The default mode network in cognition: a topographical perspective.

The default mode network (DMN) is a set of widely distributed brain regions in the parietal, temporal and frontal cortex. These regions often show reductions in activity during attention-demanding tasks but increase their activity across multiple forms of complex cognition, many of which are linked to memory or abstract thought. Within the cortex, the DMN has been shown to be located in regions furthest away from those contributing to sensory and motor systems. Here, we consider how our knowledge of the topographic characteristics of the DMN can be leveraged to better understand how this network contributes to cognition and behaviour.

APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer's disease and related dementia.

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.

Population heterogeneity in clinical cohorts affects the predictive accuracy of brain imaging.

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.

Structural covariation between cerebellum and neocortex intrinsic structural covariation links cerebellum subregions to the cerebral cortex.

The human cerebellum is increasingly recognized to be involved in nonmotor and higher-order cognitive functions. Yet, its ties with the entire cerebral cortex have not been holistically studied in a whole brain exploration with a unified analytical framework. Here, we characterized dissociable cortical-cerebellar structural covariation patterns based on regional gray matter volume (GMV) across the brain in n = 38,527 UK Biobank participants. Our results invigorate previous observations in that important shares of cortical-cerebellar structural covariation are described as 1) a dissociation between the higher-level cognitive system and lower-level sensorimotor system and 2) an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel pattern of ipsilateral, rather than contralateral, cerebral-cerebellar associations. Furthermore, phenome-wide association assays revealed key phenotypes, including cognitive phenotypes, lifestyle, physical properties, and blood assays, associated with each decomposed covariation pattern, helping to understand their real-world implications. This systems neuroscience view paves the way for future studies to explore the implications of these structural covariations, potentially illuminating new pathways in our understanding of neurological and cognitive disorders.NEW & NOTEWORTHY Cerebellum's association with the entire cerebral cortex has not been holistically studied in a unified way. Here, we conjointly characterize the population-level cortical-cerebellar structural covariation patterns leveraging ∼40,000 UK Biobank participants whole brain structural scans and ∼1,000 phenotypes. We revitalize the previous hypothesis of an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel ipsilateral cerebral-cerebellar associations. Phenome-wide association (PheWAS) revealed real-world implications of the structural covariation patterns.

Educating the future generation of researchers: A cross-disciplinary survey of trends in analysis methods.

Methods for data analysis in the biomedical, life, and social (BLS) sciences are developing at a rapid pace. At the same time, there is increasing concern that education in quantitative methods is failing to adequately prepare students for contemporary research. These trends have led to calls for educational reform to undergraduate and graduate quantitative research method curricula. We argue that such reform should be based on data-driven insights into within- and cross-disciplinary use of analytic methods. Our survey of peer-reviewed literature analyzed approximately 1.3 million openly available research articles to monitor the cross-disciplinary mentions of analytic methods in the past decade. We applied data-driven text mining analyses to the "Methods" and "Results" sections of a large subset of this corpus to identify trends in analytic method mentions shared across disciplines, as well as those unique to each discipline. We found that the t test, analysis of variance (ANOVA), linear regression, chi-squared test, and other classical statistical methods have been and remain the most mentioned analytic methods in biomedical, life science, and social science research articles. However, mentions of these methods have declined as a percentage of the published literature between 2009 and 2020. On the other hand, multivariate statistical and machine learning approaches, such as artificial neural networks (ANNs), have seen a significant increase in the total share of scientific publications. We also found unique groupings of analytic methods associated with each BLS science discipline, such as the use of structural equation modeling (SEM) in psychology, survival models in oncology, and manifold learning in ecology. We discuss the implications of these findings for education in statistics and research methods, as well as within- and cross-disciplinary collaboration.

Social belonging: brain structure and function is linked to membership in sports teams, religious groups, and social clubs.

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.

Accurate machine learning prediction of sexual orientation based on brain morphology and intrinsic functional connectivity.

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.

Home alone: A population neuroscience investigation of brain morphology substrates.

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.

Relationship between prediction accuracy and feature importance reliability: An empirical and theoretical study.

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.

Homotopic local-global parcellation of the human cerebral cortex from resting-state functional connectivity.

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).

Disentangling poststroke cognitive deficits and their neuroanatomical correlates through combined multivariable and multioutcome lesion-symptom mapping.

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.

Age differences in the functional architecture of the human 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.

Aberrant functional brain network organization is associated with relapse during 1-year follow-up in alcohol-dependent patients.

Alcohol dependence (AD) is a debilitating disease associated with high relapse rates even after long periods of abstinence. Thus, elucidating neurobiological substrates of relapse risk is fundamental for the development of novel targeted interventions that could promote long-lasting abstinence. In the present study, we analysed resting-state functional magnetic resonance imaging (rsfMRI) data from a sample of recently detoxified patients with AD (n = 93) who were followed up for 12 months after rsfMRI assessment. Specifically, we employed graph theoretic analyses to compare functional brain network topology and functional connectivity between future relapsers (REL, n = 59), future abstainers (ABS, n = 28) and age- and gender-matched controls (CON, n = 83). Our results suggest increased whole-brain network segregation, decreased global network integration and overall blunted connectivity strength in REL compared with CON. Conversely, we found evidence for a comparable network architecture in ABS relative to CON. At the nodal level, REL exhibited decreased integration and decoupling between multiple brain systems compared with CON, encompassing regions associated with higher-order executive functions, sensory and reward processing. Among patients with AD, increased coupling between nodes implicated in reward valuation and salience attribution constitutes a particular risk factor for future relapse. Importantly, aberrant network organization in REL was consistently associated with shorter abstinence duration during follow-up, portending to a putative neural signature of relapse risk in AD. Future research should further evaluate the potential diagnostic value of the identified changes in network topology and functional connectivity for relapse prediction at the individual subject level.

Interacting brains revisited: A cross-brain network neuroscience perspective.

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.

Recovery after stroke: the severely impaired are a distinct group.

INTRODUCTION: Stroke causes different levels of impairment and the degree of recovery varies greatly between patients. The majority of recovery studies are biased towards patients with mild-to-moderate impairments, challenging a unified recovery process framework. Our aim was to develop a statistical framework to analyse recovery patterns in patients with severe and non-severe initial impairment and concurrently investigate whether they recovered differently. METHODS: We designed a Bayesian hierarchical model to estimate 3-6 months upper limb Fugl-Meyer (FM) scores after stroke. When focusing on the explanation of recovery patterns, we addressed confounds affecting previous recovery studies and considered patients with FM-initial scores <45 only. We systematically explored different FM-breakpoints between severe/non-severe patients (FM-initial=5-30). In model comparisons, we evaluated whether impairment-level-specific recovery patterns indeed existed. Finally, we estimated the out-of-sample prediction performance for patients across the entire initial impairment range. RESULTS: Recovery data was assembled from eight patient cohorts (n=489). Data were best modelled by incorporating two subgroups (breakpoint: FM-initial=10). Both subgroups recovered a comparable constant amount, but with different proportional components: severely affected patients recovered more the smaller their impairment, while non-severely affected patients recovered more the larger their initial impairment. Prediction of 3-6 months outcomes could be done with an R2=63.5% (95% CI=51.4% to 75.5%). CONCLUSIONS: Our work highlights the benefit of simultaneously modelling recovery of severely-to-non-severely impaired patients and demonstrates both shared and distinct recovery patterns. Our findings provide evidence that the severe/non-severe subdivision in recovery modelling is not an artefact of previous confounds. The presented out-of-sample prediction performance may serve as benchmark to evaluate promising biomarkers of stroke recovery.

The meaning of significant mean group differences for biomarker discovery.

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.

Variability in Brain Structure and Function Reflects Lack of Peer Support.

Humans are a highly social species. Complex interactions for mutual support range from helping neighbors to building social welfare institutions. During times of distress or crisis, sharing life experiences within one's social circle is critical for well-being. By translating pattern-learning algorithms to the UK Biobank imaging-genetics cohort (n = ~40 000 participants), we have delineated manifestations of regular social support in multimodal whole-brain measurements. In structural brain variation, we identified characteristic volumetric signatures in the salience and limbic networks for high- versus low-social support individuals. In patterns derived from functional coupling, we also located interindividual differences in social support in action-perception circuits related to binding sensory cues and initiating behavioral responses. In line with our demographic profiling analysis, the uncovered neural substrates have potential implications for loneliness, substance misuse, and resilience to stress.

Signal diffusion along connectome gradients and inter-hub routing differentially contribute to dynamic human brain function.

Human cognition is dynamic, alternating over time between externally-focused states and more abstract, often self-generated, patterns of thought. Although cognitive neuroscience has documented how networks anchor particular modes of brain function, mechanisms that describe transitions between distinct functional states remain poorly understood. Here, we examined how time-varying changes in brain function emerge within the constraints imposed by macroscale structural network organization. Studying a large cohort of healthy adults (n = 326), we capitalized on manifold learning techniques that identify low dimensional representations of structural connectome organization and we decomposed neurophysiological activity into distinct functional states and their transition patterns using Hidden Markov Models. Structural connectome organization predicted dynamic transitions anchored in sensorimotor systems and those between sensorimotor and transmodal states. Connectome topology analyses revealed that transitions involving sensorimotor states traversed short and intermediary distances and adhered strongly to communication mechanisms of network diffusion. Conversely, transitions between transmodal states involved spatially distributed hubs and increasingly engaged long-range routing. These findings establish that the structure of the cortex is optimized to allow neural states the freedom to vary between distinct modes of processing, and so provides a key insight into the neural mechanisms that give rise to the flexibility of human cognition.

Loneliness is linked to specific subregional alterations in hippocampus-default network covariation.

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.

Machine learning: supervised methods.

Supervised learning algorithms extract general principles from observed examples guided by a specific prediction objective.