation in the rat brain using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) technology. Combined with multivariate variables and univariate data analysis methods, our results indicated that an orthogonal partial least squares discriminant analysis (OPLS-DA) could clearly distinguish lipid metabolites between the irradiated and control groups. Through the combination of variable weight value (VIP), variation multiple (FC), and differential (p) analyses, the significant differential lipids diacylglycerols (DAGs) were screened out. Further quantitative targeted lipidomic analyses of these DAGs in the rat brain tissue and plasma supported the notion that DAG 47:1 could be used as a potential biomarker to study brain injury induced by heavy ion irradiation.

Millions of women worldwide use oral contraceptives (i.e., birth control pill; OCs), often starting during puberty/adolescence; however, it is unknown how OC use during this critical period of development affects the brain, especially with regard to emotional working memory. Here, we examined stress reactivity, and brain structure and function in OC users using the Trier Social Stress Test and structural and functional magnetic resonance imaging (MRI). Our results show that OC use during puberty/adolescence gives rise to a blunted stress response and alters brain activation during working memory processing. OC use, in general, is also linked to increased prefrontal brain activation during working memory processing for negatively arousing stimuli. OC use is also related to significant structural changes in brain regions implicated in memory and emotional processing. Together, these findings highlight that OC use induces changes to brain structure and function and alters stress reactivity. These findings may provide a mechanistic insight for the increased vulnerability to mood-related mental illness in women after OC use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

At the end of the 19th century Pierre Janet described dissociation as an altered state of consciousness manifested in disrupted integration of psychological functions. Clinically, such disruption comprises compartmentalization symptoms like amnesia, detachment symptoms like depersonalization/derealization, and structural dissociation of personality with changes in the sense of self. The exact neuronal mechanisms leading to these different symptoms remain unclear. We here suggest to put Janet's original account of dissociation as disrupted integration of psychological functions into a novel context, that is, a neuronal context as related to current brain imaging. This requires a combined theoretical and empirical approach on data supporting such neuronal reframing of Janet. For that, we here review (i) past and (ii) recent psychological and neuronal views on dissociation together with neuroscientific theories of integration, which (iii) are supported and complemented by preliminary fMRI data. We propose three neuronal mechanisms of dynamic integration operating at different levels of the brain's spontaneous activity - temporo-spatial binding on the regional level, temporo-spatial synchronization on the network level, and temporo-spatial globalization on the global level. These neuronal mechanisms, in turn, may be related to different symptomatic manifestation of dissociation operating at different levels, e.g., compartmentalization, detachment, and structural, which, as we suggest, can all be traced to disrupted integration of neuronal and psychological functions as originally envisioned by Janet., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity., Methods: For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls., Results: Lower white matter tract disruption in a network of region-pairs centered on the precuneus and posterior cingulate (default-mode network regions) predicted greater postrehabilitation SDMT improvement (P = .048). This relationship was moderated by profiles of functional connectivity within the network (R 2 = .385, P = .017, Interaction β = -.415)., Conclusion: Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve., (© 2020 American Society of Neuroimaging.)

Although adults have matured developments of general intelligence, brain structure and brain function, many people continue to be risk takers, despite the harm that can result. The neural basis underlying risk-taking behaviors has been studied extensively in adolescents, but less so in adults. Outcome expectancies are important factors influencing individuals' risk behaviors, which comprise the expected risks (ER) and expected benefits (EB) associated with risk behaviors. In the current study, we systematically investigated inter-individual differences in adults' outcome expectancies for risk behaviors, considering the general intelligence, brain function, and brain structure. At the intelligence level, individuals with higher intelligence scores showed lower ER but higher EB associated with risk behaviors. At the brain function level, resting-state functional connectivity (FC) between regions within the default mode network is negatively correlated with ER but positively correlated with EB associated with risk behaviors, while FC between the insula and motor cortex is negatively correlated with EB associated with the risk behaviors. At the brain structure level, gray matter volume in posterior cingulate cortex (PCC) and bilateral parahippocampus were negatively correlated with the ER associated with risk behaviors. Furthermore, the relationship between the outcome expectancy associated with risk behaviors and the FC between anterior cingulate cortex and PCC is partially mediated by the general intelligence. The current study provides new insight that furthers our understanding of how individual differences in adults' risk attitudes and behaviors are modulated by general intelligence and reflected in resting-state FC and brain structures related to self-reference and inhibitory control processing., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

EEG studies have shown that interindividual differences in the electrophysiological properties of sleep spindles (e.g., density, amplitude, duration) are highly correlated with trait-like "reasoning" abilities (i.e., "fluid intelligence"; problem-solving skills; the ability to employ logic or identify complex patterns), but not interindividual differences in STM or "verbal" intellectual abilities. Previous simultaneous EEG-fMRI studies revealed brain activations time-locked to spindles. Our group has recently demonstrated that the extent of activation in a subset of these regions was related to interindividual differences in reasoning intellectual abilities, specifically. However, spindles reflect communication between spatially distant and functionally distinct brain areas. The functional communication among brain regions related to spindles and their relationship to reasoning abilities have yet to be investigated. Using simultaneous EEG-fMRI sleep recordings and psychophysiological interaction analysis, we identified spindle-related functional communication among brain regions in the thalamo-cortical-BG system, the salience network, and the default mode network. Furthermore, the extent of the functional connectivity of the cortical-striatal circuitry and the thalamo-cortical circuitry was specifically related to reasoning abilities but was unrelated to STM or verbal abilities, thus suggesting that individuals with higher fluid intelligence have stronger functional coupling among these brain areas during spontaneous spindle events. This may serve as a first step in further understanding the function of sleep spindles and the brain network functional communication, which support the capacity for fluid intelligence.