Improving Predictability, Test-Retest Reliability and Generalisability of Brain-Wide Associations for Cognitive Abilities via Multimodal Stacking.

Brain-wide association studies (BWASs) have attempted to relate cognitive abilities with brain phenotypes, but have been challenged by issues such as predictability, test-retest reliability, and cross-cohort generalisability. To tackle these challenges, we proposed "stacking" that combines brain magnetic resonance imaging of different modalities, from task-fMRI contrasts and functional connectivity during tasks and rest to structural measures, into one prediction model. We benchmarked the benefits of stacking, using the Human Connectome Projects: Young Adults and Aging and the Dunedin Multidisciplinary Health and Development Study. For predictability, stacked models led to out-of-sample r ∼.5-.6 when predicting cognitive abilities at the time of scanning and 36 years earlier. For test-retest reliability, stacked models reached an excellent level of reliability (ICC>.75), even when we stacked only task-fMRI contrasts together. For generalisability, a stacked model with non-task MRI built from one dataset significantly predicted cognitive abilities in other datasets. Altogether, stacking is a viable approach to undertake the three challenges of BWAS for cognitive abilities.

Dementia, dementia's risk factors and premorbid brain structure are concentrated in disadvantaged areas: National register and birth-cohort geographic analyses.

INTRODUCTION: Dementia risk may be elevated in socioeconomically disadvantaged neighborhoods. Reasons for this remain unclear, and this elevation has yet to be shown at a national population level. METHODS: We tested whether dementia was more prevalent in disadvantaged neighborhoods across the New Zealand population (N = 1.41 million analytic sample) over a 20-year observation. We then tested whether premorbid dementia risk factors and MRI-measured brain-structure antecedents were more prevalent among midlife residents of disadvantaged neighborhoods in a population-representative NZ-birth-cohort (N = 938 analytic sample). RESULTS: People residing in disadvantaged neighborhoods were at greater risk of dementia (HR per-quintile-disadvantage-increase = 1.09, 95% confidence interval [CI]:1.08-1.10) and, decades before clinical endpoints typically emerge, evidenced elevated dementia-risk scores (CAIDE, LIBRA, Lancet, ANU-ADRI, DunedinARB; ß's 0.31-0.39) and displayed dementia-associated brain structural deficits and cognitive difficulties/decline. DISCUSSION: Disadvantaged neighborhoods have more residents with dementia, and decades before dementia is diagnosed, residents have more dementia-risk factors and brain-structure antecedents. Whether or not neighborhoods causally influence risk, they may offer scalable opportunities for primary dementia prevention.

A blood biomarker of the pace of aging is associated with brain structure: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3380; total N individuals=2322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, greater burden of white matter microlesions, and thinner cortex. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

The Variegation of Human Brain Vulnerability to Rare Genetic Disorders and Convergence With Behaviorally Defined Disorders.

BACKGROUND: Diverse gene dosage disorders (GDDs) increase risk for psychiatric impairment, but characterization of GDD effects on the human brain has so far been piecemeal, with few simultaneous analyses of multiple brain features across different GDDs. METHODS: Here, through multimodal neuroimaging of 3 aneuploidy syndromes (XXY [total n = 191, 92 control participants], XYY [total n = 81, 47 control participants], and trisomy 21 [total n = 69, 41 control participants]), we systematically mapped the effects of supernumerary X, Y, and chromosome 21 dosage across a breadth of 15 different macrostructural, microstructural, and functional imaging-derived phenotypes (IDPs). RESULTS: The results revealed considerable diversity in cortical changes across GDDs and IDPs. This variegation of IDP change underlines the limitations of studying GDD effects unimodally. Integration across all IDP change maps revealed highly distinct architectures of cortical change in each GDD along with partial coalescence onto a common spatial axis of cortical vulnerability that is evident in all 3 GDDs. This common axis shows strong alignment with shared cortical changes in behaviorally defined psychiatric disorders and is enriched for specific molecular and cellular signatures. CONCLUSIONS: Use of multimodal neuroimaging data in 3 aneuploidies indicates that different GDDs impose unique fingerprints of change in the human brain that differ widely depending on the imaging modality that is being considered. Embedded in this variegation is a spatial axis of shared multimodal change that aligns with shared brain changes across psychiatric disorders and therefore represents a major high-priority target for future translational research in neuroscience.

Test-retest reliability and predictive utility of a macroscale principal functional connectivity gradient.

Mapping individual differences in brain function has been hampered by poor reliability as well as limited interpretability. Leveraging patterns of brain-wide functional connectivity (FC) offers some promise in this endeavor. In particular, a macroscale principal FC gradient that recapitulates a hierarchical organization spanning molecular, cellular, and circuit level features along a sensory-to-association cortical axis has emerged as both a parsimonious and interpretable measure of individual differences in behavior. However, the measurement reliabilities of this FC gradient have not been fully evaluated. Here, we assess the reliabilities of both global and regional principal FC gradient measures using test-retest data from the young adult Human Connectome Project (HCP-YA) and the Dunedin Study. Analyses revealed that the reliabilities of principal FC gradient measures were (1) consistently higher than those for traditional edge-wise FC measures, (2) higher for FC measures derived from general FC (GFC) in comparison with resting-state FC, and (3) higher for longer scan lengths. We additionally examined the relative utility of these principal FC gradient measures in predicting cognition and aging in both datasets as well as the HCP-aging dataset. These analyses revealed that regional FC gradient measures and global gradient range were significantly associated with aging in all three datasets, and moderately associated with cognition in the HCP-YA and Dunedin Study datasets, reflecting contractions and expansions of the cortical hierarchy, respectively. Collectively, these results demonstrate that measures of the principal FC gradient, especially derived using GFC, effectively capture a reliable feature of the human brain subject to interpretable and biologically meaningful individual variation, offering some advantages over traditional edge-wise FC measures in the search for brain-behavior associations.

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3,380; total N individuals=2,322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, and thinner cortex. In two datasets, faster DunedinPACE was associated with greater burden of white matter hyperintensities. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

X- vs. Y-Chromosome Influences on Human Behavior: A Deep Phenotypic Comparison of Psychopathology in XXY and XYY Syndromes.

Do different genetic disorders impart different psychiatric risk profiles? This question has major implications for biological and translational aspects of psychiatry, but has been difficult to tackle given limited access to shared batteries of fine-grained clinical data across genetic disorders. Using a new suite of generalizable analytic approaches, we examine gold-standard diagnostic ratings, scores on 66 dimensional measures of psychopathology, and measures of cognition and functioning in two different sex chromosome aneuploidies (SCAs) - Klinefelter (XXY/KS) and XYY syndrome (n=102 and 64 vs. n=74 and 60 matched XY controls, total n=300). We focus on SCAs for their high collective prevalence, informativeness regarding differential X- vs. Y-chromosome effects, and potential relevance for normative sex differences. We show that XXY/KS elevates rates for most psychiatric diagnoses as previously reported for XYY, but disproportionately so for anxiety disorders. Fine-mapping across all 66 traits provides a detailed profile of psychopathology in XXY/KS which is strongly correlated with that of XYY (r=.75 across traits) and robust to ascertainment biases, but reveals: (i) a greater penetrance of XYY than KS/XXY for most traits except mood/anxiety problems, and (ii) a disproportionate impact of XYY vs. XXY/KS on social problems. XXY/KS and XXY showed a similar coupling of psychopathology with adaptive function and caregiver strain, but not IQ. This work provides new tools for deep-phenotypic comparisons of genetic disorders in psychiatry and uses these to detail unique and shared effects of the X- and Y-chromosome on human behavior.

Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Functional Topography of the Neocortex Predicts Covariation in Complex Cognitive and Basic Motor Abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g., hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Exaggerated amygdala activation to ambiguous facial expressions is a familial vulnerability factor for posttraumatic stress disorder.

OBJECTIVE: Previous research has reported hyperresponsivity in the amygdala and hyporesponsivity in ventral portions of the medial prefrontal cortex to threat-related stimuli in posttraumatic stress disorder (PTSD). Whether such findings generalize to more ambiguous stimuli and whether such brain activation abnormalities reflect familial vulnerabilities, trauma-exposure, or acquired characteristics of PTSD remain unclear. In this study, we measured brain responses to emotionally ambiguous stimuli (i.e., surprised facial expressions) in identical twin pairs discordant for trauma exposure to elucidate the origin of brain activation abnormalities. METHODS: Participants with PTSD (n = 12) and their trauma-unexposed identical cotwins (n = 12), as well as trauma-exposed participants without PTSD (n = 15) and their trauma-unexposed identical cotwins (n = 15), passively viewed surprised and neutral facial expressions during functional magnetic resonance imaging (fMRI). Afterward, participants labeled and rated each facial expression on valence and arousal. RESULTS: Amygdala activation to Surprised and Neutral facial expressions (versus Fixation) was greater in the participants with PTSD and their trauma-unexposed identical cotwins without PTSD, compared to the control twin pairs. In contrast, medial frontal gyrus (MFG) activation to Surprised facial expressions (versus Fixation) was diminished in the PTSD group relative to the other three groups. CONCLUSIONS: Amygdala hyperresponsivity to emotionally ambiguous facial expressions may be a familial vulnerability factor that increases the likelihood of developing PTSD after experiencing a traumatic event. In contrast, MFG hyporesponsivity may be an acquired characteristic of the disorder.

Patterns of psychopathology and cognition in sex chromosome aneuploidy.

BACKGROUND: Sex chromosome aneuploidies (SCAs) are a collectively common family of genetic disorders that increase the risk for neuropsychiatric and cognitive impairment. Beyond being important medical disorders in their own right, SCAs also offer a unique naturally occurring model for studying X- and Y-chromosome influences on the human brain. However, it remains unclear if (i) different SCAs are associated with different profiles of psychopathology and (ii) the notable interindividual variation in psychopathology is related to co-occurring variation in cognitive ability. METHODS: We examined scores for 11 dimensions of psychopathology [Child/Adult Behavior Checklist (CBCL)] and general cognitive ability [full-scale IQ (FSIQ) from Wechsler tests] in 110 youth with varying SCAs (XXY = 41, XYY = 22, XXX = 27, XXYY = 20) and 131 typically developing controls (XX = 59, XY = 72). RESULTS: All SCAs were associated with elevated CBCL scores across several dimensions of psychopathology (two-sample t tests comparing the euploidic and aneuploidic groups [all |T| > 9, and p < 0.001]). Social and attentional functioning were particularly sensitive to the carriage of a supernumerary Y-chromosome. In particular, the XYY group evidenced significantly more social problems than both extra-X groups (Cohen's d effect size > 0.5, Bonferroni corrected p < .05). There was marked variability in CBCL scores within each SCA group, which generally correlated negatively with IQ, but most strongly so for social and attentional difficulties (standardized ß, - 0.3). These correlations showed subtle differences as a function of the SCA group and CBCL scale. CONCLUSIONS: There is domain-specific variation in psychopathology across SCA groups and domain-specific correlation between psychopathology and IQ within SCAs. These findings (i) help to tailor clinical assessment of this common and impactful family of genetic disorders and (ii) suggest that dosage abnormalities of X- and Y-linked genes impart somewhat distinct profiles of neuropsychiatric risk.

Sex-specific associations between subcortical morphometry in childhood and adult alcohol consumption: A 17-year follow-up study.

Men and women tend to differ in the age of first alcohol consumption, transition into disordered drinking, and the prevalence of alcohol use disorder. Here, we use a unique longitudinal dataset to test for potentially predispositonal sex-biases in brain organization prior to initial alcohol exposure. Our study combines measures of subcortical morphometry gathered in alcohol naive individuals during childhood (mean age: 9.43 years, SD = 2.06) with self-report measures of alcohol use in the same individuals an average of 17 years later (N = 81, 46 males, 35 females). We observe that pediatric amygdala and hippocampus volume both show sex-biased relationships with adult drinking. Specifically, females show a stronger association between subcortical volumetric reductions in childhood and peak drinking in adulthood as compared to males. Detailed analysis of subcortical shape localizes these effects to the rostro-medial hippocampus and basolateral amygdala subnuclei. In contrast, we did not observe sex-specific associations between striatal anatomy and peak alcohol consumption. These results are consistent with a model in which organization of the amygdala and hippocampus in childhood is more relevant for subsequent patterns of peak alcohol use in females as compared to males. Differential neuroanatomical precursors of alcohol use in males and females could provide a potential developmental basis for well recognized sex-differences in alcohol use behaviors.. Thus, our findings not only indicate that brain correlates of human alcohol consumption are manifest long before alcohol initiation, but that some of these correlates are not equivalent between males and females.

Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY).

Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.

Targeting the anterior cingulate with bipolar and high-definition transcranial direct current stimulation.

Research on the feasibility of using transcranial direct current stimulation to modulate the function of the anterior cingulate cortex is limited in part due to its anatomical depth. However, high-definition transcranial direct current stimulation may be better able to reach the anterior cingulate cortex and modulate its function and behavioral outputs. The purpose of this study was to assess the feasibility of using high-definition transcranial direct current stimulation, as compared to traditional bipolar transcranial direct current stimulation, to modulate behavioral measures of anterior cingulate cortex function. In a mixed design, 36 participants received either high-definition transcranial direct current stimulation or bipolar transcranial direct current stimulation, and experienced anodal, cathodal, and sham stimulation over the course of three visits. Two behavioral tasks were used to assess anterior cingulate cortex function before and after stimulation: the multi-source interference task and an emotional facial expression interference task. High-definition transcranial direct current stimulation and bipolar transcranial direct current stimulation groups did not differ in their performance (as measured via response times and error rates) on either task. High-definition transcranial direct current stimulation and bipolar transcranial direct current stimulation were similarly ineffective in modulating behavior related to the anterior cingulate cortex. Future research should explore other transcranial direct current stimulation montages including extracephalic montages (e.g. shoulder, neck) for targeted stimulation of the anterior cingulate cortex.