"Puberty age gap": new method of assessing pubertal timing and its association with mental health problems.

Puberty is linked to mental health problems during adolescence, and in particular, the timing of puberty is thought to be an important risk factor. This study developed a new measure of pubertal timing that was built upon multiple pubertal features and their nonlinear changes over time (i.e., with age), and investigated its association with mental health problems. Using the Adolescent Brain Cognitive Development (ABCD) cohort (N ~ 9900, aged 9-13 years), we employed three different models to assess pubertal timing. These models aimed to predict chronological age based on: (i) observed physical development, (ii) hormone levels (testosterone and dehydroepiandrosterone [DHEA]), and (iii) a combination of both physical development and hormones. To achieve this, we utilized a supervised machine learning approach, which allowed us to train the models using the available data and make age predictions based on the input pubertal features. The accuracy of these three models was evaluated, and their associations with mental health problems were examined. The new pubertal timing model performed better at capturing age variance compared to the more commonly used linear regression method. Further, the model based on physical features accounted for the most variance in mental health, such that earlier pubertal timing was associated with higher symptoms. This study demonstrates the utility of our new model of pubertal timing and suggests that, relative to hormonal measures, physical measures of pubertal maturation have a stronger association with mental health problems in early adolescence.

Connectomes for 40,000 UK Biobank participants: A multi-modal, multi-scale brain network resource.

We mapped functional and structural brain networks for more than 40,000 UK Biobank participants. Structural connectivity was estimated with tractography and diffusion MRI. Resting-state functional MRI was used to infer regional functional connectivity. We provide high-quality structural and functional connectomes for multiple parcellation granularities, several alternative measures of interregional connectivity, and a variety of common data pre-processing techniques, yielding more than one million connectomes in total and requiring more than 200,000 h of compute time. For a single subject, we provide 28 out-of-the-box versions of structural and functional brain networks, allowing users to select, e.g., the parcellation and connectivity measure that best suit their research goals. Furthermore, we provide code and intermediate data for the time-efficient reconstruction of more than 1000 different versions of a subject's connectome based on an array of methodological choices. All connectomes are available via the UK Biobank data-sharing platform and our connectome mapping pipelines are openly available. In this report, we describe our connectome resource in detail for users, outline key considerations in developing an efficient pipeline to map an unprecedented number of connectomes, and report on the quality control procedures that were completed to ensure connectome reliability and accuracy. We demonstrate that our structural and functional connectivity matrices meet a number of quality control checks and replicate previously established findings in network neuroscience. We envisage that our resource will enable new studies of the human connectome in health, disease, and aging at an unprecedented scale.

Tractography passes the test: Results from the diffusion-simulated connectivity (disco) challenge.

Estimating structural connectivity from diffusion-weighted magnetic resonance imaging is a challenging task, partly due to the presence of false-positive connections and the misestimation of connection weights. Building on previous efforts, the MICCAI-CDMRI Diffusion-Simulated Connectivity (DiSCo) challenge was carried out to evaluate state-of-the-art connectivity methods using novel large-scale numerical phantoms. The diffusion signal for the phantoms was obtained from Monte Carlo simulations. The results of the challenge suggest that methods selected by the 14 teams participating in the challenge can provide high correlations between estimated and ground-truth connectivity weights, in complex numerical environments. Additionally, the methods used by the participating teams were able to accurately identify the binary connectivity of the numerical dataset. However, specific false positive and false negative connections were consistently estimated across all methods. Although the challenge dataset doesn't capture the complexity of a real brain, it provided unique data with known macrostructure and microstructure ground-truth properties to facilitate the development of connectivity estimation methods.

Connectome spatial smoothing (CSS): Concepts, methods, and evaluation.

Structural connectomes are increasingly mapped at high spatial resolutions comprising many hundreds-if not thousands-of network nodes. However, high-resolution connectomes are particularly susceptible to image registration misalignment, tractography artifacts, and noise, all of which can lead to reductions in connectome accuracy and test-retest reliability. We investigate a network analogue of image smoothing to address these key challenges. Connectome Spatial Smoothing (CSS) involves jointly applying a carefully chosen smoothing kernel to the two endpoints of each tractography streamline, yielding a spatially smoothed connectivity matrix. We develop computationally efficient methods to perform CSS using a matrix congruence transformation and evaluate a range of different smoothing kernel choices on CSS performance. We find that smoothing substantially improves the identifiability, sensitivity, and test-retest reliability of high-resolution connectivity maps, though at a cost of increasing storage burden. For atlas-based connectomes (i.e. low-resolution connectivity maps), we show that CSS marginally improves the statistical power to detect associations between connectivity and cognitive performance, particularly for connectomes mapped using probabilistic tractography. CSS was also found to enable more reliable statistical inference compared to connectomes without any smoothing. We provide recommendations for optimal smoothing kernel parameters for connectomes mapped using both deterministic and probabilistic tractography. We conclude that spatial smoothing is particularly important for the reliability of high-resolution connectomes, but can also provide benefits at lower parcellation resolutions. We hope that our work enables computationally efficient integration of spatial smoothing into established structural connectome mapping pipelines.

Network communication models narrow the gap between the modular organization of structural and functional brain networks.

Structural and functional brain networks are modular. Canonical functional systems, such as the default mode network, are well-known modules of the human brain and have been implicated in a large number of cognitive, behavioral and clinical processes. However, modules delineated in structural brain networks inferred from tractography generally do not recapitulate canonical functional systems. Neuroimaging evidence suggests that functional connectivity between regions in the same systems is not always underpinned by anatomical connections. As such, direct structural connectivity alone would be insufficient to characterize the functional modular organization of the brain. Here, we demonstrate that augmenting structural brain networks with models of indirect (polysynaptic) communication unveils a modular network architecture that more closely resembles the brain's established functional systems. We find that diffusion models of polysynaptic connectivity, particularly communicability, narrow the gap between the modular organization of structural and functional brain networks by 20-60%, whereas routing models based on single efficient paths do not improve mesoscopic structure-function correspondence. This suggests that functional modules emerge from the constraints imposed by local network structure that facilitates diffusive neural communication. Our work establishes the importance of modeling polysynaptic communication to understand the structural basis of functional systems.

High-resolution connectomic fingerprints: Mapping neural identity and behavior.

Connectomes are typically mapped at low resolution based on a specific brain parcellation atlas. Here, we investigate high-resolution connectomes independent of any atlas, propose new methodologies to facilitate their mapping and demonstrate their utility in predicting behavior and identifying individuals. Using structural, functional and diffusion-weighted MRI acquired in 1000 healthy adults, we aimed to map the cortical correlates of identity and behavior at ultra-high spatial resolution. Using methods based on sparse matrix representations, we propose a computationally feasible high-resolution connectomic approach that improves neural fingerprinting and behavior prediction. Using this high-resolution approach, we find that the multimodal cortical gradients of individual uniqueness reside in the association cortices. Furthermore, our analyses identified a striking dichotomy between the facets of a person's neural identity that best predict their behavior and cognition, compared to those that best differentiate them from other individuals. Functional connectivity was one of the most accurate predictors of behavior, yet resided among the weakest differentiators of identity; whereas the converse was found for morphological properties, such as cortical curvature. This study provides new insights into the neural basis of personal identity and new tools to facilitate ultra-high-resolution connectomics.

Temporal complexity of fMRI is reproducible and correlates with higher order cognition.

It has been hypothesized that resting state networks (RSNs), extracted from resting state functional magnetic resonance imaging (rsfMRI), likely display unique temporal complexity fingerprints, quantified by their multiscale entropy patterns (McDonough and Nashiro, 2014). This is a hypothesis with a potential capacity for developing digital biomarkers of normal brain function, as well as pathological brain dysfunction. Nevertheless, a limitation of McDonough and Nashiro (2014) was that rsfMRI data from only 20 healthy individuals was used for the analysis. To validate this hypothesis in a larger cohort, we used rsfMRI datasets of 987 healthy young adults from the Human Connectome Project (HCP), aged 22-35, each with four 14.4-min rsfMRI recordings and parcellated into 379 brain regions. We quantified multiscale entropy of rsfMRI time series averaged at different cortical and sub-cortical regions. We performed effect-size analysis on the data in 8 RSNs. Given that the morphology of multiscale entropy is affected by the choice of its tolerance parameter (r) and embedding dimension (m), we repeated the analyses at multiple values of r and m including the values used in McDonough and Nashiro (2014). Our results reinforced high temporal complexity in the default mode and frontoparietal networks. Lowest temporal complexity was observed in the subcortical areas and limbic system. We investigated the effect of temporal resolution (determined by the repetition time TR) after downsampling of rsfMRI time series at two rates. At a low temporal resolution, we observed increased entropy and variance across datasets. Test-retest analysis showed that findings were likely reproducible across individuals over four rsfMRI runs, especially when the tolerance parameter r is equal to 0.5. The results confirmed that the relationship between functional brain connectivity strengths and rsfMRI temporal complexity changes over time scales. Finally, a non-random correlation was observed between temporal complexity of RSNs and fluid intelligence suggesting that complex dynamics of the human brain is an important attribute of high-level brain function.

Functional dedifferentiation of the brain during healthy aging.

Nonpathological aging is associated with significant cognitive deficits. Thus, the underlying neurobiology of aging-associated cognitive decline warrants investigation. In a recent study, Chong et al. (Chong JSX, Ng KK, Tandi J, Wang C, Poh J-H, Lo JC, Chee MWL, Zhou JH. J Neurosci 39: 5534-5550, 2019) provided insights into the association between cognitive decline and the loss of functional specialization in the brains of older adults. Here, we introduce the novel graph theoretical approach utilized and discuss the significance of their findings and broader implications on aging. We also provide alternate perspectives of their findings and suggest directions for future work.

Topological cluster statistic (TCS): Toward structural connectivity-guided fMRI cluster enhancement.

Functional magnetic resonance imaging (fMRI) studies most commonly use cluster-based inference to detect local changes in brain activity. Insufficient statistical power and disproportionate false-positive rates reportedly hinder optimal inference. We propose a structural connectivity-guided clustering framework, called topological cluster statistic (TCS), that enhances sensitivity by leveraging white matter anatomical connectivity information. TCS harnesses multimodal information from diffusion tractography and functional imaging to improve task fMRI activation inference. Compared to conventional approaches, TCS consistently improves power over a wide range of effects. This improvement results in a 10%-50% increase in local sensitivity with the greatest gains for medium-sized effects. TCS additionally enables inspection of underlying anatomical networks and thus uncovers knowledge regarding the anatomical underpinnings of brain activation. This novel approach is made available in the PALM software to facilitate usability. Given the increasing recognition that activation reflects widespread, coordinated processes, TCS provides a way to integrate the known structure underlying widespread activations into neuroimaging analyses moving forward.

Neuroimaging studies often encounter challenges in reliable inference of statistical maps due to limited statistical power. This article introduces TCS, a novel method that integrates anatomical connectivity data from diffusion tractography into cluster-based inference techniques. Our findings demonstrate that TCS enhances statistical power, improves the detection of spatially disjoint localized activations, and identifies the underlying network linking distant inferred active regions. By elucidating the coordinated network supporting inferred effects, TCS enables data-driven interpretation of inference results. The availability of TCS as a publicly accessible tool offers a promising avenue for future neuroimaging research to leverage anatomical connectivity for enhanced inference and interpretation.

Brain-Predicted Age Associates With Psychopathology Dimensions in Youths.

BACKGROUND: This study aimed to investigate whether dimensional constructs of psychopathology relate to variation in patterns of brain development and to determine whether these constructs share common neurodevelopmental profiles. METHODS: Psychiatric symptom ratings from 9312 youths (8-21 years old) from the Philadelphia Neurodevelopmental Cohort were parsed into 7 independent dimensions of clinical psychopathology representing conduct, anxiety, obsessive-compulsive, attention, depression, bipolar, and psychosis symptoms. Using a subset of this cohort with structural magnetic resonance imaging (n = 1313), a normative model of brain morphology was established and the model was then applied to predict the age of youths with clinical symptoms. We investigated whether the deviation of brain-predicted age from true chronological age, called the brain age gap, explained individual variation in each psychopathology dimension. RESULTS: Individual variation in the brain age gap significantly associated with clinical dimensions representing psychosis (t = 3.16, p = .0016), obsessive-compulsive symptoms (t = 2.5, p = .01), and general psychopathology (t = 4.08, p < .0001). Greater symptom severity along these dimensions was associated with brain morphology that appeared older than expected for typically developing youths of the same age. Psychopathology dimensions clustered into 2 modules based on shared brain loci where putative accelerated neurodevelopment was most prominent. Patterns of morphological development were accelerated in frontal cortices for depression, psychosis, and conduct symptoms (module 1), whereas acceleration was most evident in subcortex and insula for the remaining dimensions (module 2). CONCLUSIONS: Our findings suggest that increased brain age, particularly in frontal cortex and subcortical nuclei, underpins clinical psychosis and obsessive-compulsive symptoms in youths. Psychopathology dimensions share common neural substrates, despite representing clinically independent symptom profiles.