Sex differences in the functional topography of association networks in youth.

Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here, we leveraged an advanced machine learning method (sparsity-regularized non-negative matrix factorization) to define individualized functional networks in 693 youth (ages 8 to 23 y) who underwent functional MRI as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 82.9% accuracy (P < 0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention, default mode, and frontoparietal networks. Mass univariate analyses using generalized additive models with penalized splines provided convergent results. Furthermore, transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography were spatially correlated with the expression of genes on the X chromosome. These results highlight the role of sex as a biological variable in shaping functional topography.

Estrogen and the prefrontal cortex: towards a new understanding of estrogen's effects on executive functions in the menopause transition.

Midlife decline in cognition, specifically in areas of executive functioning, is a frequent concern for which menopausal women seek clinical intervention. The dependence of executive processes on prefrontal cortex function suggests estrogen effects on this brain region may be key in identifying the sources of this decline. Recent evidence from rodent, nonhuman primate, and human subject studies indicates the importance of considering interactions of estrogen with neurotransmitter systems, stress, genotype, and individual life events when determining the cognitive effects of menopause and estrogen therapy.

ComBatLS: A location- and scale-preserving method for multi-site image harmonization.

Recent work has leveraged massive datasets and advanced harmonization methods to construct normative models of neuroanatomical features and benchmark individuals' morphology. However, current harmonization tools do not preserve the effects of biological covariates including sex and age on features' variances; this failure may induce error in normative scores, particularly when such factors are distributed unequally across sites. Here, we introduce a new extension of the popular ComBat harmonization method, ComBatLS, that preserves biological variance in features' locations and scales. We use UK Biobank data to show that ComBatLS robustly replicates individuals' normative scores better than other ComBat methods when subjects are assigned to sex-imbalanced synthetic "sites". Additionally, we demonstrate that ComBatLS significantly reduces sex biases in normative scores compared to traditional methods. Finally, we show that ComBatLS successfully harmonizes consortium data collected across over 50 studies. R implementation of ComBatLS is available at https://github.com/andy1764/ComBatFamily.

Generalizable Links Between Borderline Personality Traits and Functional Connectivity.

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 ppermuted = .001) and older adolescents (HCP-D ppermuted = .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.

Reproducible Sex Differences in Personalized Functional Network Topography in Youth.

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.

Generalizable links between symptoms of borderline personality disorder and functional connectivity.

Background |: Symptoms of borderline personality disorder (BPD) often manifest in adolescence, yet 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 symptoms of BPD in a large sample of young adults and adolescents. Methods |: We used high-quality functional Magnetic Resonance Imaging (fMRI) data from young adults from the Human Connectome Project: Young Adults (HCP-YA; N = 870, ages 22-37 years, 457 female) and youth from the Human Connectome Project: Development (HCP-D; N = 223, age range 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five Factor Inventory (NEO-FFI). A ridge regression model with 10-fold cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity, while controlling for in-scanner motion, age, and sex. 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 proxy scores in unseen data in both young adults (HCP-YA; pperm = 0.001) and older adolescents (HCP-D; pperm = 0.001). Predictive capacity of regions 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 proxy scores aligned with those associated with development in youth. Conclusion |: Individual differences in functional connectivity in developmentally-sensitive regions are associated with the symptoms of BPD.

XCP-D: A Robust Pipeline for the post-processing of fMRI data.

Functional neuroimaging is an essential tool for neuroscience research. Pre-processing pipelines produce standardized, minimally pre-processed data to support a range of potential analyses. However, post-processing is not similarly standardized. While several options for post-processing exist, they tend not to support output from disparate pre-processing pipelines, may have limited documentation, and may not follow BIDS best practices. Here we present XCP-D, which presents a solution to these issues. XCP-D is a collaborative effort between PennLINC at the University of Pennsylvania and the DCAN lab at the University at Minnesota. XCP-D uses an open development model on GitHub and incorporates continuous integration testing; it is distributed as a Docker container or Singularity image. XCP-D generates denoised BOLD images and functional derivatives from resting-state data in either NifTI or CIFTI files, following pre-processing with fMRIPrep, HCP, and ABCD-BIDS pipelines. Even prior to its official release, XCP-D has been downloaded >3,000 times from DockerHub. Together, XCP-D facilitates robust, scalable, and reproducible post-processing of fMRI data.

Personalized functional brain network topography is associated with individual differences in youth cognition.

Individual differences in cognition during childhood are associated with important social, physical, and mental health outcomes in adolescence and adulthood. Given that cortical surface arealization during development reflects the brain's functional prioritization, quantifying variation in the topography of functional brain networks across the developing cortex may provide insight regarding individual differences in cognition. We test this idea by defining personalized functional networks (PFNs) that account for interindividual heterogeneity in functional brain network topography in 9-10 year olds from the Adolescent Brain Cognitive Development℠ Study. Across matched discovery (n = 3525) and replication (n = 3447) samples, the total cortical representation of fronto-parietal PFNs positively correlates with general cognition. Cross-validated ridge regressions trained on PFN topography predict cognition in unseen data across domains, with prediction accuracy increasing along the cortex's sensorimotor-association organizational axis. These results establish that functional network topography heterogeneity is associated with individual differences in cognition before the critical transition into adolescence.

Linking Individual Differences in Personalized Functional Network Topography to Psychopathology in Youth.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Dissociable multi-scale patterns of development in personalized brain networks.

The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derive personalized functional networks across 29 scales in a large sample of youths (n = 693, ages 8-23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling reflect and strengthen a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks are dissociably related to the emergence of executive function. These results suggest that the development of functional brain networks align with and refine a hierarchy linked to cognition.

Impact of childhood adversity on network reconfiguration dynamics during working memory in hypogonadal women.

Many women with no history of cognitive difficulties experience executive dysfunction during menopause. Significant adversity during childhood negatively impacts executive function into adulthood and may be an indicator of women at risk of a mid-life cognitive decline. Previous studies have indicated that alterations in functional network connectivity underlie these negative effects of childhood adversity. There is growing evidence that functional brain networks are not static during executive tasks; instead, such networks reconfigure over time. Optimal dynamics are necessary for efficient executive function; while too little reconfiguration is insufficient for peak performance, too much reconfiguration (supra-optimal reconfiguration) is also maladaptive and associated with poorer performance. Here we examined the impact of adverse childhood experiences (ACEs) on network flexibility, a measure of dynamic reconfiguration, during a letter n-back task within three networks that support executive function: frontoparietal, salience, and default mode networks. Several animal and human subject studies have suggested that childhood adversity exerts lasting effects on executive function via serotonergic mechanisms. Tryptophan depletion (TD) was used to examine whether serotonin function drives ACE effects on network flexibility. We hypothesized that ACE would be associated with higher flexibility (supra-optimal flexibility) and that TD would further increase this measure. Forty women underwent functional imaging at two time points in this double-blind, placebo controlled, crossover study. Participants also completed the Penn Conditional Exclusion Test, a task assessing abstraction and mental flexibility. The effects of ACE and TD were evaluated using generalized estimating equations. ACE was associated with higher flexibility across networks (frontoparietal ß = 0.00748, D = 2.79, p = 0.005; salience ß = 0.00679, D = 3.02, p = 0.003; and default mode ß = 0.00910, D = 3.53, p = 0.0004). While there was no interaction between ACE and TD, active TD increased network flexibility in both ACE groups in comparison to sham depletion (frontoparietal ß = 0.00489, D = 2.15, p = 0.03; salience ß = 0.00393, D = 1.91, p = 0.06; default mode ß = 0.00334, D = 1.73, p = 0.08). These results suggest that childhood adversity has lasting impacts on dynamic reconfiguration of functional brain networks supporting executive function and that decreasing serotonin levels may exacerbate these effects.

Executive function after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: does current mood and early life adversity matter?

OBJECTIVE: Despite the fact that negative mood and executive dysfunction are common after risk-reducing salpingo-oophorectomy (RRSO), occurring in up to a third of women, little is known about risk factors predicting these negative outcomes. Adverse childhood experiences (ACE) predict poorer health in adulthood and may be a risk factor for negative outcomes after RRSO. Given the complex relationship between early life stress, affective disorders, and cognitive dysfunction, we hypothesized that ACE would be associated with poorer executive function and that mood symptoms would partially mediate this relationship. METHODS: Women who had undergone RRSO were included in the study (N = 552; age 30-73 y). We measured executive function (continuous performance task, letter n-back task, and Brown Attention Deficit Disorder Scale Score), exposure to early life stress (ACE questionnaire), and mood symptoms (Hospital Anxiety and Depression Scale). Generalized estimating equations were used to evaluate the association between ACE and executive dysfunction and the role of mood symptoms as a mediator in this relationship. RESULTS: ACE was associated with greater severity of subjective executive dysfunction (adjusted mean difference [aMD] = 7.1, P = 0.0005) and worse performance on both cognitive tasks (continuous performance task: aMD = -0.1, P = 0.03; n-back: aMD = -0.17, P = 0.007). Mood symptoms partially mediated ACE associations with sustained attention (21.3% mediated; 95% CI: 9.3%-100%) and subjective report of executive dysfunction (62.8% mediated; 95% CI: 42.3%-100%). CONCLUSIONS: The relationship between childhood adversity and executive dysfunction is partially mediated by mood symptoms. These data indicate that assessing history of childhood adversity and current anxiety and depression symptoms may play a role in treating women who report cognitive complaints after RRSO. : Video Summary:http://links.lww.com/MENO/A571.

Video Summary:http://links.lww.com/MENO/A571.

Impact of early life adversity and tryptophan depletion on functional connectivity in menopausal women: A double-blind, placebo-controlled crossover study.

During the menopause transition, women are at increased risk of subjective symptoms of executive dysfunction. Evidence from animal and human participant studies suggests adverse childhood experiences (ACE) may be a risk factor for executive complaints during this hormonal transition. Preclinical literature indicates early life adversity effects on serotonin function may play a role in this increased susceptibility. However, the mechanisms underlying this increase in vulnerability in human participants remain relatively unknown. Here we examined the impact of ACE and tryptophan depletion (TD), a paradigm used to lower central serotonin levels, on functional network connectivity in discovery and replication datasets. We hypothesized that ACE would be associated with decreased within-network connectivity. We predicted that TD would further lower connectivity in women with high levels of early adversity, but have no effect in women with low levels of early adversity. Forty women underwent two functional imaging sequences at two time points (141 total scans) in a double-blind, placebo controlled, crossover study. The effects of ACE and TD were evaluated using generalized estimating equations (GEE). As predicted, ACE was associated with lower within-network connectivity. While TD had no effect on connectivity in the low ACE group, TD increased connectivity in the high ACE group. The robust effect of ACE remained significant in the replication dataset, though the ACE×TD interaction did not. Together, these results suggest that early life adversity has lasting impacts on large-scale functional networks underlying executive function. Alterations in functional network connectivity may be one mechanism by which early life adversity increases the risk of cognitive disorders during menopause.

Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties.

Many women with no history of executive dysfunction report difficulties in this domain during the menopause transition. Lisdexamfetamine (LDX) has been suggested to be a safe and effective treatment option for these women. However, the mechanism by which LDX improves executive functioning in these women is not known. Here we investigated the effects of LDX on brain activation and neurochemistry, hypothesizing that LDX would be associated with increased activation and decreased glutamate in executive regions. Fourteen women underwent multimodal neuroimaging at 7T at three time points in this baseline-corrected, double-blind, placebo-controlled, crossover study. Effects of LDX on symptom severity, blood-oxygen-level-dependent (BOLD) signal, and dorsolateral prefrontal cortex (DLPFC) glutamate+glutamine (Glx) were measured using a clinician-administered questionnaire, fMRI during performance of a fractal n-back task, and 1H-MRS, respectively. The effect of treatment (LDX minus baseline vs placebo minus baseline) on these behavioral and neural markers of executive function was examined using repeated measures mixed effects models. LDX treatment was associated with decreased symptom severity, increased activation in the insula and DLPFC, and decreased DLPFC Glx. In addition, the magnitude of LDX-induced improvement in symptom severity predicted both direction and magnitude of LDX-induced change in insular and DLPFC activation. Moreover, symptom severity was positively correlated with Glx concentration in the left DLPFC at baseline. These findings provide novel evidence that the neural mechanisms by which LDX acts to improve self-reported executive functioning in healthy menopausal women with midlife onset of executive difficulties include modulation of insular and DLPFC recruitment as well as decrease in DLPFC Glx concentration.

Impact of Tryptophan Depletion on Executive System Function during Menopause is Moderated by Childhood Adversity.

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Preclinical literature suggests latent effects of early life adversity on serotonin function may play a role in this phenomenon. However, evidence in human participants regarding the mechanisms by which loss of estradiol contributes to this vulnerability is lacking. Here we examined the impact of tryptophan depletion (TD) and adverse childhood experiences (ACE) on brain activation during a working memory task in menopausal women. We hypothesized that an interactive effect between ACE and TD would be observed when women were hypogonadal, and that treatment with estradiol would attenuate this effect. Thirty-three women underwent functional imaging at four time points (123 total scans) in this double-blind, placebo controlled, cross-over study. The effects of TD, ACE, and TD × ACE were evaluated using a voxel-wise, mixed-effects, 2 × 2 ANOVA. In the absence of exogenous estradiol, a TD by ACE interaction was observed on BOLD signal in the right DLPFC such that TD increased activation in high ACE subjects but decreased activation in low ACE subjects. While a similar interaction was observed with placebo treatment, treatment with estradiol attenuated the effects of ACE and TD such that no between or within group differences were observed. Together, these results suggest that early life adversity may have a lasting impact on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause.

Neural Markers of the Development of Executive Function: Relevance for Education.

Executive functions are involved in the development of academic skills and are critical for functioning in school settings. The relevance of executive functions to education begins early and continues throughout development, with clear impact on achievement. Diverse efforts increasingly suggest ways in which facilitating development of executive function may be used to improve academic performance. Such interventions seek to alter the trajectory of executive development, which exhibits a protracted course of maturation that stretches into young adulthood. As such, it may be useful to understand how the executive system develops normally and abnormally in order to tailor interventions within educational settings. Here we review recent work investigating the neural basis for executive development during childhood and adolescence.

Common and Dissociable Mechanisms of Executive System Dysfunction Across Psychiatric Disorders in Youth.

OBJECTIVE: Disruption of executive function is present in many neuropsychiatric disorders. However, determining the specificity of executive dysfunction across these disorders is challenging given high comorbidity of conditions. Here the authors investigate executive system deficits in association with dimensions of psychiatric symptoms in youth using a working memory paradigm. The authors hypothesize that common and dissociable patterns of dysfunction would be present. METHOD: The authors studied 1,129 youths who completed a fractal n-back task during functional magnetic resonance imaging at 3-T as part of the Philadelphia Neurodevelopmental Cohort. Factor scores of clinical psychopathology were calculated using an item-wise confirmatory bifactor model, describing overall psychopathology as well as four orthogonal dimensions of symptoms: anxious-misery (mood and anxiety), behavioral disturbance (attention deficit hyperactivity disorder and conduct disorder), psychosis-spectrum symptoms, and fear (phobias). The effect of psychopathology dimensions on behavioral performance and executive system recruitment (2-back > 0-back) was examined using both multivariate (matrix regression) and mass-univariate (linear regression) analyses. RESULTS: Overall psychopathology was associated with both abnormal multivariate patterns of activation and a failure to activate executive regions within the cingulo-opercular control network, including the frontal pole, cingulate cortex, and anterior insula. In addition, psychosis-spectrum symptoms were associated with hypoactivation of the left dorsolateral prefrontal cortex, whereas behavioral symptoms were associated with hypoactivation of the frontoparietal cortex and cerebellum. In contrast, anxious-misery symptoms were associated with widespread hyperactivation of the executive network. CONCLUSIONS: These findings provide novel evidence that common and dissociable deficits within the brain's executive system are present in association with dimensions of psychopathology in youth.

New onset executive function difficulties at menopause: a possible role for lisdexamfetamine.

RATIONALE: Reports of cognitive decline, particularly in the domains of executive functions (EFs), are common among menopausal women. OBJECTIVE: This study aims to determine the impact of the psychostimulant lisdexamfetamine (LDX) on subjective and objective cognitive function among menopausal women who report new-onset EF complaints. METHODS: Thirty-two healthy perimenopausal and early postmenopausal women experiencing mid-life-onset executive function difficulties as measured using the Brown Attention Deficit Disorder Scale (BADDS) were administered LDX 40-60 mg/day for 4 weeks in this double-blind, placebo-controlled, cross-over study. Diagnosis of lifetime ADHD was exclusionary. BADDS total and subscale scores and performance on verbal memory and working memory tasks were outcomes of interest. RESULTS: Analyses revealed a significant effect of LDX treatment over placebo for total BADDS scores (p = 0.0001) and for four out of the five BADDS subscales (all p < 0.004). LDX treatment also resulted in significant improvement in delayed paragraph recall (p = 0.018), but there was no significant effect of treatment on other cognitive measures. Systolic blood pressure (p = 0.017) and heart rate increased significantly (p = 0.006) when women were on LDX but remained, on average, within the normal range. CONCLUSIONS: LDX 40-60 mg/day was well tolerated and improved the subjective measures of executive function as well as objective measures of delayed verbal recall in this sample of healthy menopausal women.