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Background: Pain is a complex problem that is triaged, diagnosed, treated, and billed based on which body part is painful, almost without exception. While the "body part framework" guides the organization and treatment of individual patients' pain conditions, it remains unclear how to best conceptualize, study, and treat pain conditions at the population level. Here, we investigate (1) how the body part framework agrees with population-level, biologically derived pain profiles; (2) how do data-derived pain profiles interface with other symptom domains from a whole-body perspective; and (3) whether biologically derived pain profiles capture clinically salient differences in medical history., Methods: To understand how pain conditions might be best organized, we applied a carefully designed a multi-variate pattern-learning approach to a subset of the UK Biobank (n = 34,337), the largest publicly available set of real-world pain experience data to define common population-level profiles. We performed a series of post hoc analyses to validate that each pain profile reflects real-world, clinically relevant differences in patient function by probing associations of each profile across 137 medication categories, 1425 clinician-assigned ICD codes, and 757 expert-curated phenotypes., Results: We report four unique, biologically based pain profiles that cut across medical specialties: pain interference, depression, medical pain, and anxiety, each representing different facets of functional impairment. Importantly, these profiles do not specifically align with variables believed to be important to the standard pain evaluation, namely painful body part, pain intensity, sex, or BMI. Correlations with individual-level clinical histories reveal that our pain profiles are largely associated with clinical variables and treatments of modifiable, chronic diseases, rather than with specific body parts. Across profiles, notable differences include opioids being associated only with the pain interference profile, while antidepressants linked to the three complimentary profiles. We further provide evidence that our pain profiles offer valuable, additional insights into patients' wellbeing that are not captured by the body-part framework and make recommendations for how our pain profiles might sculpt the future design of healthcare delivery systems., Conclusion: Overall, we provide evidence for a shift in pain medicine delivery systems from the conventional, body-part-based approach to one anchored in the pain experience and holistic profiles of patient function. This transition facilitates a more comprehensive management of chronic diseases, wherein pain treatment is integrated into broader health strategies. By focusing on holistic patient profiles, our approach not only addresses pain symptoms but also supports the management of underlying chronic conditions, thereby enhancing patient outcomes and improving quality of life. This model advocates for a seamless integration of pain management within the continuum of care for chronic diseases, emphasizing the importance of understanding and treating the interdependencies between chronic conditions and pain., Competing Interests: Declarations. Ethics approval and consent to participate: Analysis of UK Biobank non-identifiable data received IRB approval from MassGeneralBrigham and McGill IRBs as Not Human Subjects Research (Protocol # 2021P003252). Further information on the consent procedure can be found here: biobank.ctsu.ox.ac.uk/crystal/field.cgi?id=200 . Consent for publication: All authors consent for this manuscript to be published. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The human brain comprises large-scale networks that flexibly interact to support diverse cognitive functions and adapt to variability in daily life. The inferior parietal lobe (IPL) is a hub of multiple brain networks that sustain various cognitive domains. It remains unclear how networks respond to acute regional perturbations to maintain normal function. To provoke network-level adaptive responses to local inhibition, we combined offline transcranial magnetic stimulation (TMS) over left or right IPL with neuroimaging during attention, semantic and social cognition tasks, and rest. Across tasks, TMS specifically affected task-active network activity with inhibition and facilitation. Network interaction responses differed between rest and tasks. After TMS over both IPL regions, large-scale network interactions were exclusively facilitated at rest, but mainly inhibited during tasks. Overall, responses to TMS primarily occurred in and between domain-general default mode and frontoparietal subnetworks. These findings elucidate short-term adaptive plasticity in response to network node inhibition., Competing Interests: 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., (© 2024 The Authors.)

A pervasive dilemma in neuroimaging is whether to prioritize sample size or scan time given fixed resources. Here, we systematically investigate this trade-off in the context of brain-wide association studies (BWAS) using functional magnetic resonance imaging (fMRI). We find that total scan duration (sample size × scan time per participant) robustly explains individual-level phenotypic prediction accuracy via a logarithmic model, suggesting that sample size and scan time are broadly interchangeable up to 20-30 min of data. However, the returns of scan time diminish relative to sample size, which we explain with principled theoretical derivations. When accounting for fixed overhead costs associated with each participant (e.g., recruitment, non-imaging measures), prediction accuracy in many small-scale and some large-scale BWAS might benefit from longer scan time than typically assumed. These results generalize across phenotypic domains, scanners, acquisition protocols, racial groups, mental disorders, age groups, as well as resting-state and task-state functional connectivity. Overall, our study emphasizes the importance of scan time, which is ignored in standard power calculations. Standard power calculations maximize sample size, at the expense of scan time, which can result in sub-optimal prediction accuracies and inefficient use of resources. Our empirically informed reference is available for future study design: WEB_APPLICATION_LINK., Competing Interests: Conflict of interest DB is shareholder and advisory board member of MindState Design Labs, USA.

Finding an interpretable and compact representation of complex neuroimaging data is extremely useful for understanding brain behavioral mapping and hence for explaining the biological underpinnings of mental disorders. However, hand-crafted representations, as well as linear transformations, may inadequately capture the considerable variability across individuals. Here, we implemented a data-driven approach using a three-dimensional autoencoder on two large-scale datasets. This approach provides a latent representation of high-dimensional task-fMRI data which can account for demographic characteristics whilst also being readily interpretable both in the latent space learned by the autoencoder and in the original voxel space. This was achieved by addressing a joint optimization problem that simultaneously reconstructs the data and predicts clinical or demographic variables. We then applied normative modeling to the latent variables to define summary statistics ('latent indices') and establish a multivariate mapping to non-imaging measures. Our model, trained with multi-task fMRI data from the Human Connectome Project (HCP) and UK biobank task-fMRI data, demonstrated high performance in age and sex predictions and successfully captured complex behavioral characteristics while preserving individual variability through a latent representation. Our model also performed competitively with respect to various baseline models including several variants of principal components analysis, independent components analysis and classical regions of interest, both in terms of reconstruction accuracy and strength of association with behavioral variables., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zabihi 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.)

Late onset Alzheimer's disease (AD) is a progressive neurodegenerative disease, with brain changes beginning years before symptoms surface. AD is characterized by neuronal loss, the classic feature of the disease that underlies brain atrophy. However, GWAS reports and recent single-nucleus RNA sequencing (snRNA-seq) efforts have highlighted that glial cells, particularly microglia, claim a central role in AD pathophysiology. Here, we tailor pattern-learning algorithms to explore distinct gene programs by integrating the entire transcriptome, yielding distributed AD-predictive modules within the brain's major cell-types. We show that these learned modules are biologically meaningful through the identification of new and relevant enriched signaling cascades. The predictive nature of our modules, especially in microglia, allows us to infer each subject's progression along a disease pseudo-trajectory, confirmed by post-mortem pathological brain tissue markers. Additionally, we quantify the interplay between pairs of cell-type modules in the AD brain, and localized known AD risk genes to enriched module gene programs. Our collective findings advocate for a transition from cell-type-specificity to gene modules specificity to unlock the potential of unique gene programs, recasting the roles of recently reported genome-wide AD risk loci., (© 2024. The Author(s).)

The amygdala nuclei modulate distributed neural circuits that most likely evolved to respond to environmental threats and opportunities. So far, the specific role of unique amygdala nuclei in the context processing of salient environmental cues lacks adequate characterization across neural systems and over time. Here, we present amygdala nuclei morphometry and behavioral findings from longitudinal population data (>1400 subjects, age range 40-69 years, sampled 2-3 years apart): the UK Biobank offers exceptionally rich phenotyping along with brain morphology scans. This allows us to quantify how 18 microanatomical amygdala subregions undergo plastic changes in tandem with coupled neural systems and delineating their associated phenome-wide profiles. In the context of population change, the basal, lateral, accessory basal, and paralaminar nuclei change in lockstep with the prefrontal cortex, a region that subserves planning and decision-making. The central, medial and cortical nuclei are structurally coupled with the insular and anterior-cingulate nodes of the salience network, in addition to the MT/V5, basal ganglia, and putamen, areas proposed to represent internal bodily states and mediate attention to environmental cues. The central nucleus and anterior amygdaloid area are longitudinally tied with the inferior parietal lobule, known for a role in bodily awareness and social attention. These population-level amygdala-brain plasticity regimes in turn are linked with unique collections of phenotypes, ranging from social status and employment to sleep habits and risk taking. The obtained structural plasticity findings motivate hypotheses about the specific functions of distinct amygdala nuclei in humans., (© 2024. The Author(s).)

Stroke is the leading cause of long-term disability worldwide. Incurred brain damage can disrupt cognition, often with persisting deficits in language and executive capacities. Yet, despite their clinical relevance, the commonalities and differences between language versus executive control impairments remain under-specified. To fill this gap, we tailored a Bayesian hierarchical modelling solution in a largest-of-its-kind cohort (1080 patients with stroke) to deconvolve language and executive control with respect to the stroke topology. Cognitive function was assessed with a rich neuropsychological test battery including global cognitive function (tested with the Mini-Mental State Exam), language (assessed with a picture naming task), executive speech function (tested with verbal fluency tasks), executive control functions (Trail Making Test and Digit Symbol Coding Task), visuospatial functioning (Rey Complex Figure), as well as verbal learning and memory function (Soul Verbal Learning). Bayesian modelling predicted interindividual differences in eight cognitive outcome scores three months after stroke based on specific tissue lesion topologies. A multivariate factor analysis extracted four distinct cognitive factors that distinguish left- and right-hemispheric contributions to ischaemic tissue lesions. These factors were labelled according to the neuropsychological tests that had the strongest factor loadings: One factor delineated language and general cognitive performance and was mainly associated with damage to left-hemispheric brain regions in the frontal and temporal cortex. A factor for executive control summarized mental flexibility, task switching and visual-constructional abilities. This factor was strongly related to right-hemispheric brain damage of posterior regions in the occipital cortex. The interplay of language and executive control was reflected in two distinct factors that were labelled as executive speech functions and verbal memory. Impairments on both factors were mainly linked to left-hemispheric lesions. These findings shed light onto the causal implications of hemispheric specialization for cognition; and make steps towards subgroup-specific treatment protocols after stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities., (© 2024. The Author(s).)

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types' contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration., Competing Interests: VP, QA, DB, MD, YZ, YI No competing interests declared, (© 2023, Pak et al.)

This study examines the impact of sample size on predicting cognitive and mental health phenotypes from brain imaging via machine learning. Our analysis shows a 3- to 9-fold improvement in prediction performance when sample size increases from 1,000 to 1 M participants. However, despite this increase, the data suggest that prediction accuracy remains worryingly low and far from fully exploiting the predictive potential of brain imaging data. Additionally, we find that integrating multiple imaging modalities boosts prediction accuracy, often equivalent to doubling the sample size. Interestingly, the most informative imaging modality often varied with increasing sample size, emphasizing the need to consider multiple modalities. Despite significant performance reserves for phenotype prediction, achieving substantial improvements may necessitate prohibitively large sample sizes, thus casting doubt on the practical or clinical utility of machine learning in some areas of neuroimaging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Individualized phenotypic prediction based on structural MRI is an important goal in neuroscience. Prediction performance increases with larger samples, but small-scale datasets with fewer than 200 participants are often unavoidable. We have previously proposed a "meta-matching" framework to translate models trained from large datasets to improve the prediction of new unseen phenotypes in small collection efforts. Meta-matching exploits correlations between phenotypes, yielding large improvement over classical machine learning when applied to prediction models using resting-state functional connectivity as input features. Here, we adapt the two best performing meta-matching variants ("meta-matching finetune" and "meta-matching stacking") from our previous study to work with T1-weighted MRI data by changing the base neural network architecture to a 3D convolution neural network. We compare the two meta-matching variants with elastic net and classical transfer learning using the UK Biobank (N = 36,461), Human Connectome Project Young Adults (HCP-YA) dataset (N = 1,017) and HCP-Aging dataset (N = 656). We find that meta-matching outperforms elastic net and classical transfer learning by a large margin, both when translating models within the same dataset, as well as translating models across datasets with different MRI scanners, acquisition protocols and demographics. For example, when translating a UK Biobank model to 100 HCP-YA participants, meta-matching finetune yielded a 136% improvement in variance explained over transfer learning, with an average absolute gain of 2.6% (minimum = -0.9%, maximum = 17.6%) across 35 phenotypes. Overall, our results highlight the versatility of the meta-matching framework., Competing Interests: Competing Interests The authors declare no competing interests.

Big neuroscience datasets are not big small datasets when it comes to quantitative data analysis. Neuroscience has now witnessed the advent of many population cohort studies that deep-profile participants, yielding hundreds of measures, capturing dimensions of each individual's position in the broader society. Indeed, there is a rebalancing from small, strictly selected, and thus homogenized cohorts toward always larger, more representative, and thus diverse cohorts. This shift in cohort composition is prompting the revision of incumbent modeling practices. Major sources of population stratification increasingly overshadow the subtle effects that neuroscientists are typically studying. In our opinion, as we sample individuals from always wider diversity backgrounds, we will require a new stack of quantitative tools to realize diversity-aware modeling. We here take inventory of candidate analytical frameworks. Better incorporating driving factors behind population structure will allow refining our understanding of how brain-behavior relationships depend on human subgroups., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

Resting-state functional connectivity (RSFC) is widely used to predict phenotypic traits in individuals. Large sample sizes can significantly improve prediction accuracies. However, for studies of certain clinical populations or focused neuroscience inquiries, small-scale datasets often remain a necessity. We have previously proposed a "meta-matching" approach to translate prediction models from large datasets to predict new phenotypes in small datasets. We demonstrated large improvement of meta-matching over classical kernel ridge regression (KRR) when translating models from a single source dataset (UK Biobank) to the Human Connectome Project Young Adults (HCP-YA) dataset. In the current study, we propose two meta-matching variants ("meta-matching with dataset stacking" and "multilayer meta-matching") to translate models from multiple source datasets across disparate sample sizes to predict new phenotypes in small target datasets. We evaluate both approaches by translating models trained from five source datasets (with sample sizes ranging from 862 participants to 36,834 participants) to predict phenotypes in the HCP-YA and HCP-Aging datasets. We find that multilayer meta-matching modestly outperforms meta-matching with dataset stacking. Both meta-matching variants perform better than the original "meta-matching with stacking" approach trained only on the UK Biobank. All meta-matching variants outperform classical KRR and transfer learning by a large margin. In fact, KRR is better than classical transfer learning when less than 50 participants are available for finetuning, suggesting the difficulty of classical transfer learning in the very small sample regime. The multilayer meta-matching model is publicly available at GITHUB_LINK., Competing Interests: Competing Interests The authors declare no competing interests.

The human brain is characterised by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain: both with respect to the brains of other individuals, and the brains of another species. We report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organised: it co-localises with the archetypal sensory-association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol, and reversed upon recovery. Providing convergent evidence, we show that under anaesthesia the functional connectivity of the human brain becomes more similar to the macaque brain. Finally, anaesthesia diminishes the match between spontaneous brain activity and meta-analytic brain patterns aggregated from the NeuroSynth engine. Collectively, the present results reveal that anaesthetised human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia., Competing Interests: Competing interests D.B. is shareholder and advisory board member of MindState Design Labs, USA. The other authors declare no competing interests.

Stroke is the leading cause of long-term disability worldwide. Incurred brain damage disrupts cognition, often with persisting deficits in language and executive capacities. Despite their clinical relevance, the commonalities, and differences of language versus executive control impairments remain under-specified. We tailored a Bayesian hierarchical modeling solution in a largest-of-its-kind cohort (1080 stroke patients) to deconvolve language and executive control in the brain substrates of stroke insults. Four cognitive factors distinguished left- and right-hemispheric contributions to ischemic tissue lesion. One factor delineated language and general cognitive performance and was mainly associated with damage to left-hemispheric brain regions in the frontal and temporal cortex. A factor for executive control summarized control and visual-constructional abilities. This factor was strongly related to right-hemispheric brain damage of posterior regions in the occipital cortex. The interplay of language and executive control was reflected in two factors: executive speech functions and verbal memory. Impairments on both were mainly linked to left-hemispheric lesions. These findings shed light onto the causal implications of hemispheric specialization for cognition; and make steps towards subgroup-specific treatment protocols after stroke.

Background: Many studies of brain-behavior relationships rely on univariate approaches where each variable of interest is tested independently, which does not allow for the simultaneous investigation of multiple correlated variables. Alternatively, multivariate approaches allow for examining relationships between psychopathology and neural substrates simultaneously. There are multiple multivariate methods to choose from that each have assumptions which can affect the results; however, many studies employ one method without a clear justification for its selection. Additionally, there are few studies illustrating how differences between methods manifest in examining brain-behavior relationships. The purpose of this study was to exemplify how the choice of multivariate approach can change brain-behavior interpretations., Method: We used data from 9,027 9- to 10-year-old children from the Adolescent Brain Cognitive Development SM Study (ABCD Study ® ) to examine brain-behavior relationships with three commonly used multivariate approaches: canonical correlation analysis (CCA), partial least squares correlation (PLSC), and partial least squares regression (PLSR). We examined the associations between psychopathology dimensions including general psychopathology, attention-deficit/hyperactivity symptoms, conduct problems, and internalizing symptoms with regional brain volumes., Results: The results of CCA, PLSC, and PLSR showed both consistencies and differences in the relationship between psychopathology symptoms and brain structure. The leading significant component yielded by each method demonstrated similar patterns of associations between regional brain volumes and psychopathology symptoms. However, the additional significant components yielded by each method demonstrated differential brain-behavior patterns that were not consistent across methods., Conclusion: Here we show that CCA, PLSC, and PLSR yield slightly different interpretations regarding the relationship between child psychopathology and brain volume. In demonstrating the divergence between these approaches, we exemplify the importance of carefully considering the method's underlying assumptions when choosing a multivariate approach to delineate brain-behavior relationships., 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 © 2023 Durham, Ghanem, Stier, Cardenas-Iniguez, Reimann, Jeong, Dupont, Dong, Moore, Berman, Lahey, Bzdok and Kaczkurkin.)

Neuroscientific studies exploring real-world dynamic perception often overlook the influence of continuous changes in narrative content. In our research, we utilize machine learning tools for natural language processing to examine the relationship between movie narratives and neural responses. By analyzing over 50,000 brain images of participants watching Forrest Gump from the studyforrest dataset, we find distinct brain states that capture unique semantic aspects of the unfolding story. The default network, associated with semantic information integration, is the most engaged during movie watching. Furthermore, we identify two mechanisms that underlie how the default network liaises with the amygdala and hippocampus. Our findings demonstrate effective approaches to understanding neural processes in everyday situations and their relation to conscious awareness., (© 2023. The Author(s).)

There is significant interest in using neuroimaging data to predict behavior. The predictive models are often interpreted by the computation of feature importance, which quantifies the predictive relevance of an imaging feature. Tian and Zalesky (2021) suggest that feature importance estimates exhibit low split-half reliability, as well as a trade-off between prediction accuracy and feature importance reliability across parcellation resolutions. However, it is unclear whether the trade-off between prediction accuracy and feature importance reliability is universal. Here, we demonstrate that, with a sufficient sample size, feature importance (operationalized as Haufe-transformed weights) can achieve fair to excellent split-half reliability. With a sample size of 2600 participants, Haufe-transformed weights achieve average intra-class correlation coefficients of 0.75, 0.57 and 0.53 for cognitive, personality and mental health measures respectively. Haufe-transformed weights are much more reliable than original regression weights and univariate FC-behavior correlations. Original regression weights are not reliable even with 2600 participants. Intriguingly, feature importance reliability is strongly positively correlated with prediction accuracy across phenotypes. Within a particular behavioral domain, there is no clear relationship between prediction performance and feature importance reliability across regression models. Furthermore, we show mathematically that feature importance reliability is necessary, but not sufficient, for low feature importance error. In the case of linear models, lower feature importance error is mathematically related to lower prediction error. Therefore, higher feature importance reliability might yield lower feature importance error and higher prediction accuracy. Finally, we discuss how our theoretical results relate with the reliability of imaging features and behavioral measures. Overall, the current study provides empirical and theoretical insights into the relationship between prediction accuracy and feature importance reliability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Loneliness is associated with differences in resting-state functional connectivity (RSFC) within and between large-scale networks in early- and middle-aged adult cohorts. However, age-related changes in associations between sociality and brain function into late adulthood are not well understood. Here, we examined age differences in the association between two dimensions of sociality-loneliness and empathic responding-and RSFC of the cerebral cortex. Self-report measures of loneliness and empathy were inversely related across the entire sample of younger (mean age = 22.6y, n = 128) and older (mean age = 69.0y, n = 92) adults. Using multivariate analyses of multi-echo fMRI RSFC, we identified distinct functional connectivity patterns for individual and age group differences associated with loneliness and empathic responding. Loneliness in young and empathy in both age groups was related to greater visual network integration with association networks (e.g., default, fronto-parietal control). In contrast, loneliness was positively related to within- and between-network integration of association networks for older adults. These results extend our previous findings in early- and middle-aged cohorts, demonstrating that brain systems associated with loneliness, as well as empathy, differ in older age. Further, the findings suggest that these two aspects of social experience engage different neurocognitive processes across human life-span development., (© 2023 Massachusetts Institute of Technology.)

Resting-state fMRI is commonly used to derive brain parcellations, which are widely used for dimensionality reduction and interpreting human neuroscience studies. We previously developed a model that integrates local and global approaches for estimating areal-level cortical parcellations. The resulting local-global parcellations are often referred to as the Schaefer parcellations. However, the lack of homotopic correspondence between left and right Schaefer parcels has limited their use for brain lateralization studies. Here, we extend our previous model to derive homotopic areal-level parcellations. Using resting-fMRI and task-fMRI across diverse scanners, acquisition protocols, preprocessing and demographics, we show that the resulting homotopic parcellations are as homogeneous as the Schaefer parcellations, while being more homogeneous than five publicly available parcellations. Furthermore, weaker correlations between homotopic parcels are associated with greater lateralization in resting network organization, as well as lateralization in language and motor task activation. Finally, the homotopic parcellations agree with the boundaries of a number of cortical areas estimated from histology and visuotopic fMRI, while capturing sub-areal (e.g., somatotopic and visuotopic) features. Overall, these results suggest that the homotopic local-global parcellations represent neurobiologically meaningful subdivisions of the human cerebral cortex and will be a useful resource for future studies. Multi-resolution parcellations estimated from 1479 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Yan2023_homotopic)., (Copyright © 2023. Published by Elsevier Inc.)

Asymmetry between the left and right brain is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variant studies, which typically exert small effects on brain phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We quantitatively dissected the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior mapping highlights the consequences of genetically controlled brain lateralization on human-defining cognitive traits.

Studies in patients with brain lesions play a fundamental role in unraveling the brain's functional anatomy. Lesion-symptom mapping (LSM) techniques can relate lesion location to cognitive performance. However, a limitation of current LSM approaches is that they can only evaluate one cognitive outcome at a time, without considering interdependencies between different cognitive tests. To overcome this challenge, we implemented canonical correlation analysis (CCA) as combined multivariable and multioutcome LSM approach. We performed a proof-of-concept study on 1075 patients with acute ischemic stroke to explore whether addition of CCA to a multivariable single-outcome LSM approach (support vector regression) could identify infarct locations associated with deficits in three well-defined verbal memory functions (encoding, consolidation, retrieval) based on four verbal memory subscores derived from the Seoul Verbal Learning Test (immediate recall, delayed recall, recognition, learning ability). We evaluated whether CCA could extract cognitive score patterns that matched prior knowledge of these verbal memory functions, and if these patterns could be linked to more specific infarct locations than through single-outcome LSM alone. Two of the canonical modes identified with CCA showed distinct cognitive patterns that matched prior knowledge on encoding and consolidation. In addition, CCA revealed that each canonical mode was linked to a distinct infarct pattern, while with multivariable single-outcome LSM individual verbal memory subscores were associated with largely overlapping patterns. In conclusion, our findings demonstrate that CCA can complement single-outcome LSM techniques to help disentangle cognitive functions and their neuroanatomical correlates., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Human behavior across the life span is driven by the psychological need to belong, right from kindergarten to bingo nights. Being part of social groups constitutes a backbone for communal life and confers many benefits for the physical and mental health. Capitalizing on the neuroimaging and behavioral data from ∼40,000 participants from the UK Biobank population cohort, we used structural and functional analyses to explore how social participation is reflected in the human brain. Across 3 different types of social groups, structural analyses point toward the variance in ventromedial prefrontal cortex, fusiform gyrus, and anterior cingulate cortex as structural substrates tightly linked to social participation. Functional connectivity analyses not only emphasized the importance of default mode and limbic network but also showed differences for sports teams and religious groups as compared to social clubs. Taken together, our findings establish the structural and functional integrity of the default mode network as a neural signature of social belonging., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

As a social species, ready exchange with peers is a pivotal asset - our "social capital". Yet, single-person households have come to pervade metropolitan cities worldwide, with unknown consequences in the long run. Here, we systematically explore the morphological manifestations associated with singular living in ∼40,000 UK Biobank participants. The uncovered population-level signature spotlights the highly associative default mode network, in addition to findings such as in the amygdala central, cortical and corticoamygdaloid nuclei groups, as well as the hippocampal fimbria and dentate gyrus. Both positive effects, equating to greater gray matter volume associated with living alone, and negative effects, which can be interpreted as greater gray matter associations with not living alone, were found across the cortex and subcortical structures Sex-stratified analyses revealed male-specific neural substrates, including somatomotor, saliency and visual systems, while female-specific neural substrates centered on the dorsomedial prefrontal cortex. In line with our demographic profiling results, the discovered neural pattern of living alone is potentially linked to alcohol and tobacco consumption, anxiety, sleep quality as well as daily TV watching. The persistent trend for solitary living will require new answers from public-health decision makers. SIGNIFICANCE STATEMENT: Living alone has profound consequences for mental and physical health. Despite this, there has been a rapid increase in single-person households worldwide, with the long-term consequences yet unknown. In the largest study of its kind, we investigate how the objective lack of everyday social interaction, through living alone, manifests in the brain. Our population neuroscience approach uncovered a gray matter signature that converged on the 'default network', alongside targeted subcortical, sex and demographic profiling analyses. The human urge for social relationships is highlighted by the evolving COVID-19 pandemic. Better understanding of how social isolation relates to the brain will influence health and social policy decision-making of pandemic planning, as well as social interventions in light of global shifts in houseful structures., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Ischemic cerebrovascular events often lead to aphasia. Previous work provided hints that such strokes may affect women and men in distinct ways. Women tend to suffer strokes with more disabling language impairment, even if the lesion size is comparable to men. In 1401 patients, we isolate data-led representations of anatomical lesion patterns and hand-tailor a Bayesian analytical solution to carefully model the degree of sex divergence in predicting language outcomes ~3 months after stroke. We locate lesion-outcome effects in the left-dominant language network that highlight the ventral pathway as a core lesion focus across different tests of language performance. We provide detailed evidence for sex-specific brain-behavior associations in the domain-general networks associated with cortico-subcortical pathways, with unique contributions of the fornix in women and cingular fiber bundles in men. Our collective findings suggest diverging white matter substrates in how stroke causes language deficits in women and men. Clinically acknowledging such sex disparities has the potential to improve personalized treatment for stroke patients worldwide., (© 2023. The Author(s).)

Background: Sexual orientation in humans represents a multilevel construct that is grounded in both neurobiological and environmental factors., Objective: Here, we bring to bear a machine learning approach to predict sexual orientation from gray matter volumes (GMVs) or resting-state functional connectivity (RSFC) in a cohort of 45 heterosexual and 41 homosexual participants., Methods: In both brain assessments, we used penalized logistic regression models and nonparametric permutation., Results: We found an average accuracy of 62% (±6.72) for predicting sexual orientation based on GMV and an average predictive accuracy of 92% (±9.89) using RSFC. Regions in the precentral gyrus, precuneus and the prefrontal cortex were significantly informative for distinguishing heterosexual from homosexual participants in both the GMV and RSFC settings., Conclusions: These results indicate that, aside from self-reports, RSFC offers neurobiological information valuable for highly accurate prediction of sexual orientation. We demonstrate for the first time that sexual orientation is reflected in specific patterns of RSFC, which enable personalized, brain-based predictions of this highly complex human trait. While these results are preliminary, our neurobiologically based prediction framework illustrates the great value and potential of RSFC for revealing biologically meaningful and generalizable predictive patterns in the human brain., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patterns of neural activity underlie human cognition. Transitions between these patterns are orchestrated by the brain's network architecture. What are the mechanisms linking network structure to cognitively relevant activation patterns? Here we implement principles of network control to investigate how the architecture of the human connectome shapes transitions between 123 experimentally defined cognitive activation maps (cognitive topographies) from the NeuroSynth meta-analytic engine. We also systematically incorporate neurotransmitter receptor density maps (18 receptors and transporters) and disease-related cortical abnormality maps (11 neurodegenerative, psychiatric and neurodevelopmental diseases; N = 17 000 patients, N = 22 000 controls). Integrating large-scale multimodal neuroimaging data from functional MRI, diffusion tractography, cortical morphometry, and positron emission tomography, we simulate how anatomically-guided transitions between cognitive states can be reshaped by pharmacological or pathological perturbation. Our results provide a comprehensive look-up table charting how brain network organisation and chemoarchitecture interact to manifest different cognitive topographies. This computational framework establishes a principled foundation for systematically identifying novel ways to promote selective transitions between desired cognitive topographies., Competing Interests: Conflicts of interest D.B. is shareholder and advisory board member of MindState Design Labs, USA. All other authors have no conflicts of interest to report.

Alzheimer's disease and related dementias is a major public health burden-compounding over upcoming years due to longevity. Recently, clinical evidence hinted at the experience of social isolation in expediting dementia onset. In 502,506 UK Biobank participants and 30,097 participants from the Canadian Longitudinal Study of Aging, we revisited traditional risk factors for developing dementia in the context of loneliness and lacking social support. Across these measures of subjective and objective social deprivation, we have identified strong links between individuals' social capital and various indicators of Alzheimer's disease and related dementias risk, which replicated across both population cohorts. The quality and quantity of daily social encounters had deep connections with key aetiopathological factors, which represent 1) personal habits and lifestyle factors, 2) physical health, 3) mental health, and 4) societal and external factors. Our population-scale assessment suggest that social lifestyle determinants are linked to most neurodegeneration risk factors, highlighting them as promising targets for preventive clinical action., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Shafighi 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.)

The current World Health Organization classification integrates histological and molecular features of brain tumours. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumours. We applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumour profiles of 936 patients with neuroepithelial tumours and brain metastases. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumour patterns, termed meta-topologies . The optimal part-based representation was automatically determined in 10 000 split-half iterations. We further characterized each meta-topology's unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patterns. In neuroepithelial tumours, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumours. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.Using a novel data-driven approach, we identified generalizable topological patterns in both neuroepithelial tumours and brain metastases. Differences in the histopathologic profiles and prognosis of these anatomical tumour classes provide insights into the heterogeneity of tumour biology and might add to personalized clinical decision-making., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The intrinsic functional organization of the brain changes into older adulthood. Age differences are observed at multiple spatial scales, from global reductions in modularity and segregation of distributed brain systems, to network-specific patterns of dedifferentiation. Whether dedifferentiation reflects an inevitable, global shift in brain function with age, circumscribed, experience-dependent changes, or both, is uncertain. We employed a multimethod strategy to interrogate dedifferentiation at multiple spatial scales. Multi-echo (ME) resting-state fMRI was collected in younger (n = 181) and older (n = 120) healthy adults. Cortical parcellation sensitive to individual variation was implemented for precision functional mapping of each participant while preserving group-level parcel and network labels. ME-fMRI processing and gradient mapping identified global and macroscale network differences. Multivariate functional connectivity methods tested for microscale, edge-level differences. Older adults had lower BOLD signal dimensionality, consistent with global network dedifferentiation. Gradients were largely age-invariant. Edge-level analyses revealed discrete, network-specific dedifferentiation patterns in older adults. Visual and somatosensory regions were more integrated within the functional connectome; default and frontoparietal control network regions showed greater connectivity; and the dorsal attention network was more integrated with heteromodal regions. These findings highlight the importance of multiscale, multimethod approaches to characterize the architecture of functional brain aging., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Alzheimer's disease is marked by intracellular tau aggregates in the medial temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we examined codependent structural variations between the MTL's most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer's disease and related dementia (ADRD). By leveraging the power of the approximately 40,000 participants of the UK Biobank cohort, we assessed impacts from the protective APOE ɛ2 and the deleterious APOE ɛ4 Alzheimer's disease alleles on these structural relationships. We demonstrate ɛ2 and ɛ4 genotype effects on the inter-individual expression of HC-DN co-variation structural patterns at the population level. Across these HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornix's fimbria, and their cortical partners related to ADRD risk. Analyses of the rich phenotypic profiles in the UK Biobank cohort further revealed male-specific HC-DN associations with air pollution and female-specific associations with cardiovascular traits. We also showed that APOE ɛ2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our structural, genetic, and phenotypic analyses in this large epidemiological cohort reinvigorate the often-neglected interplay between APOE ɛ2 dosage and sex and link APOE alleles to inter-individual brain structural differences indicative of ADRD familial risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Savignac 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.)

Equity is widely held to be fundamental to the ethics of healthcare. In the context of clinical decision-making, it rests on the comparative fidelity of the intelligence - evidence-based or intuitive - guiding the management of each individual patient. Though brought to recent attention by the individuating power of contemporary machine learning, such epistemic equity arises in the context of any decision guidance, whether traditional or innovative. Yet no general framework for its quantification, let alone assurance, currently exists. Here we formulate epistemic equity in terms of model fidelity evaluated over learnt multidimensional representations of identity crafted to maximise the captured diversity of the population, introducing a comprehensive framework for Representational Ethical Model Calibration. We demonstrate the use of the framework on large-scale multimodal data from UK Biobank to derive diverse representations of the population, quantify model performance, and institute responsive remediation. We offer our approach as a principled solution to quantifying and assuring epistemic equity in healthcare, with applications across the research, clinical, and regulatory domains., (© 2022. The Author(s).)

Elucidating the neural basis of social behavior is a long-standing challenge in neuroscience. Such endeavors are driven by attempts to extend the isolated perspective on the human brain by considering interacting persons' brain activities, but a theoretical and computational framework for this purpose is still in its infancy. Here, we posit a comprehensive framework based on bipartite graphs for interbrain networks and address whether they provide meaningful insights into the neural underpinnings of social interactions. First, we show that the nodal density of such graphs exhibits nonrandom properties. While the current hyperscanning analyses mostly rely on global metrics, we encode the regions' roles via matrix decomposition to obtain an interpretable network representation yielding both global and local insights. With Bayesian modeling, we reveal how synchrony patterns seeded in specific brain regions contribute to global effects. Beyond inferential inquiries, we demonstrate that graph representations can be used to predict individual social characteristics, outperforming functional connectivity estimators for this purpose. In the future, this may provide a means of characterizing individual variations in social behavior or identifying biomarkers for social interaction and disorders., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Elaborate social interaction is a pivotal asset of the human species. The complexity of people's social lives may constitute the dominating factor in the vibrancy of many individuals' environment. The neural substrates linked to social cognition thus appear especially susceptible when people endure periods of social isolation: here, we zoom in on the systematic inter-relationships between two such neural substrates, the allocortical hippocampus (HC) and the neocortical default network (DN). Previous human social neuroscience studies have focused on the DN, while HC subfields have been studied in most detail in rodents and monkeys. To bring into contact these two separate research streams, we directly quantified how DN subregions are coherently co-expressed with specific HC subfields in the context of social isolation. A two-pronged decomposition of structural brain scans from ∼40 000 UK Biobank participants linked lack of social support to mostly lateral subregions in the DN patterns. This lateral DN association co-occurred with HC patterns that implicated especially subiculum, presubiculum, CA2, CA3 and dentate gyrus. Overall, the subregion divergences within spatially overlapping signatures of HC-DN co-variation followed a clear segregation into the left and right brain hemispheres. Separable regimes of structural HC-DN co-variation also showed distinct associations with the genetic predisposition for lacking social support at the population level., (© The Author(s) 2022. Published by Oxford University Press.)

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.

For most neuroimaging questions the range of possible analytic choices makes it unclear how to evaluate conclusions from any single analytic method. One possible way to address this issue is to evaluate all possible analyses using a multiverse approach, however, this can be computationally challenging and sequential analyses on the same data can compromise predictive power. Here, we establish how active learning on a low-dimensional space capturing the inter-relationships between pipelines can efficiently approximate the full spectrum of analyses. This approach balances the benefits of a multiverse analysis without incurring the cost on computational and predictive power. We illustrate this approach with two functional MRI datasets (predicting brain age and autism diagnosis) demonstrating how a multiverse of analyses can be efficiently navigated and mapped out using active learning. Furthermore, our presented approach not only identifies the subset of analysis techniques that are best able to predict age or classify individuals with autism spectrum disorder and healthy controls, but it also allows the relationships between analyses to be quantified., (© 2022. The Author(s).)

Socioeconomic status (SES) anchors individuals in their social network layers. Our embedding in the societal fabric resonates with habitus, world view, opportunity, and health disparity. It remains obscure how distinct facets of SES are reflected in the architecture of the central nervous system. Here, we capitalized on multivariate multi-output learning algorithms to explore possible imprints of SES in gray and white matter structure in the wider population ( n  ≈ 10,000 UK Biobank participants). Individuals with higher SES, compared with those with lower SES, showed a pattern of increased region volumes in the left brain and decreased region volumes in the right brain. The analogous lateralization pattern emerged for the fiber structure of anatomical white matter tracts. Our multimodal findings suggest hemispheric asymmetry as an SES-related brain signature, which was consistent across six different indicators of SES: degree, education, income, job, neighborhood and vehicle count. Hence, hemispheric specialization may have evolved in human primates in a way that reveals crucial links to SES., (© The Author(s) 2022. Published by Oxford University Press.)

Socioeconomic status (SES) correlates with brain structure, a relation of interest given the long-observed relations of SES to cognitive abilities and health. Yet, major questions remain open, in particular, the pattern of causality that underlies this relation. In an unprecedently large study, here, we assess genetic and environmental contributions to SES differences in neuroanatomy. We first establish robust SES-gray matter relations across a number of brain regions, cortical and subcortical. These regional correlates are parsed into predominantly genetic factors and those potentially due to the environment. We show that genetic effects are stronger in some areas (prefrontal cortex, insula) than others. In areas showing less genetic effect (cerebellum, lateral temporal), environmental factors are likely to be influential. Our results imply a complex interplay of genetic and environmental factors that influence the SES-brain relation and may eventually provide insights relevant to policy.

Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships., Methods: Using cross-sectional data from 306 previously concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures., Results: Early multi-tract multi-symptom pairs explained the most covariance and represented broad symptom categories, such as a general problems pair, or a pair representing all cognitive symptoms, and implicated more distributed networks of white matter tracts. Further pairs represented more specific symptom combinations, such as a pair representing attention problems exclusively, and were associated with more localized white matter abnormalities. Symptom representation was not systematically related to tract representation across pairs. Sleep problems were implicated across most pairs, but were related to different connections across these pairs. Expression of multi-tract features was not driven by sociodemographic and injury-related variables, as well as by clinical subgroups defined by the presence of ADHD. Analyses performed on a replication dataset showed consistent results., Conclusions: Using a double-multivariate approach, we identified clinically-informative, cross-demographic multi-tract multi-symptom relationships. These results suggest that rather than clear one-to-one symptom-connectivity disturbances, concussions may be characterized by subtypes of symptom/connectivity relationships. The symptom/connectivity relationships identified in multi-tract multi-symptom pairs were not apparent in single-tract/single-symptom analyses. Future studies aiming to better understand connectivity/symptom relationships should take into account multi-tract multi-symptom heterogeneity., Funding: Financial support for this work came from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (G.I.G.), an Ontario Graduate Scholarship (S.S.), a Restracomp Research Fellowship provided by the Hospital for Sick Children (S.S.), an Institutional Research Chair in Neuroinformatics (M.D.), as well as a Natural Sciences and Engineering Research Council CREATE grant (M.D.)., Competing Interests: GG, SS, EN, AP, DB, AW No competing interests declared, MD works as Chief Scientific Officer for IMEKA. He holds the following patents: DETERMINATION OF WHITE-MATTER NEURODEGENERATIVE DISEASE BIOMARKERS (Patent Application No.: 63/222,914), PROCESSING OF TRACTOGRAPHY RESULTS USING AN AUTOENCODER (Patent Application No.: 17/337,413), (© 2022, Guberman et al.)

Brain imaging research enjoys increasing adoption of supervised machine learning for single-participant disease classification. Yet, the success of these algorithms likely depends on population diversity, including demographic differences and other factors that may be outside of primary scientific interest. Here, we capitalize on propensity scores as a composite confound index to quantify diversity due to major sources of population variation. We delineate the impact of population heterogeneity on the predictive accuracy and pattern stability in 2 separate clinical cohorts: the Autism Brain Imaging Data Exchange (ABIDE, n = 297) and the Healthy Brain Network (HBN, n = 551). Across various analysis scenarios, our results uncover the extent to which cross-validated prediction performances are interlocked with diversity. The instability of extracted brain patterns attributable to diversity is located preferentially in regions part of the default mode network. Collectively, our findings highlight the limitations of prevailing deconfounding practices in mitigating the full consequences of population diversity., Competing Interests: The authors have declared that no competing interests exist.

How individual differences in brain network organization track behavioral variability is a fundamental question in systems neuroscience. Recent work suggests that resting-state and task-state functional connectivity can predict specific traits at the individual level. However, most studies focus on single behavioral traits, thus not capturing broader relationships across behaviors. In a large sample of 1858 typically developing children from the Adolescent Brain Cognitive Development (ABCD) study, we show that predictive network features are distinct across the domains of cognitive performance, personality scores and mental health assessments. On the other hand, traits within each behavioral domain are predicted by similar network features. Predictive network features and models generalize to other behavioral measures within the same behavioral domain. Although tasks are known to modulate the functional connectome, predictive network features are similar between resting and task states. Overall, our findings reveal shared brain network features that account for individual variation within broad domains of behavior in childhood., (© 2022. The Author(s).)

Algorithmic biases that favor majority populations pose a key challenge to the application of machine learning for precision medicine. Here, we assessed such bias in prediction models of behavioral phenotypes from brain functional magnetic resonance imaging. We examined the prediction bias using two independent datasets (preadolescent versus adult) of mixed ethnic/racial composition. When predictive models were trained on data dominated by white Americans (WA), out-of-sample prediction errors were generally higher for African Americans (AA) than for WA. This bias toward WA corresponds to more WA-like brain-behavior association patterns learned by the models. When models were trained on AA only, compared to training only on WA or an equal number of AA and WA participants, AA prediction accuracy improved but stayed below that for WA. Overall, the results point to the need for caution and further research regarding the application of current brain-behavior prediction models in minority populations.

Psychedelics probably alter states of consciousness by disrupting how the higher association cortex governs bottom-up sensory signals. Individual hallucinogenic drugs are usually studied in participants in controlled laboratory settings. Here, we have explored word usage in 6850 free-form testimonials about 27 drugs through the prism of 40 neurotransmitter receptor subtypes, which were then mapped to three-dimensional coordinates in the brain via their gene transcription levels from invasive tissue probes. Despite high interindividual variability, our pattern-learning approach delineated how drug-induced changes of conscious awareness are linked to cortex-wide anatomical distributions of receptor density proxies. Each discovered receptor-experience factor spanned between a higher-level association pole and a sensory input pole, which may relate to the previously reported collapse of hierarchical order among large-scale networks. Coanalyzing many psychoactive molecules and thousands of natural language descriptions of drug experiences, our analytical framework finds the underlying semantic structure and maps it directly to the brain.

Here we present the viewpoint that art essentially engages the social brain, by demonstrating how art processing maps onto the social brain connectome-the most comprehensive diagram of the neural dynamics that regulate human social cognition to date. We start with a brief history of the rise of neuroaesthetics as the scientific study of art perception and appreciation, in relation to developments in contemporary art practice and theory during the same period. Building further on a growing awareness of the importance of social context in art production and appreciation, we then set out how art engages the social brain and outline candidate components of the "artistic brain connectome." We explain how our functional model for art as a social brain phenomenon may operate when engaging with artworks. We call for closer collaborations between the burgeoning field of neuroaesthetics and arts professionals, cultural institutions and diverse audiences in order to fully delineate and contextualize this model. Complementary to the unquestionable value of art for art's sake, we argue that its neural grounding in the social brain raises important practical implications for mental health, and the care of people living with dementia and other neurological conditions., Competing Interests: JL was the founder of the Thinking Eye, a social enterprise which translates novel insights from research into relationships between visual art processes and the social brain into services that aim to support psychological wellbeing and optimal cognitive functioning. The remaining 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 van Leeuwen, Boomgaard, Bzdok, Crutch and Warren.)

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Social interaction complexity makes humans unique. But in times of social deprivation, this strength risks exposure of important vulnerabilities. Human social neuroscience studies have placed a premium on the default network (DN). In contrast, hippocampus (HC) subfields have been intensely studied in rodents and monkeys. To bridge these two literatures, we here quantified how DN subregions systematically covary with specific HC subfields in the context of subjective social isolation (i.e., loneliness). By codecomposition using structural brain scans of ∼40,000 UK Biobank participants, loneliness was specially linked to midline subregions in the uncovered DN patterns. These association cortex patterns coincided with concomitant HC patterns implicating especially CA1 and molecular layer. These patterns also showed a strong affiliation with the fornix white matter tract and the nucleus accumbens. In addition, separable signatures of structural HC-DN covariation had distinct associations with the genetic predisposition for loneliness at the population level. NEW & NOTEWORTHY The hippocampus and default network have been implicated in rich social interaction. Yet, these allocortical and neocortical neural systems have been interrogated in mostly separate literatures. Here, we conjointly investigate the hippocampus and default network at a subregion level, by capitalizing structural brain scans from ∼40,000 participants. We thus reveal unique insights on the nature of the "lonely brain" by estimating the regimes of covariation between the hippocampus and default network at population scale.

Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between "cases" and "controls," which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research-autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen's d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the "on average" when summarising their findings in their abstracts ("autistic people have deficits in X"), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Jan K Buitelaar has been a consultant to / member of advisory board of / and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties.Christopher Chatham is a full-time employee of D Hoffmann-La Roche Ltd. Declan Murphy has served on a SAB for Roche; and is running a clinical trial with them. Antonia San José Cáceres is a consultant for Servier Laboratories and is involved in clinical trials conducted by Servier. All other authors declare no conflict of interest.