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The cognitive neuroscience of human aging seeks to identify neural mechanisms behind the commonalities and individual differences in age-related behavioral changes. This goal has been pursued predominantly through structural or "task-free" resting-state functional neuroimaging. The former has elucidated the material foundations of behavioral decline, and the latter has provided key insight into how functional brain networks change with age. Crucially, however, neither is able to capture brain activity representing specific cognitive processes as they occur. In contrast, task-based functional imaging allows a direct probe into how aging affects real-time brain-behavior associations in any cognitive domain, from perception to higher-order cognition. Here, we outline why task-based functional neuroimaging must move center stage to better understand the neural bases of cognitive aging. In turn, we sketch a multi-modal, behavior-first research framework that is built upon cognitive experimentation and emphasizes the importance of theory and longitudinal design., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epilepsy, as a chronic noncommunicable disease with recurrent seizures, may be a marker of deterioration or alteration in other underlying neurological diseases. This study aimed to investigate the relationship of epilepsy with brain function, other common brain disorders, and their underlying mechanisms., Methods: The study was based on clinical diagnostic and test data from 426,527 participants in the UK Biobank, of whom 3,251 were diagnosed with epilepsy at baseline. Multiple linear and Cox regression models were used to explore the association between epilepsy, brain function, and other brain disorders., Results: This study demonstrated consistent deleterious effects of epilepsy on cognitive and motor function and mental health. The risk of neurological diseases and psychiatric disorders was significantly elevated in the epilepsy population during the 17-year follow-up period, according to the longitudinal analysis. We also identified several brain regions associated with epilepsy, including the pallidum, hippocampus, and precentral regions. Mediation analyses revealed mediating effects of peripheral markers and proteins (e.g., GGT, HDL, ACE2, and GDF15), suggesting that liver function and lipid metabolism may be involved in the development of other brain disorders in individuals with epilepsy., Conclusions: Our study provides robust evidence of the association between epilepsy and poor brain health, underscoring the importance of early intervention for epilepsy., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted following the Declaration of Helsinki. The UK Biobank has research tissue bank approval from the North West Multi-Center Research Ethics Committee (11/NW/0382). Written informed consent was obtained from all participants. The present study was approved by UK Biobank under application number 19542. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

The ability to prioritize among input features according to relevance enables adaptive behaviors across the human lifespan. However, relevance often remains ambiguous, and such uncertainty increases demands for dynamic control. While both cognitive stability and flexibility decline during healthy ageing, it is unknown whether aging alters how uncertainty impacts perception and decision-making, and if so, via which neural mechanisms. Here, we assess uncertainty adjustment across the adult lifespan (N = 100; cross-sectional) via behavioral modeling and a theoretically informed set of EEG-, fMRI-, and pupil-based signatures. On the group level, older adults show a broad dampening of uncertainty adjustment relative to younger adults. At the individual level, older individuals whose modulation more closely resembled that of younger adults also exhibit better maintenance of cognitive control. Our results highlight neural mechanisms whose maintenance plausibly enables flexible task-set, perception, and decision computations across the adult lifespan., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Circadian rhythms are approximate 24-hour rhythms present in nearly all aspects of human physiology, including proper brain function. These rhythms are produced at the cellular level through a transcriptional-translational feedback loop known as the molecular clock. Diurnal variation in gene expression has been demonstrated in brain tissue from multiple species, including humans, in both cortical and subcortical regions. Interestingly, these rhythms in gene expression have been shown to be disrupted across psychiatric disorders and may be implicated in their underlying pathophysiology. However, little is known regarding molecular rhythms in specific cell types in the brain and how they might be involved in psychiatric disease. Although glial cells (e.g., astrocytes, microglia, and oligodendrocytes) have been historically understudied compared to neurons, evidence of the molecular clock is found within each of these cell subtypes. Here, we review the current literature, which suggests that molecular rhythmicity is essential to functional physiologic outputs from each glial subtype. Furthermore, disrupted molecular rhythms within these cells and the resultant functional deficits may be relevant to specific phenotypes across psychiatric illnesses. Given that circadian rhythm disruptions have been so integrally tied to psychiatric disease, the molecular mechanisms governing these associations could represent exciting new avenues for future research and potential novel pharmacologic targets for treatment., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function., (© 2024 Ghasempour et al.)

Objective: Mind-wandering is a pervasive human brain state and, when in excess, may promote negative affect and neuropsychiatric conditions. Mindfulness meditation may promote alternate brain states, improving affect and reducing stress. An understanding of the neural basis between these brain states could thus advance treatment of neuropsychiatric conditions, including those associated with epilepsy., Methods: To explore the neural basis of mindfulness meditation versus mind-wandering, we enrolled eight patients in a trial of structured mindfulness meditation and open mind-wandering who underwent stereo electroencephalography (sEEG) within the mesial temporal lobe for seizure localization. Electrophysiology was compared between mind-wandering and mindfulness separately for epileptic and non-epileptic MTL. Using fitting-one-over-f modeling, periodic components of electrophysiology were compared in canonical frequency bands of theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-55 Hz). Aperiodic components of the power spectra were assessed by the model offset, knee, and exponent., Results: We found a significant reduction in gamma power (30-55 Hz) within the mesial temporal lobe (MTL) during mindfulness meditation compared with mind-wandering in non-epileptic (p = 1.20E-4) but not in epileptic MTL (p = 0.352).There was also a significant difference between epileptic versus non-epileptic MTL in gamma power between conditions (p = 0.011). There were no significant changes in power across any frequency band within epileptic mesial temporal MTL between brain states. Conversely, there were significant differences between mind-wandering and mindfulness within epileptic MTL in aperiodic components (offset, knee, and exponent, all p < 0.05), while no differences in aperiodic components were seen in non-epileptic MTL (all p > 0.70)., Significance: Intracranial electrophysiologic modulations between brain state (mind-wandering versus mindfulness) may differ between epileptic and non-epileptic MTL. Modulations in gamma activity in non-epileptic MTL may represent functional changes in brain state, while aperiodic changes in epileptic MTL may modulate propensity for seizures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Fedor Panov, MD is a paid speaker for NeuroPace. The remaining authors have no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O 2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia-neuronal activity-to-vascular response-the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae., (© 2024. The Author(s).)

The fruit fly Drosophila melanogaster has emerged as a key model organism in neuroscience, in large part due to the concentration of collaboratively generated molecular, genetic and digital resources available for it. Here we complement the approximately 140,000 neuron FlyWire whole-brain connectome 1 with a systematic and hierarchical annotation of neuronal classes, cell types and developmental units (hemilineages). Of 8,453 annotated cell types, 3,643 were previously proposed in the partial hemibrain connectome 2 , and 4,581 are new types, mostly from brain regions outside the hemibrain subvolume. Although nearly all hemibrain neurons could be matched morphologically in FlyWire, about one-third of cell types proposed for the hemibrain could not be reliably reidentified. We therefore propose a new definition of cell type as groups of cells that are each quantitatively more similar to cells in a different brain than to any other cell in the same brain, and we validate this definition through joint analysis of FlyWire and hemibrain connectomes. Further analysis defined simple heuristics for the reliability of connections between brains, revealed broad stereotypy and occasional variability in neuron count and connectivity, and provided evidence for functional homeostasis in the mushroom body through adjustments of the absolute amount of excitatory input while maintaining the excitation/inhibition ratio. Our work defines a consensus cell type atlas for the fly brain and provides both an intellectual framework and open-source toolchain for brain-scale comparative connectomics., (© 2024. The Author(s).)

Connections between neurons can be mapped by acquiring and analysing electron microscopic brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative 1-6 , but nevertheless inadequate for understanding brain function more globally. Here we present a neuronal wiring diagram of a whole brain containing 5 × 10 7 chemical synapses 7 between 139,255 neurons reconstructed from an adult female Drosophila melanogaster 8,9 . The resource also incorporates annotations of cell classes and types, nerves, hemilineages and predictions of neurotransmitter identities 10-12 . Data products are available for download, programmatic access and interactive browsing and have been made interoperable with other fly data resources. We derive a projectome-a map of projections between regions-from the connectome and report on tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine and descending neurons) across both hemispheres and between the central brain and the optic lobes. Tracing from a subset of photoreceptors to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviours. The technologies and open ecosystem reported here set the stage for future large-scale connectome projects in other species., (© 2024. The Author(s).)

Introduction : Age-related cognitive decline and mental health problems are accompanied by changes in resting-state functional connectivity (rsFC) indices, such as reduced brain network segregation. Meanwhile, exercise can improve cognition, mood, and neural network function in older adults. Studies on effects of exercise on rsFC outcomes in older adults have chiefly focused on changes after exercise training and suggest improved network segregation through enhanced within-network connectivity. However, effects of acute exercise on rsFC measures of neural network integrity in older adults, which presumably underlie changes observed after exercise training, have received less attention. In this study, we hypothesized that acute exercise in older adults would improve functional segregation of major cognition and affect-related brain networks. Methods: To test this, we analyzed rsFC data from 37 healthy and physically active older adults after they completed 30 min of moderate-to-vigorous intensity cycling and after they completed a seated rest control condition. Conditions were performed in a counterbalanced order across separate days in a within-subject crossover design. We considered large-scale brain networks associated with cognition and affect, including the frontoparietal network (FPN), salience network (SAL), default mode network (DMN), and affect-reward network (ARN). Results: We observed that after acute exercise, there was greater segregation between SAL and DMN, as well as greater segregation between SAL and ARN. Conclusion: These findings indicate that acute exercise in active older adults alters rsFC measures in key cognition and affect-related networks in a manner that opposes age-related dedifferentiation of neural networks that may be detrimental to cognition and mental health.

Functional coactivation between human brain regions is partly explained by white matter connections; however, how the structure-function relationship varies by function remains unclear. Here, we reference large data repositories to compute maps of structure-function correspondence across hundreds of specific functions and brain regions. We use natural language processing to accurately predict structure-function correspondence for specific functions and to identify macroscale gradients across the brain that correlate with structure-function correspondence as well as cortical thickness. Our findings suggest structure-function correspondence unfolds along a sensory-fugal organizational axis, with higher correspondence in primary sensory and motor cortex for perceptual and motor functions, and lower correspondence in association cortex for cognitive functions. Our study bridges neuroscience and natural language to describe how structure-function coupling varies by region and function in the brain, offering insight into the diversity and evolution of neural network properties., (© 2024. The Author(s).)

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [ 11 C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mental fatigue during driving poses significant risks to road safety, necessitating accurate assessment methods to mitigate potential hazards. This study explores the impact of individual variability in brain networks on driving fatigue assessment, hypothesizing that subject-specific connectivity patterns play a pivotal role in understanding fatigue dynamics. By conducting a linear regression analysis of subject-specific brain networks in different frequency bands, this research aims to elucidate the relationships between frequency-specific connectivity patterns and driving fatigue. As such, an EEG sustained driving simulation experiment was carried out, estimating individuals' brain networks using the Phase Lag Index (PLI) to capture shared connectivity patterns. The results unveiled notable variability in connectivity patterns across frequency bands, with the alpha band exhibiting heightened sensitivity to driving fatigue. Individualized connectivity analysis underscored the complexity of fatigue assessment and the potential for personalized approaches. These findings emphasize the importance of subject-specific brain networks in comprehending fatigue dynamics, while providing sensor space minimization, advocating for the development of efficient mobile sensor applications for real-time fatigue detection in driving scenarios.

Understanding the brain response to thermal stimuli is crucial in the sensory experience. This study focuses on non-painful thermal stimuli, which are sensations induced by temperature changes without causing discomfort. These stimuli are transmitted to the central nervous system through specific nerve fibers and are processed in various regions of the brain, including the insular cortex, the prefrontal cortex, and anterior cingulate cortex. Despite the prevalence of studies on painful stimuli, non-painful thermal stimuli have been less explored. This research aims to bridge this gap by investigating brain functional connectivity during the perception of non-painful warm and cold stimuli using electroencephalography (EEG) and the partial directed coherence technique (PDC). Our results demonstrate a clear contrast in the direction of information flow between warm and cold stimuli, particularly in the theta and alpha frequency bands, mainly in frontal and temporal regions. The use of PDC highlights the complexity of brain connectivity during these stimuli and reinforces the existence of different pathways in the brain to process different types of non-painful warm and cold stimuli., (© 2024 IOP Publishing Ltd.)

Human brain experimental models recapitulating age- and disease-related characteristics are lacking. There is urgent need for human-specific tools that model the complex molecular and cellular interplay between different cell types to assess underlying disease mechanisms and test therapies. Here we present an adapted ex vivo organotypic slice culture method using human post-mortem brain tissue cultured at an air-liquid interface to also study brain white matter. We assessed whether these human post-mortem brain slices recapitulate the in vivo neuropathology and if they are suitable for pathophysiological, experimental and pre-clinical treatment development purposes, specifically regarding leukodystrophies. Human post-mortem brain tissue and cerebrospinal fluid were obtained from control, psychiatric and leukodystrophy donors. Slices were cultured up to six weeks, in culture medium with or without human cerebrospinal fluid. Human post-mortem organotypic brain slice cultures remained viable for at least six weeks ex vivo and maintained tissue structure and diversity of (neural) cell types. Supplementation with cerebrospinal fluid could improve slice recovery. Patient-derived organotypic slice cultures recapitulated and maintained known in vivo neuropathology. The cultures also showed physiologic multicellular responses to lysolecithin-induced demyelination ex vivo, indicating their suitability to study intrinsic repair mechanisms upon injury. The slice cultures were applicable for various experimental studies, as multi-electrode neuronal recordings. Finally, the cultures showed successful cell-type dependent transduction with gene therapy vectors. These human post-mortem organotypic brain slice cultures represent an adapted ex vivo model suitable for multifaceted studies of brain disease mechanisms, boosting translation from human ex vivo to in vivo. This model also allows for assessing potential treatment options, including gene therapy applications. Human post-mortem brain slice cultures are thus a valuable tool in preclinical research to study the pathomechanisms of a wide variety of brain diseases in living human tissue., (© 2024. The Author(s).)

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer's disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit ( P2RX5 and TRPV3 ) and excitatory neurons ( DPY30 and MEMO1 ). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders.

How is conscious experience related to material brain processes? A variety of theories aiming to answer this age-old question have emerged from the recent surge in consciousness research, and some are now hotly debated. Although most researchers have so far focused on the development and validation of their preferred theory in relative isolation, this article, written by a group of scientists representing different theories, takes an alternative approach. Noting that various theories often try to explain different aspects or mechanistic levels of consciousness, we argue that the theories do not necessarily contradict each other. Instead, several of them may converge on fundamental neuronal mechanisms and be partly compatible and complementary, so that multiple theories can simultaneously contribute to our understanding. Here, we consider unifying, integration-oriented approaches that have so far been largely neglected, seeking to combine valuable elements from various theories., Competing Interests: Declaration of interests M.M. is co-founder and shareholder of Intrinsic Powers. P.R. is a co-founder and shareholder of neurotechnology start-up Phosphoenix BV (the Netherlands) (https://phosphoenix.nl)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 μL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C&#95;(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 μm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T&#95;(max) of 15 min and 30 min, the C&#95;(max) of(2 866.43±135.39) and(1 462.14±197.38) μg·L~(-1), the AUC&#95;(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) μg·min·L~(-1), the MRT&#95;(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL&#95;Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of &quot;automatic blood collection-microdialysis/PK-PD&quot; in the research on neuropathic pain.

Although the primate brain contains numerous functionally distinct structures that have experienced diverse genetic changes during the course of evolution and development, these changes remain to be explored in detail. Here we utilize two classic metrics from evolutionary biology, the evolutionary rate index (ERI) and the transcriptome age index (TAI), to investigate the evolutionary alterations that have occurred in each area and developmental stage of the primate brain. We observed a higher evolutionary rate for those genes expressed in the non-cortical areas during primate evolution, particularly in human, with the highest rate of evolution being exhibited at brain developmental stages between late infancy and early childhood. Further, the transcriptome age of the non-cortical areas was lower than that of the cerebral cortex, with the youngest age apparent at brain developmental stages between late infancy and early childhood. Our exploration of the evolutionary patterns manifest in each brain area and developmental stage provides important reference points for further research into primate brain evolution., Competing Interests: Conflict of Interest The authors are unaware of any competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Greater physical activity and better sleep are associated with reduced risk of cognitive decline and dementia among older adults, but little is known about their combined associations with measures of brain function and neuropathology. This study investigated potential independent and interactive cross-sectional relationships between actigraphy-estimated total volume of physical activity (TVPA) and sleep patterns [i.e., total sleep time (TST), sleep efficiency (SE)] with resting-state functional magnetic resonance imaging (rs-fMRI) measures of large scale network connectivity and positron emission tomography (PET) measures of amyloid-β. Participants were 135 non-demented older adults from the BIOCARD study (116 cognitively normal and 19 with mild cognitive impairment; mean age = 70.0 years). Using multiple linear regression analyses, we assessed the association between TVPA, TST, and SE with connectivity within the default-mode, salience, and fronto-parietal control networks, and with network modularity, a measure of network segregation. Higher TVPA and SE were independently associated with greater network modularity, although the positive relationship of SE with modularity was only present in amyloid-negative individuals. Additionally, higher TVPA was associated with greater connectivity within the default-mode network, while greater SE was related to greater connectivity within the salience network. In contrast, longer TST was associated with lower network modularity, particularly among amyloid-positive individuals, suggesting a relationship between longer sleep duration and greater network disorganization. Physical activity and sleep measures were not associated with amyloid positivity. These data suggest that greater physical activity levels and more efficient sleep may promote more segregated and potentially resilient functional networks and increase functional connectivity within specific large-scale networks and that the relationship between sleep and functional networks connectivity may depend on amyloid status., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prospective isolation of defined cell types is critical for the functional study of stem cells, especially in primary human tissues. Here, we present a protocol for purifying 10 transcriptomically and functionally distinct neural stem and progenitor cell types from the developing human brain using fluorescence-activated cell sorting. We describe steps for tissue dissociation, staining, and cell sorting as well as downstream functional experiments for measuring clonogenicity, differentiation, and engraftment potential of purified populations. For complete details on the use and execution of this protocol, please refer to Liu et al. (2023). 1 ., Competing Interests: Declaration of interests D.D.L., J.Q.H., R.S., N.U., and I.L.W. are listed as inventors on a pending patent related to this protocol. I.L.W. is a co-founder of Bitterroot Bio, Inc. and Pheast, Inc., neither of which are related to the current protocol. I.L.W. was an initial co-founder and N.U. a former employee of StemCells, Inc., but they are not currently consultants or employees at the company or its successor., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The well-elucidated improvement of mood immediately after exercise in older adults presumably involves adaptations in emotion-processing brain networks. However, little is known about effects of acute exercise on appetitive and aversive emotion-related network recruitment in older adults. The purpose of this study was to determine the effect of acute exercise, compared to a seated rest control condition, on pleasant and unpleasant emotion-related regional activation in healthy older adults. Functional MRI data were acquired from 32 active older adults during blocked presentations of pleasant, neutral and unpleasant images from the International Affective Pictures System. fMRI data were collected after participants completed 30 min of moderate to vigorous intensity cycling or seated rest, performed in a counterbalanced order across separate days in a within-subject design. The findings suggest three ways that emotional processing in the brain may be different immediately after exercise (relative to immediately after rest): First, reduced demands on emotional regulation during pleasant emotional processing as indicated by lower precuneus activation for pleasant stimuli; second, reduced processing of negative emotional stimuli in visual association areas as indicated by lower activation for unpleasant stimuli in the bilateral fusiform and ITG; third, an increased recruitment in activation associated with regulating/inhibiting unpleasant emotional processing in the bilateral medial superior frontal gyrus (dorsomedial prefrontal cortex), angular gyri, supramarginal gyri, left cerebellar crus I/II and a portion of right dorsolateral prefrontal cortex. Overall, these findings support that acute exercise in active older adults alters activation in key emotional processing and regulating brain regions., (© 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

People spend much of their free time engaging with narrative fiction. Research shows that, like real-life friends, fictional characters can sometimes influence individuals' attitudes, behaviors, and self-beliefs. Moreover, for certain individuals, fictional characters can stand in for real-life friends by providing the experience of belonging. Despite these parallels between how people think of real and fictional others, it is unclear whether, and to what degree, their neural representations are similar. Does the brain treat psychologically close fictional others as it does close real-world friends, or are real others somehow privileged in their neural representation? In the present study, fans of the HBO series Game of Thrones performed a trait-evaluation task for the self, 9 real-life friends/acquaintances, and 9 fictional characters from Game of Thrones while undergoing functional magnetic resonance imaging. Using both brain decoding and representational similarity analysis, we found evidence of a categorical boundary between real and fictional others within the medial prefrontal cortex. However, the boundary between these categories was blurred in lonelier individuals. These results suggest that lonelier individuals may turn to fictional characters to meet belongingness needs, and this, in turn, alters the manner in which these categories are encoded within the social brain., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Objective.: Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD)., Methods.: Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS., Results.: Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal., Conclusion.: Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.

The thalamus is a small, bilateral structure in the diencephalon that integrates signals from many areas of the CNS. This critical anatomical position allows the thalamus to influence whole-brain activity and adaptive behaviour. However, traditional research paradigms have struggled to attribute specific functions to the thalamus, and it has remained understudied in the human neuroimaging literature. Recent advances in analytical techniques and increased accessibility to large, high-quality data sets have brought forth a series of studies and findings that (re-)establish the thalamus as a core region of interest in human cognitive neuroscience, a field that otherwise remains cortico-centric. In this Perspective, we argue that using whole-brain neuroimaging approaches to investigate the thalamus and its interaction with the rest of the brain is key for understanding systems-level control of information processing. To this end, we highlight the role of the thalamus in shaping a range of functional signatures, including evoked activity, interregional connectivity, network topology and neuronal variability, both at rest and during the performance of cognitive tasks., (© 2023. Springer Nature Limited.)

Cross-frequency coupling between the phase of slower oscillatory activity and the amplitude of faster oscillatory activity in the brain (phase-amplitude coupling; PAC), is a promising new biological marker for mental health. Prior research has demonstrated that PAC is associated with mental health. However, most research has focused on within-region theta-gamma PAC in adults. Our recent preliminary study found increased theta-beta PAC was associated with increased psychological distress in 12 year olds. It is important to investigate how PAC biomarkers relate to mental health and wellbeing in youth. Thus, in this study, we investigated longitudinal associations between interregional (posterior-anterior cortex) resting-state theta-beta PAC (Modulation Index [MI]), psychological distress and wellbeing in N = 99 adolescents (aged 12-15 years). In the right hemisphere, there was a significant relationship, whereby increased psychological distress was associated with decreased theta-beta PAC and psychological distress increased with increased age. In the left hemisphere, there was a significant relationship, whereby decreased wellbeing was associated with decreased theta-beta PAC and wellbeing scores decreased with increased age. This study presents novel findings demonstrating longitudinal relationships between interregional, resting-state theta-beta PAC and mental health and wellbeing in early adolescents. This EEG marker may facilitate improved early identification of emerging psychopathology., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Narratives are paradigmatic examples of natural language, where nouns represent a proxy of information. Functional magnetic resonance imaging (fMRI) studies revealed the recruitment of temporal cortices during noun processing and the existence of a noun-specific network at rest. Yet, it is unclear whether, in narratives, changes in noun density influence the brain functional connectivity, so that the coupling between regions correlates with information load. We acquired fMRI activity in healthy individuals listening to a narrative with noun density changing over time and measured whole-network and node-specific degree and betweenness centrality. Network measures were correlated with information magnitude with a time-varying approach. Noun density correlated positively with the across-regions average number of connections and negatively with the average betweenness centrality, suggesting the pruning of peripheral connections as information decreased. Locally, the degree of the bilateral anterior superior temporal sulcus (aSTS) was positively associated with nouns. Importantly, aSTS connectivity cannot be explained by changes in other parts of speech (e.g., verbs) or syllable density. Our results indicate that the brain recalibrates its global connectivity as a function of the information conveyed by nouns in natural language. Also, using naturalistic stimulation and network metrics, we corroborate the role of aSTS in noun processing., (© 2023. The Author(s).)

Imaging across different scales is essential for understanding healthy organ morphology and pathophysiological changes. The macro- and microscale three-dimensional morphology of large samples, including intact human organs, is possible with X-ray microtomography (using laboratory or synchrotron sources). Preparation of large samples for high-resolution imaging, however, is challenging due to limitations such as sample shrinkage, insufficient contrast, movement of the sample and bubble formation during mounting or scanning. Here, we describe the preparation, stabilization, dehydration and mounting of large soft-tissue samples for X-ray microtomography. We detail the protocol applied to whole human organs and hierarchical phase-contrast tomography at the European Synchrotron Radiation Facility, yet it is applicable to a range of biological samples, including complete organisms. The protocol enhances the contrast when using X-ray imaging, while preventing sample motion during the scan, even with different sample orientations. Bubbles trapped during mounting and those formed during scanning (in the case of synchrotron X-ray imaging) are mitigated by multiple degassing steps. The sample preparation is also compatible with magnetic resonance imaging, computed tomography and histological observation. The sample preparation and mounting require 24-36 d for a large organ such as a whole human brain or heart. The preparation time varies depending on the composition, size and fragility of the tissue. Use of the protocol enables scanning of intact organs with a diameter of 150 mm with a local voxel size of 1 μm. The protocol requires users with expertise in handling human or animal organs, laboratory operation and X-ray imaging., (© 2023. Springer Nature Limited.)

Inadequate levels of exercise is one of the most potent modifiable risk factors for preventing cognitive decline and dementia as we age. Meanwhile, network science-based measures of structural brain network global and local efficiency show promise as robust biomarkers of aging, cognitive decline, and pathological disease progression. Despite this, little to no work has established how maintaining physical activity (PA) and physical fitness might relate to cognition and network efficiency measures across the lifespan. Therefore the purpose of this study was to determine the relationship between (1) PA and fitness and cognition, (2) fitness and network efficiency, and (3) how network efficiency measures relate to cognition. To accomplish this, we analyzed a large cross-sectional data set (n = 720; 36-100 years) from the aging human connectome project, which included the Trail Making Task (TMT) A and B, a measure of fitness (2-min walk test), physical activity (International Physical Activity Questionnaire), and high-resolution diffusion imaging data. Our analysis consisted of employing multiple linear regression while controlling for age, sex, and education. Age was associated with lower global and local brain network efficiency and poorer Trail A & B performance. Meanwhile, fitness, but not physical activity, was related to better Trail A and B performance and fitness, and was positively associated with local and global brain efficiency. Finally, local efficiency was related to better TMT B performance and partially mediated the relationship between fitness and TMT B performance. These results indicate aging may be associated with a shift towards less efficient local and global neural networks and that maintaining physical fitness might protect against age-related cognitive performance deterioration by bolstering structural network efficiency., 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.)

When we look at an image, its features are represented in our visual system in a highly distributed manner, calling for a mechanism that binds them into coherent object representations. There have been different proposals for the neuronal mechanisms that can mediate binding. One hypothesis is that binding is achieved by oscillations that synchronize neurons representing features of the same perceptual object. This view allows separate communication channels between different brain areas. Another hypothesis is that binding of features that are represented in different brain regions occurs when the neurons in these areas that respond to the same object simultaneously enhance their firing rate, which would correspond to directing object-based attention to these features. This review summarizes evidence in favor of and against these two hypotheses, examining the neuronal correlates of binding and assessing the time course of perceptual grouping. I conclude that enhanced neuronal firing rates bind features into coherent object representations, whereas oscillations and synchrony are unrelated to binding., Competing Interests: Declaration of interests Pieter Roelfsema is cofounder and shareholder of a neurotechnology start-up, Phosphoenix (Netherlands)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The human brain operates in large-scale functional networks. These networks are an expression of temporally correlated activity across brain regions, but how global network properties relate to the neural dynamics of individual regions remains incompletely understood. Here, we show that the brain's network architecture is tightly linked to critical episodes of neural regularity, visible as spontaneous "complexity drops" in functional magnetic resonance imaging signals. These episodes closely explain functional connectivity strength between regions, subserve the propagation of neural activity patterns, and reflect interindividual differences in age and behavior. Furthermore, complexity drops define neural activity states that dynamically shape the connectivity strength, topological configuration, and hierarchy of brain networks and comprehensively explain known structure-function relationships within the brain. These findings delineate a principled complexity architecture of neural activity-a human "complexome" that underpins the brain's functional network organization.

Delineating neurobiological markers of youth mental health is crucial for early identification and treatment. One promising marker is phase-amplitude coupling (PAC), cross-frequency coupling between the phase of slower oscillatory activity and the amplitude of faster oscillatory activity in the brain. Prior research has demonstrated that PAC is associated with both cognition and mental health and can be modulated using neurostimulation. However, to date research investigating PAC has focused primarily on adults, and only within-region theta-gamma coupling in the context of mental health. We investigated associations between interregional resting-state PAC (posterior-anterior cortex), and cognition and psychological distress in N = 77 (M age  = 12.58 years, SD = 0.31; 51 % female) 12-year-olds. Firstly, while left theta-beta PAC showed a moderate positive correlation (r = 0.529, p < .01), right theta-gamma PAC showed a weak positive correlation, with psychological distress (r = 0.283, p < .05). In terms of cognition, moderate correlations were observed between: (i) increased left theta-beta PAC and increased psychomotor speed (r = -0.367, p < .05); (ii) increased left alpha-beta PAC and decreased attention (r = 0.355, p ≤0.01); and (iii) increased left alpha-beta PAC and decreased verbal learning and memory (r = -0.352, p < .01). Whereas weak associations were observed for: (i) increased left alpha-beta PAC and decreased executive functioning scores (r = 0.284, p < .05); and (ii) increased left alpha-gamma PAC and increased attention (r = -0.272, p < .05). The overall findings of this exploratory study are encouraging, although all the correlations were in the weak-to-moderate range and require replication. Further research may confirm interregional resting-state PAC as a biomarker that can help us better understand the link between mental health and cognition in adolescents and improve treatment of cognitive related deficits in mental illness., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neuroscientists have sought to identify the underlying neural systems supporting social processing that allow interaction and communication, forming social relationships, and navigating the social world. Through the use of NIMH's Research Domain Criteria (RDoC) framework, we evaluated consensus among studies that examined brain activity during social tasks to elucidate regions comprising the "social brain". We examined convergence across tasks corresponding to the four RDoC social constructs, including Affiliation and Attachment, Social Communication, Perception and Understanding of Self, and Perception and Understanding of Others. We performed a series of coordinate-based meta-analyses using the activation likelihood estimate (ALE) method. Meta-analysis was performed on whole-brain coordinates reported from 864 fMRI contrasts using the NiMARE Python package, revealing convergence in medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, temporoparietal junction, bilateral insula, amygdala, fusiform gyrus, precuneus, and thalamus. Additionally, four separate RDoC-based meta-analyses revealed differential convergence associated with the four social constructs. These outcomes highlight the neural support underlying these social constructs and inform future research on alterations among neurotypical and atypical populations., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cognitive functions are well-preserved for some older individuals, but the underlying brain mechanisms remain disputed. Here, 5-year longitudinal 3-back in-scanner and offline data classified individuals in a healthy older sample (baseline age = 64-68 years) into having stable or declining working-memory (WM). Consistent with a vital role of the prefrontal cortex (PFC), WM stability or decline was related to maintained or reduced longitudinal PFC functional responses. Subsequent analyses of imaging markers of general brain maintenance revealed higher levels in the stable WM group on measures of neurotransmission and vascular health. Also, categorical and continuous analyses showed that rate of WM decline was related to global (ventricles) and local (hippocampus) measures of neuronal integrity. Thus, our findings support a role of the PFC as well as general brain maintenance in explaining heterogeneity in longitudinal WM trajectories in aging., (© 2022. The Author(s).)

Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood. Here, we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states, is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF-1) knock-out (KO) mice as a genetic model of constitutively activated BAT and positive cardiometabolic traits and found a reduction of depression-like and anxiety-like behaviours associated with USF-1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF-1 KO mice. Further, the absence of USF-1 did not lead to alterations of adult hippocampal neural progenitor cell proliferation, differentiation, or survival. RNA-seq analysis characterised the molecular signature of USF-1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b. Xlr genes are the mouse orthologues of the human FAM9 gene family and are implicated in the regulation of dendritic branching, dendritic spine number and morphology. The transcriptional changes were associated with morphological alterations in hippocampal neurons, manifested in reduced dendritic length and complexity in USF-1 KO mice. Collectively these data suggest that the metabolic regulator USF-1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF-1-dependent BAT activation, but reflected in structural changes in the brain., (© 2022. The Author(s).)

Precise cortical brain localization presents an important challenge in the literature. Brain atlases provide data-guided parcellation based on functional and structural brain metrics, and each atlas has its own unique benefits for localization. We offer a parcellation guided by intracranial electroencephalography, a technique which has historically provided pioneering advances in our understanding of brain structure-function relationships. We used a consensus boundary mapping approach combining anatomical designations in Duvernoy's Atlas of the Human Brain, a widely recognized textbook of human brain anatomy, with the anatomy of the MNI152 template and the magnetic resonance imaging scans of an epilepsy surgery cohort. The Yale Brain Atlas consists of 690 one-square centimeter parcels based around conserved anatomical features and each with a unique identifier to communicate anatomically unambiguous localization. We report on the methodology we used to create the Atlas along with the findings of a neuroimaging study assessing the accuracy and clinical usefulness of cortical localization using the Atlas. We also share our vision for the Atlas as a tool in the clinical and research neurosciences, where it may facilitate precise localization of data on the cortex, accurate description of anatomical locations, and modern data science approaches using standardized brain regions., (© 2022. The Author(s).)

There is an increased need and focus to understand how local brain microstructure affects the transport of drug molecules directly administered to the brain tissue, for example in convection-enhanced delivery procedures. This study reports a systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fibres, namely the corpus callosum, the fornix and the corona radiata, with the specific aim to map different regions of the tissue and provide essential information for the development of accurate models of brain biomechanics. Ovine samples are imaged using scanning electron microscopy combined with focused ion beam milling to generate 3D volume reconstructions of the tissue at subcellular spatial resolution. Focus is placed on the characteristic cytological feature of the white matter: the axons and their alignment in the tissue. For each tract, a 3D reconstruction of relatively large volumes, including a significant number of axons, is performed and outer axonal ellipticity, outer axonal cross-sectional area and their relative perimeter are measured. The study of well-resolved microstructural features provides useful insight into the fibrous organization of the tissue, whose micromechanical behaviour is that of a composite material presenting elliptical tortuous tubular axonal structures embedded in the extra-cellular matrix. Drug flow can be captured through microstructurally-based models using 3D volumes, either reconstructed directly from images or generated in silico using parameters extracted from the database of images, leading to a workflow to enable physically-accurate simulations of drug delivery to the targeted tissue., (© 2022. The Author(s).)

Increasing studies have provided cognitive and neuron evidence for not only the similarities, but also the differences between physical pain and social pain in the brain basis. Comparing the similarities and differences of the brain basis of physical pain and social pain helps us to clarify the mechanism of the occurrence and change of pain, and provide theoretical evidence for clinical pain treatment. In this review, we summarized studies to delineate the brain mechanisms of physical pain and social pain. Through the review of existing studies, we found that both physical pain and social pain can invoke the same brain regions that process emotional experience (the dorsal anterior cingulate cortex, anterior insula), emotion regulation (lateral prefrontal cortex) and somatosensory (the posterior insula, secondary sensory cortex). However, the voxel-level activated patterns of physical and social pain differ in the same brain region (dorsal anterior cingulate gyrus, dorsolateral prefrontal cortex, etc.), and the overlapping brain regions (for example, ventrolateral prefrontal cortex) have varied effect on these two types of pain. In addition, studies have shown that the brain activation pattern for social pain may be influenced by the experimental paradigm. Future studies should actively adopt a data-driven way to examine the brain basis of physical pain and social pain, especially the nerve activation mode, aiming to consummate the theory of pain.

Intracranial cerebrospinal and interstitial fluid (ISF) flow and solute transport have important clinical implications, but limited in vivo access to the brain interior leaves gaping holes in human understanding of the nature of these neurophysiological phenomena. Models can address some gaps, but only insofar as model inputs are accurate. We perform a sensitivity analysis using a Monte Carlo approach on a lumped-parameter network model of cerebrospinal and ISF in perivascular and extracellular spaces in the murine brain. We place bounds on model predictions given the uncertainty in input parameters. Péclet numbers for transport in penetrating perivascular spaces (PVSs) and within the parenchyma are separated by at least two orders of magnitude. Low permeability in penetrating PVSs requires unrealistically large driving pressure and/or results in poor perfusion and are deemed unlikely. The model is most sensitive to the permeability of penetrating PVSs, a parameter whose value is largely unknown, highlighting an important direction for future experiments. Until the value of the permeability of penetrating PVSs is more accurately measured, the uncertainty of any model that includes flow in penetrating PVSs is so large that absolute numbers have little meaning and practical application is limited.

Background: Biomarkers of psychiatric treatment response remain elusive. Functional magnetic resonance imaging (fMRI) has shown promise, but low reliability has limited the utility of typical fMRI measures (e.g., average brain signal) as harbingers of treatment success. Notably, although historically considered a source of noise, temporal brain signal variability continues to gain momentum as a sensitive and reliable indicator of individual differences in neural efficacy, yet has not been examined in relation to psychiatric treatment outcomes., Methods: A total of 45 patients with social anxiety disorder were scanned twice (11 weeks apart) using simple task-based and resting-state fMRI to capture moment-to-moment neural variability. After fMRI test-retest, patients underwent a 9-week cognitive behavioral therapy. Multivariate modeling and reliability-based cross-validation were used to perform brain-based prediction of treatment outcomes., Results: Task-based brain signal variability was the strongest contributor in a treatment outcome prediction model (total r ACTUAL,PREDICTED  = 0.77), outperforming self-reports, resting-state neural variability, and standard mean-based measures of neural activity. Notably, task-based brain signal variability showed excellent test-retest reliability (intraclass correlation coefficient = 0.80), even with a task length less than 3 minutes long., Conclusions: Rather than a source of undesirable noise, moment-to-moment fMRI signal variability may instead serve as a highly reliable and efficient prognostic indicator of clinical outcome., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Co-variations in resting state activity are thought to arise from a variety of correlated inputs to neurons, such as bottom-up activity from lower areas, feedback from higher areas, recurrent processing in local circuits, and fluctuations in neuromodulatory systems. Most studies have examined resting state activity throughout the brain using MRI scans, or observed local co-variations in activity by recording from a small number of electrodes. We carried out electrophysiological recordings from over a thousand chronically implanted electrodes in the visual cortex of non-human primates, yielding a resting state dataset with unprecedentedly high channel counts and spatiotemporal resolution. Such signals could be used to observe brain waves across larger regions of cortex, offering a temporally detailed picture of brain activity. In this paper, we provide the dataset, describe the raw and processed data formats and data acquisition methods, and indicate how the data can be used to yield new insights into the 'background' activity that influences the processing of visual information in our brain., (© 2022. The Author(s).)

Theories of language organization in the brain commonly posit that different regions underlie distinct linguistic mechanisms. However, such theories have been criticized on the grounds that many neuroimaging studies of language processing find similar effects across regions. Moreover, condition by region interaction effects, which provide the strongest evidence of functional differentiation between regions, have rarely been offered in support of these theories. Here we address this by using lesion-symptom mapping in three large, partially-overlapping groups of aphasia patients with left hemisphere brain damage due to stroke (N = 121, N = 92, N = 218). We identified multiple measure by region interaction effects, associating damage to the posterior middle temporal gyrus with syntactic comprehension deficits, damage to posterior inferior frontal gyrus with expressive agrammatism, and damage to inferior angular gyrus with semantic category word fluency deficits. Our results are inconsistent with recent hypotheses that regions of the language network are undifferentiated with respect to high-level linguistic processing., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Background: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs., Objective and Methods: To document neuroimaging data in six patients with PNPT1 highlighting novel findings., Results: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection., Conclusion: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions., Methods: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs., Results: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case., Interpretation: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Experimental investigation of early postnatal brain development in infant mice (

Brain disorders are characterized by the progressive loss of structure and function of the brain as a consequence of progressive degeneration and/or death of nerve cells. Aging is a major risk factor for brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. Various cellular and molecular events have been shown to play a role in the progress of neurodegenerative diseases. Emerging studies suggest that primary cilia could be a key regulator in brain diseases. The primary cilium is a singular cellular organelle expressed on the surface of many cell types, such as astrocytes and neurons in the mature brain. Primary cilia detect extracellular cues, such as Sonic Hedgehog (SHH) protein, and transduce these signals into cells to regulate various signaling pathways. Abnormalities in ciliary length and frequency (ratio of ciliated cells) have been implicated in various human diseases, including brain disorders. This review summarizes current findings and thoughts on the role of primary cilia and ciliary signaling pathways in aging and age-related brain disorders., (Copyright © 2021. Published by Elsevier Inc.)