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In this perspective, we describe how developmental improvements in youth executive function (EF) are supported by hierarchically organized maturational changes in functional brain systems. We first highlight evidence that functional brain systems are embedded within a hierarchical sensorimotor-association axis of cortical organization. We then review data showing that functional system developmental profiles vary along this axis: systems near the associative end become more functionally segregated, while those in the middle become more integrative. Developmental changes that strengthen the hierarchical organization of the cortex may support EF by facilitating top-down information flow and balancing within- and between-system communication. We propose a central role for attention and frontoparietal control systems in the maturation of healthy EF and suggest that reduced functional system differentiation across the sensorimotor-association axis contributes to transdiagnostic EF deficits. Executive function relies on both specialized processing within functional systems and flexible communication between functional systems. Functional systems exhibit graded differences in connectivity profiles that are embedded within a sensorimotor-association axis, a hierarchical axis of cortical organization. Functional systems at the top of this hierarchical axis tend to become more functionally segregated during development, while regions in middle-axis systems become more integrated; this balance may support healthy executive function. Integrative attention and control systems may drive large-scale functional connectome reorganization during late childhood and adolescence, facilitating hierarchical information flow and multisystem coordination. Abnormal functional system development in youth may lead to executive dysfunction, thereby increasing risk for psychopathology. [ABSTRACT FROM AUTHOR]

Correlations between cognitive ability and psychopathology are well recognized, but prior research has been limited by focusing on individuals with intellectual disability, single-diagnosis psychiatric populations, or few measures of psychopathology. Here, we quantify relationships between full-scale IQ and multiple dimensions of psychopathology in a diverse care-seeking population, with a novel focus on differential coupling between psychopathology dimensions as a function of IQ. A total of 70 dimensional measures of psychopathology, plus IQ and demographic data, were collated for 2,752 children and adolescents from the Healthy Brain Network dataset. We first examined univariate associations between IQ and psychopathology, and then characterized how the correlational architecture of psychopathology differs between groups at extremes of the IQ distribution. Associations with IQ vary in magnitude between different domains of psychopathology: IQ shows the strongest negative correlations with attentional and social impairments, but is largely unrelated to affective symptoms and psychopathy. Lower IQ is associated with stronger coupling between internalizing problems and aggression, repetitive behaviors, and hyperactivity/inattentiveness. Our analyses reveal that variation in general cognitive ability is associated not only with significant and selective shifts in severity of psychopathology, but also in the coupling between different dimensions of psychopathology. These findings have relevance for the clinical assessment of mental health in populations with varying IQ, and may also inform ongoing efforts to improve the measurement of psychopathology and to understand how relationships between cognition and behavior are reflected in brain organization. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. [ABSTRACT FROM AUTHOR]

The spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in the association cortex, implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth. The authors studied 790 youths ages 8 to 23 years who had 27 minutes of high-quality functional magnetic resonance imaging data as part of the Philadelphia Neurodevelopmental Cohort. Four correlated dimensions were estimated using a confirmatory correlated traits factor analysis on 112 item-level clinical symptoms, and one overall psychopathology factor with 4 orthogonal dimensions were extracted using a confirmatory factor analysis. Spatially regularized nonnegative matrix factorization was used to identify 17 individual-specific functional networks for each participant. Partial least square regression with split-half cross-validation was conducted to evaluate to what extent the topography of personalized functional networks encodes major dimensions of psychopathology. Personalized functional network topography significantly predicted unseen individuals' major dimensions of psychopathology, including fear, psychosis, externalizing, and anxious-misery. Reduced representation of association networks was among the most important features for the prediction of all 4 dimensions. Further analysis revealed that personalized functional network topography predicted overall psychopathology (r = 0.16, permutation testing p <.001), which drove prediction of the 4 correlated dimensions. These results suggest that individual differences in functional network topography in association networks is related to overall psychopathology in youth. Such results underscore the importance of considering functional neuroanatomy for personalized diagnostics and therapeutics in psychiatry. [ABSTRACT FROM AUTHOR]

The article discusses a 2022 study on network control energy for simulating brain circuit activation. Topics covered include using the temporal lobe epilepsy model which showed that patients require comparatively higher control energy for network activation, the imbalance between ipsilateral and contralateral temporolimbic regions, and asymmetric gray matter loss. Also noted is the study's integration of gray matter integrity, metabolism, and energetic generation of neural dynamics.

Objective: Despite the overall success of responsive neurostimulation (RNS) therapy for drug‐resistant focal epilepsy, clinical outcomes in individuals vary significantly and are hard to predict. Biomarkers that indicate the clinical efficacy of RNS—ideally before device implantation—are critically needed, but challenges include the intrinsic heterogeneity of the RNS patient population and variability in clinical management across epilepsy centers. The aim of this study is to use a multicenter dataset to evaluate a candidate biomarker from intracranial electroencephalographic (iEEG) recordings that predicts clinical outcome with subsequent RNS therapy. Methods: We assembled a federated dataset of iEEG recordings, collected prior to RNS implantation, from a retrospective cohort of 30 patients across three major epilepsy centers. Using ictal iEEG recordings, each center independently calculated network synchronizability, a candidate biomarker indicating the susceptibility of epileptic brain networks to RNS therapy. Results: Ictal measures of synchronizability in the high‐γ band (95–105 Hz) significantly distinguish between good and poor RNS responders after at least 3 years of therapy under the current RNS therapy guidelines (area under the curve =.83). Additionally, ictal high‐γ synchronizability is inversely associated with the degree of therapeutic response. Significance: This study provides a proof‐of‐concept roadmap for collaborative biomarker evaluation in federated data, where practical considerations impede full data sharing across centers. Our results suggest that network synchronizability can help predict therapeutic response to RNS therapy. With further validation, this biomarker could facilitate patient selection and help avert a costly, invasive intervention in patients who are unlikely to benefit. [ABSTRACT FROM AUTHOR]

Intrinsically motivated information seeking is an expression of curiosity believed to be central to human nature. However, most curiosity research relies on small, Western convenience samples. Here, we analyze a naturalistic population of 482,760 readers using Wikipedia's mobile app in 14 languages from 50 countries or territories. By measuring the structure of knowledge networks constructed by readers weaving a thread through articles in Wikipedia, we replicate two styles of curiosity previously identified in laboratory studies: the nomadic "busybody" and the targeted "hunter." Further, we find evidence for another style-the "dancer"-which was previously predicted by a historico-philosophical examination of texts over two millennia and is characterized by creative modes of knowledge production. We identify associations, globally, between the structure of knowledge networks and population-level indicators of spatial navigation, education, mood, well-being, and inequality. These results advance our understanding of Wikipedia's global readership and demonstrate how cultural and geographical properties of the digital environment relate to different styles of curiosity.

α-Synuclein misfolding and progressive accumulation drives a pathogenic process in Parkinson's disease. To understand cellular and network vulnerability to α-synuclein pathology, we developed a framework to quantify network-level vulnerability and identify new therapeutic targets at the cellular level. Full brain α-synuclein pathology was mapped in mice over 9 months. Empirical pathology data was compared to theoretical pathology estimates from a diffusion model of pathology progression along anatomical connections. Unexplained variance in the model enabled us to derive regional vulnerability that we compared to regional gene expression. We identified gene expression patterns that relate to regional vulnerability, including 12 kinases that were enriched in vulnerable regions. Among these, an inhibitor of group II PAKs demonstrated protection from neuron death and α-synuclein pathology, even after delayed compound treatment. This study provides a framework for the derivation of cellular vulnerability from network-based studies and identifies a promising therapeutic pathway for Parkinson's disease., Highlights: Longitudinal α-synuclein pathology assessment in 1046 brain regions over 9 monthsLinear diffusion modeling derivation of network vulnerability to α-synuclein pathologyPANGEA: assessment of over 19,000 genes in 302 brain regionsGroup II PAK inhibitor prevents α-synuclein pathology and neuron death.

Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks-especially the cerebellum-as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain-especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC-but not CBF-started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.

Precisely how the anatomical structure of the brain gives rise to a repertoire of complex functions remains incompletely understood. A promising manifestation of this mapping from structure to function is the dependency of the functional activity of a brain region on the underlying white matter architecture. Here, we review the literature examining the macroscale coupling between structural and functional connectivity, and we establish how this structure-function coupling (SFC) can provide more information about the underlying workings of the brain than either feature alone. We begin by defining SFC and describing the computational methods used to quantify it. We then review empirical studies that examine the heterogeneous expression of SFC across different brain regions, among individuals, in the context of the cognitive task being performed, and over time, as well as its role in fostering flexible cognition. Last, we investigate how the coupling between structure and function is affected in neurological and psychiatric conditions, and we report how aberrant SFC is associated with disease duration and disease-specific cognitive impairment. By elucidating how the dynamic relationship between the structure and function of the brain is altered in the presence of neurological and psychiatric conditions, we aim to not only further our understanding of their aetiology but also establish SFC as a new and sensitive marker of disease symptomatology and cognitive performance. Overall, this Review collates the current knowledge regarding the regional interdependency between the macroscale structure and function of the human brain in both neurotypical and neuroatypical individuals., (© 2024. Springer Nature Limited.)

Background: A key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex., Aims: We aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks., Method: We leveraged person-specific atlases of functional brain networks defined using nonnegative matrix factorization in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout ("topography") of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants' sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression., Results: Sex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants' PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons., Conclusions: Sex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence., Competing Interests: Declaration of Interest: R.T.S. and A.A-B. have received consulting income from Octave Bioscience and compensation for scientific reviewing from the American Medical Association. J.S. and A.A-B. are co-founders and equity holders in Centile Bioscience, and J.S. is on the board of directors for Centile Bioscience. All other authors declare no conflicts of interest.

Background: Symptoms of borderline personality disorder (BPD) often manifest during adolescence, but the underlying relationship between these debilitating symptoms and the development of functional brain networks is not well understood. Here, we aimed to investigate how multivariate patterns of functional connectivity are associated with borderline personality traits in large samples of young adults and adolescents., Methods: We used functional magnetic resonance imaging data from young adults and adolescents from the HCP-YA (Human Connectome Project Young Adult) (n = 870, ages 22-37 years, 457 female) and the HCP-D (Human Connectome Project Development) (n = 223, ages 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five-Factor Inventory. A ridge regression model with cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity. The trained model was further tested on data from HCP-D without further tuning. Finally, we tested how the connectivity patterns associated with BPD aligned with age-related changes in connectivity., Results: Multivariate functional connectivity patterns significantly predicted out-of-sample BPD scores in unseen data in young adults (HCP-YA p perm u ted  = .001) and older adolescents (HCP-D p perm ut ed  = .001). Regional predictive capacity was heterogeneous; the most predictive regions were found in functional systems relevant for emotion regulation and executive function, including the ventral attention network. Finally, regional functional connectivity patterns that predicted BPD scores aligned with those associated with development in youth., Conclusions: Individual differences in functional connectivity in developmentally sensitive regions are associated with borderline personality traits., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

In the brain, functional connections form a network whose topological organization can be described by graph-theoretic network diagnostics. These include characterizations of the community structure, such as modularity and participation coefficient, which have been shown to change over the course of childhood and adolescence. To investigate if such changes in the functional network are associated with changes in cognitive performance during development, network studies often rely on an arbitrary choice of preprocessing parameters, in particular the proportional threshold of network edges. Because the choice of parameter can impact the value of the network diagnostic, and therefore downstream conclusions, we propose to circumvent that choice by conceptualizing the network diagnostic as a function of the parameter. As opposed to a single value, a network diagnostic curve describes the connectome topology at multiple scales-from the sparsest group of the strongest edges to the entire edge set. To relate these curves to executive function and other covariates, we use scalar-on-function regression, which is more flexible than previous functional data-based models used in network neuroscience. We then consider how systematic differences between networks can manifest in misalignment of diagnostic curves, and consequently propose a supervised curve alignment method that incorporates auxiliary information from other variables. Our algorithm performs both functional regression and alignment via an iterative, penalized, and nonlinear likelihood optimization. The illustrated method has the potential to improve the interpretability and generalizability of neuroscience studies where the goal is to study heterogeneity among a mixture of function- and scalar-valued measures., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

Human cortical development follows a sensorimotor-to-association sequence during childhood and adolescence 1-6 . The brain's capacity to enact this sequence over decades indicates that it relies on intrinsic mechanisms to regulate inter-regional differences in the timing of cortical maturation, yet regulators of human developmental chronology are not well understood. Given evidence from animal models that thalamic axons modulate windows of cortical plasticity 7-12 , here we evaluate the overarching hypothesis that structural connections between the thalamus and cortex help to coordinate cortical maturational heterochronicity during youth. We first introduce, cortically annotate, and anatomically validate a new atlas of human thalamocortical connections using diffusion tractography. By applying this atlas to three independent youth datasets (ages 8-23 years; total N = 2,676), we reproducibly demonstrate that thalamocortical connections develop along a maturational gradient that aligns with the cortex's sensorimotor-association axis. Associative cortical regions with thalamic connections that take longest to mature exhibit protracted expression of neurochemical, structural, and functional markers indicative of higher circuit plasticity as well as heightened environmental sensitivity. This work highlights a central role for the thalamus in the orchestration of hierarchically organized and environmentally sensitive windows of cortical developmental malleability., Competing Interests: Competing Interests The authors declare no competing interests.

Deterministic chaos permits a precise notion of a "perfect measurement" as one that, when obtained repeatedly, captures all of the information created by the system's evolution with minimal redundancy. Finding an optimal measurement is challenging and has generally required intimate knowledge of the dynamics in the few cases where it has been done. We establish an equivalence between a perfect measurement and a variant of the information bottleneck. As a consequence, we can employ machine learning to optimize measurement processes that efficiently extract information from trajectory data. We obtain approximately optimal measurements for multiple chaotic maps and lay the necessary groundwork for efficient information extraction from general time series.

Humans are exposed to sequences of events in the environment, and the interevent transition probabilities in these sequences can be modeled as a graph or network. Many real-world networks are organized hierarchically and while much is known about how humans learn basic transition graph topology, whether and to what degree humans can learn hierarchical structures in such graphs remains unknown. We probe the mental estimates of transition probabilities via the surprisal effect phenomenon: humans react more slowly to less expected transitions. Using mean-field predictions and numerical simulations, we show that surprisal effects are stronger for finer-level than coarser-level hierarchical transitions, and that surprisal effects at coarser levels are difficult to detect for limited learning times or in small samples. Using a serial response experiment with human participants (n=100), we replicate our predictions by detecting a surprisal effect at the finer level of the hierarchy but not at the coarser level of the hierarchy. We then evaluate the presence of a trade-off in learning, whereby humans who learned the finer level of the hierarchy better also tended to learn the coarser level worse, and vice versa. This study elucidates the processes by which humans learn sequential events in hierarchical contexts. More broadly, our work charts a road map for future investigation of the neural underpinnings and behavioral manifestations of graph learning.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages., Methods: Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2 G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3-6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression., Results: Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2 G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2 G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers., Conclusions: This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development., (© 2024. The Author(s).)

A fundamental goal of research in neuroscience is to uncover the causal structure of the brain. This focus on causation makes sense, because causal information can provide explanations of brain function and identify reliable targets with which to understand cognitive function and prevent or change neurological conditions and psychiatric disorders. In this research, one of the most frequently used causal concepts is 'mechanism' - this is seen in the literature and language of the field, in grant and funding inquiries that specify what research is supported, and in journal guidelines on which contributions are considered for publication. In these contexts, mechanisms are commonly tied to expressions of the main aims of the field and cited as the 'fundamental', 'foundational' and/or 'basic' unit for understanding the brain. Despite its common usage and perceived importance, mechanism is used in different ways that are rarely distinguished. Given that this concept is defined in different ways throughout the field - and that there is often no clarification of which definition is intended - there remains a marked ambiguity about the fundamental goals, orientation and principles of the field. Here we provide an overview of causation and mechanism from the perspectives of neuroscience and philosophy of science, in order to address these challenges., (© 2024. Springer Nature Limited.)

Neurodevelopment is not merely a process of brain maturation, but an adaptation to constraints unique to each individual and to the environments we co-create. However, our theoretical and methodological toolkits often ignore this reality. There is growing awareness that a shift is needed that allows us to study divergence of brain and behaviour across conventional categorical boundaries. However, we argue that in future our study of divergence must also incorporate the developmental dynamics that capture the emergence of those neurodevelopmental differences. This crucial step will require adjustments in study design and methodology. If our ultimate aim is to incorporate the developmental dynamics that capture how, and ultimately when, divergence takes place then we will need an analytic toolkit equal to these ambitions. We argue that the over reliance on group averages has been a conceptual dead-end with regard to the neurodevelopmental differences. This is in part because any individual differences and developmental dynamics are inevitably lost within the group average. Instead, analytic approaches which are themselves new, or simply newly applied within this context, may allow us to shift our theoretical and methodological frameworks from groups to individuals. Likewise, methods capable of modelling complex dynamic systems may allow us to understand the emergent dynamics only possible at the level of an interacting neural system., (Copyright © 2024. Published by Elsevier Ltd.)

It is typically assumed that large networks of neurons exhibit a large repertoire of nonlinear behaviours. Here we challenge this assumption by leveraging mathematical models derived from measurements of local field potentials via intracranial electroencephalography and of whole-brain blood-oxygen-level-dependent brain activity via functional magnetic resonance imaging. We used state-of-the-art linear and nonlinear families of models to describe spontaneous resting-state activity of 700 participants in the Human Connectome Project and 122 participants in the Restoring Active Memory project. We found that linear autoregressive models provide the best fit across both data types and three performance metrics: predictive power, computational complexity and the extent of the residual dynamics unexplained by the model. To explain this observation, we show that microscopic nonlinear dynamics can be counteracted or masked by four factors associated with macroscopic dynamics: averaging over space and over time, which are inherent to aggregated macroscopic brain activity, and observation noise and limited data samples, which stem from technological limitations. We therefore argue that easier-to-interpret linear models can faithfully describe macroscopic brain dynamics during resting-state conditions., (© 2023. The Author(s).)

Many scientific questions can be formulated as hypotheses about conditional correlations. For instance, in tests of cognitive and physical performance, the trade-off between speed and accuracy motivates study of the two variables together. A natural question is whether speed-accuracy coupling depends on other variables, such as sustained attention. Classical regression techniques, which posit models in terms of covariates and outcomes, are insufficient to investigate the effect of a third variable on the symmetric relationship between speed and accuracy. In response, we propose a conditional correlation model with association size, a likelihood-based statistical framework to estimate the conditional correlation between speed and accuracy as a function of additional variables. We propose novel measures of the association size, which are analogous to effect sizes on the correlation scale while adjusting for confound variables. In simulation studies, we compare likelihood-based estimators of conditional correlation to semiparametric estimators adapted from genomic studies and find that the former achieves lower bias and variance under both ideal settings and model assumption misspecification. Using neurocognitive data from the Philadelphia Neurodevelopmental Cohort, we demonstrate that greater sustained attention is associated with stronger speed-accuracy coupling in a complex reasoning task while controlling for age. By highlighting conditional correlations as the outcome of interest, our model provides complementary insights to traditional regression modeling and partitioned correlation analyses., (© The Author 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Evidence on the harms and benefits of social media use is mixed, in part because the effects of social media on well-being depend on a variety of individual difference moderators. Here, we explored potential neural moderators of the link between time spent on social media and subsequent negative affect. We specifically focused on the strength of correlation among brain regions within the frontoparietal system, previously associated with the top-down cognitive control of attention and emotion. Participants (N = 54) underwent a resting state functional magnetic resonance imaging scan. Participants then completed 28 days of ecological momentary assessment and answered questions about social media use and negative affect, twice a day. Participants who spent more than their typical amount of time on social media since the previous time point reported feeling more negative at the present moment. This within-person temporal association between social media use and negative affect was mainly driven by individuals with lower resting state functional connectivity within the frontoparietal system. By contrast, time spent on social media did not predict subsequent affect for individuals with higher frontoparietal functional connectivity. Our results highlight the moderating role of individual functional neural connectivity in the relationship between social media and affect., (© 2023. The Author(s).)

Neurodegenerative diseases are the most common cause of dementia. Although their underlying molecular pathologies have been identified, there is substantial heterogeneity in the patterns of progressive brain alterations across and within these diseases. Recent advances in neuroimaging methods have revealed that pathological proteins accumulate along specific macroscale brain networks, implicating the network architecture of the brain in the system-level pathophysiology of neurodegenerative diseases. However, the extent to which 'network-based neurodegeneration' applies across the wide range of neurodegenerative disorders remains unclear. Here, we discuss the state-of-the-art of neuroimaging-based connectomics for the mapping and prediction of neurodegenerative processes. We review findings supporting brain networks as passive conduits through which pathological proteins spread. As an alternative view, we also discuss complementary work suggesting that network alterations actively modulate the spreading of pathological proteins between connected brain regions. We conclude this Perspective by proposing an integrative framework in which connectome-based models can be advanced along three dimensions of innovation: incorporating parameters that modulate propagation behaviour on the basis of measurable biological features; building patient-tailored models that use individual-level information and allowing model parameters to interact dynamically over time. We discuss promises and pitfalls of these strategies for improving disease insights and moving towards precision medicine., (© 2023. Springer Nature Limited.)

Recent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders., (© 2023. The Author(s).)

Background: Loss of control (LOC) eating, the subjective sense that one cannot control what or how much one eats, characterizes binge-eating behaviors pervasive in obesity and related eating disorders. Closed-loop deep-brain stimulation (DBS) for binge eating should predict LOC and trigger an appropriately timed intervention., Objective/hypothesis: This study aimed to identify a sensitive and specific biomarker to detect LOC onset for DBS. We hypothesized that changes in phase-locking value (PLV) predict the onset of LOC-associated cravings and distinguish them from potential confounding states., Methods: Using DBS data recorded from the nucleus accumbens (NAc) of two patients with binge eating disorder (BED) and severe obesity, we compared PLV between inter- and intra-hemispheric NAc subregions for three behavioral conditions: craving (associated with LOC eating), hunger (not associated with LOC), and sleep., Results: In both patients, PLV in the high gamma frequency band was significantly higher for craving compared to sleep and significantly higher for hunger compared to craving. Maximum likelihood classifiers achieved accuracies above 88% when differentiating between the three conditions., Conclusions: High-frequency inter- and intra-hemispheric PLV in the NAc is a promising biomarker for closed-loop DBS that differentiates LOC-associated cravings from physiologic states such as hunger and sleep. Future trials should assess PLV as a LOC biomarker across a larger cohort and a wider patient population transdiagnostically., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Myelination is a key developmental process that promotes rapid and efficient information transfer. Myelin also stabilizes existing brain networks and thus may constrain neuroplasticity, defined here as the brain's potential to change in response to experiences rather than the canonical definition as the process of change. Characterizing individual differences in neuroplasticity may shed light on mechanisms by which early experiences shape learning, brain and body development, and response to interventions. The T1-weighted/T2-weighted (T1w/T2w) MRI signal ratio is a proxy measure of cortical microstructure and thus neuroplasticity. Here, in pre-registered analyses, we investigated individual differences in T1w/T2w ratios in children (ages 4-10, n = 157). T1w/T2w ratios were positively associated with age within early-developing sensorimotor and attention regions. We also tested whether socioeconomic status, cognition (crystallized knowledge or fluid reasoning), and biological age (as measured with molar eruption) were related to T1w/T2w signal but found no significant effects. Associations among T1w/T2w ratios, early experiences, and cognition may emerge later in adolescence and may not be strong enough to detect in moderate sample sizes., 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 Authors. Published by Elsevier Ltd.. All rights reserved.)

Schizophrenia is marked by deficits in facial affect processing associated with abnormalities in GABAergic circuitry, deficits also found in first-degree relatives. Facial affect processing involves a distributed network of brain regions including limbic regions like amygdala and visual processing areas like fusiform cortex. Pharmacological modulation of GABAergic circuitry using benzodiazepines like alprazolam can be useful for studying this facial affect processing network and associated GABAergic abnormalities in schizophrenia. Here, we use pharmacological modulation and computational modeling to study the contribution of GABAergic abnormalities toward emotion processing deficits in schizophrenia. Specifically, we apply principles from network control theory to model persistence energy - the control energy required to maintain brain activation states - during emotion identification and recall tasks, with and without administration of alprazolam, in a sample of first-degree relatives and healthy controls. Here, persistence energy quantifies the magnitude of theoretical external inputs during the task. We find that alprazolam increases persistence energy in relatives but not in controls during threatening face processing, suggesting a compensatory mechanism given the relative absence of behavioral abnormalities in this sample of unaffected relatives. Further, we demonstrate that regions in the fusiform and occipital cortices are important for facilitating state transitions during facial affect processing. Finally, we uncover spatial relationships (i) between regional variation in differential control energy (alprazolam versus placebo) and (ii) both serotonin and dopamine neurotransmitter systems, indicating that alprazolam may exert its effects by altering neuromodulatory systems. Together, these findings provide a new perspective on the distributed emotion processing network and the effect of GABAergic modulation on this network, in addition to identifying an association between schizophrenia risk and abnormal GABAergic effects on persistence energy during threat processing., (© 2023. The Author(s).)

Modifying behaviors, such as alcohol consumption, is difficult. Creating psychological distance between unhealthy triggers and one's present experience can encourage change. Using two multisite, randomized experiments, we examine whether theory-driven strategies to create psychological distance-mindfulness and perspective-taking-can change drinking behaviors among young adults without alcohol dependence via a 28-day smartphone intervention (Study 1, N = 108 participants, 5492 observations; Study 2, N = 218 participants, 9994 observations). Study 2 presents a close replication with a fully remote delivery during the COVID-19 pandemic. During weeks when they received twice-a-day intervention reminders, individuals in the distancing interventions reported drinking less frequently than on control weeks-directionally in Study 1, and significantly in Study 2. Intervention reminders reduced drinking frequency but did not impact amount. We find that smartphone-based mindfulness and perspective-taking interventions, aimed to create psychological distance, can change behavior. This approach requires repeated reminders, which can be delivered via smartphones., (© 2023. The Author(s).)

Brain structure deteriorates with aging and predisposes an individual to more severe language impairments (aphasia) after a stroke. However, the underlying mechanisms of this relation are not well understood. Here we use an approach to model brain network properties outside the stroke lesion, network controllability, to investigate relations among individualized structural brain connections, brain age, and aphasia severity in 93 participants with chronic post-stroke aphasia. Controlling for the stroke lesion size, we observe that lower average controllability of the posterior superior temporal gyrus (STG) mediates the relation between advanced brain aging and aphasia severity. Lower controllability of the left posterior STG signifies that activity in the left posterior STG is less likely to yield a response in other brain regions due to the topological properties of the structural brain networks. These results indicate that advanced brain aging among individuals with post-stroke aphasia is associated with disruption of dynamic properties of a critical language-related area, the STG, which contributes to worse aphasic symptoms. Because brain aging is variable among individuals with aphasia, our results provide further insight into the mechanisms underlying the variance in clinical trajectories in post-stroke aphasia., (© 2023. The Author(s).)

Together, data from brain scanners and smartphones have sufficient coverage of biology, psychology, and environment to articulate between-person differences in the interplay within and across biological, psychological, and environmental systems thought to underlie psychopathology. An important next step is to develop frameworks that combine these two modalities in ways that leverage their coverage across layers of human experience to have maximum impact on our understanding and treatment of psychopathology. We review literature published in the last 3 years highlighting how scanners and smartphones have been combined to date, outline and discuss the strengths and weaknesses of existing approaches, and sketch a network science framework heretofore underrepresented in work combining scanners and smartphones that can push forward our understanding of health and disease., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Animal studies of neurodevelopment have shown that recordings of intrinsic cortical activity evolve from synchronized and high amplitude to sparse and low amplitude as plasticity declines and the cortex matures. Leveraging resting-state functional MRI (fMRI) data from 1,033 youths (ages 8-23 years), we find that this stereotyped refinement of intrinsic activity occurs during human development and provides evidence for a cortical gradient of neurodevelopmental change. Declines in the amplitude of intrinsic fMRI activity were initiated heterochronously across regions and were coupled to the maturation of intracortical myelin, a developmental plasticity regulator. Spatiotemporal variability in regional developmental trajectories was organized along a hierarchical, sensorimotor-association cortical axis from ages 8 to 18. The sensorimotor-association axis furthermore captured variation in associations between youths' neighborhood environments and intrinsic fMRI activity; associations suggest that the effects of environmental disadvantage on the maturing brain diverge most across this axis during midadolescence. These results uncover a hierarchical neurodevelopmental axis and offer insight into the progression of cortical plasticity in humans., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome., Method: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes., Results: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network., Conclusions: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Given its subject matter, biological psychiatry is uniquely poised to lead STEM (science, technology, engineering, and mathematics) DEI (diversity, equity, and inclusion) initiatives related to disability. Drawing on literatures in science, philosophy, psychiatry, and disability studies, we outline how that leadership might be undertaken. We first review existing opportunities for the advancement of DEI in biological psychiatry around axes of gender and race. We then explore the expansion of biological psychiatry's DEI efforts to disability, especially along the lines of representation and access, community accountability, first-person testimony, and revised theoretical frameworks for pathology. We close with concrete recommendations for scholarship and practice going forward. By tackling head-on the challenge of disability inclusion, biological psychiatry has the opportunity to be a force of transformation in the biological sciences and beyond., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The waxing and waning of negative affect in daily life is normative, reflecting an adaptive capacity to respond flexibly to changing circumstances. However, understanding of the brain structure correlates of affective variability in naturalistic settings has been limited. Using network control theory, we examine facets of brain structure that may enable negative affect variability in daily life., Methods: We used diffusion-weighted imaging data from 95 young adults (age [in years]: mean = 20.19, SD = 1.80; 56 women) to construct structural connectivity networks that map white matter fiber connections between 200 cortical and 14 subcortical regions. We applied network control theory to these structural networks to estimate the degree to which each brain region's pattern of structural connectivity facilitates the spread of activity to other brain systems. We examined how the average controllability of functional brain systems relates to negative affect variability, computed by taking the standard deviation of negative affect self-reports collected via smartphone-based experience sampling twice per day over 28 days as participants went about their daily lives., Results: We found that high average controllability of the cingulo-insular system is associated with increased negative affect variability. We also found that greater negative affect variability is related to the presence of more depressive symptoms, yet average controllability of the cingulo-insular system was not associated with depressive symptoms., Conclusions: Our results highlight the role that brain structure plays in affective dynamics as observed in the context of daily life, suggesting that average controllability of the cingulo-insular system promotes normative negative affect variability., (© 2021 The Authors.)