Biology subjects

Knodt, A. R.

Publications and source records attributed to Knodt, A. R..

At least 19 recordsLinked to original sources

bioRxiv2024

An estimate of the longitudinal pace of aging from a single brain scan predicts dementia conversion, morbidity, and mortality

To understand how aging affects functional decline and increases disease risk, it is necessary to develop accurate and reliable measures of how fast a person is aging. Epigenetic clocks measure aging but require DNA methylation data, which many studies lack. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain MRI: the Dunedin Pace of Aging Calculated from NeuroImaging or DunedinPACNI. Exporting this measure to the Alzheimers Disease Neuroimaging Initiative and UK Biobank datasets revealed that faster DunedinPACNI predicted participants cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed an established socioeconomic health gradient with people of lower socioeconomic status showing faster DunedinPACNI. Associations between DunedinPACNI and cognitive impairment were replicated in BrainLat, a sample of Latin American patients with dementia. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a "next generation" MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

neuroscience↗

bioRxiv2023

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.

neuroscience↗

bioRxiv2022

Associations between thinner retinal neuronal layers and suboptimal brain structural integrity: Are the eyes a window to the brain?

We investigated the extent to which measures of retinal neuronal thickness capture variability in the structural integrity of the brain in a large population-based cohort followed from birth to midlife. Using data from the Dunedin Multidisciplinary Health and Development Study (n=1037; analytic n=828, aged 45 years), we specifically tested for associations between optical coherence tomography-measured retinal neuronal layers and MRI-measured structural brain integrity. We found that Study members who had thinner retinal neuronal layers had thinner average cortex, smaller total cortical surface area, smaller subcortical grey matter volumes, larger volume of white matter hyperintensities as well as older looking brains. This suggests that retinal neuronal thickness reflects differences in midlife structural brain integrity consistent with accelerated cognitive decline and increased risk for later dementia, further supporting the proposition that the retina may be a biomarker of brain aging as early as midlife.

neuroscience↗

bioRxiv2020

Associations between childhood family emotional health, fronto-limbic grey matter volume, and saliva 5mC in young adulthood

BackgroundPoor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in DNA methylation (DNAm) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded. ResultsSelf-reported childhood FEH was nominally associated with right hemisphere hippocampus (b=10.4, p=0.005), left hemisphere amygdala (b=5.3, p=0.009), and right hemisphere amygdala (b=5.8, p=0.016) volumes. Childhood FEH was also nominally associated with 49 DNAm MEs (prange=3x10-6 to 0.047). After limiting analyses to probes correlated between saliva and brain, saliva-derived DNAm MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b=-111, p=0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b=-48, p=0.026). Modules were enriched with probes falling in genes with immune, CNS, and metabolic functions. ConclusionsFindings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.

genomics↗

bioRxiv2020

A connectome-wide functional signature of trait anger

Past research on the brain correlates of trait anger has been limited by small sample sizes, a focus on relatively few regions-of-interest, and poor test-retest reliability of functional brain measures. To address these limitations, we conducted a data-driven analysis of variability in connectome-wide general functional connectivity, which has good test-retest reliability, in a sample of 1,048 young adult volunteers. Multi-dimensional matrix regression analysis showed that individual differences in self-reported trait anger maps onto variability in the whole-brain functional connectivity patterns of three brain regions that serve action-related functions: bilateral supplementary motor area (SMA) and the right lateral frontal pole. Follow-up seed-based analysis confirmed that high trait anger is associated with hyperconnectivity between these three regions and the somatomotor network as well as hyperconnectivity and hypoconnectivity between SMA and default mode and visual networks, respectively. Supplementary targeted analyses based on theoretical and empirical grounds further revealed that high trait anger is associated with hyperconnectivity between the amygdala and dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, and striatum. These patterns suggest that the dispositional tendency to more easily experience frustration and anger is associated with variability in the functional connectivity of brain networks supporting somatomotor, affective, self-referential, and visual information processes. The emergence of action-related brain regions from our connectome-wide analysis is consistent with trait anger as reflecting a greater propensity to provoked action.

neuroscience↗

bioRxiv2019

Meta-analytic activation maps can help identify affective processes captured by contrast-based task fMRI: the case of threat-related facial expressions

Meta-analysis of functional magnetic resonance imaging (fMRI) data is an effective method for capturing the distributed patterns of brain activity supporting discrete cognitive and affective processes. One opportunity presented by the resulting meta-analysis maps (MAMs) is as a reference for better understanding the nature of individual contrast maps (ICMs) derived from specific task fMRI data. Here, we compared MAMs from 148 neuroimaging studies representing the broad emotion categories of fear, anger, disgust, happiness, and sadness with ICMs from fearful > neutral and angry > neutral facial expressions from an independent dataset of task fMRI (n = 1263). Analyses revealed that both fear and anger ICMs exhibited the greatest pattern similarity to fear MAMs. As the number of voxels included for the computation of pattern similarity became more selective, the specificity of MAM-ICM correspondence decreased. Notably, amygdala activity long considered critical for processing threat-related facial expressions was neither sufficient nor necessary for detecting MAM-ICM pattern similarity effects. Our analyses suggest that both fearful and angry facial expressions are best captured by distributed patterns of brain activity associated with fear. More generally, our analyses demonstrate how MAMs can be leveraged to better understand affective processes captured by ICMs in task fMRI data.

neuroscience↗

bioRxiv2019

A pervasively thinner neocortex is a transdiagnostic feature of general psychopathology

ObjectiveNeuroimaging research has revealed that structural brain alterations are common across broad diagnostic families of disorders rather than specific to a single psychiatric disorder. Such overlap in the structural brain correlates of mental disorders mirrors already well-documented phenotypic comorbidity of psychiatric symptoms and diagnoses, which can be indexed by a general psychopathology or p factor. We hypothesized that if general psychopathology drives the convergence of structural alterations common across disorders then 1) there should be few associations unique to any one diagnostic family of disorders, and 2) associations with the p factor should overlap with those for the broader diagnostic families. MethodsAnalyses were conducted on structural MRI and psychopathology data collected from 861 members of the population representative Dunedin Study at age 45. ResultsStudy members with high scores across three broad diagnostic families of disorders (Externalizing, Internalizing, Thought Disorder) exhibited highly overlapping patterns of reduced global and widely distributed parcel-wise neocortical thickness. Study members with high p factor scores exhibited patterns of reduced global and parcel-wise neocortical thickness nearly identical to those associated with the three broad diagnostic families. ConclusionsA pattern of pervasively reduced neocortical thickness appears common across all forms of mental disorders and may represent a transdiagnostic feature of general psychopathology. As has been documented with regard to symptoms and diagnoses, the underlying brain structural correlates of mental disorders may not exhibit specificity, the continued pursuit of which may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.

neuroscience↗

bioRxiv2019

Brain-age in midlife is associated with accelerated biological aging and cognitive decline in a longitudinal birth-cohort

An individuals brain-age is the difference between chronological age and age predicted from machine-learning models of brain-imaging data. Brain-age has been proposed as a biomarker of age-related deterioration of the brain. Having an older brain-age has been linked to Alzheimers, dementia and mortality. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. To illuminate the validity of brain-age a biomarker of accelerated brain aging, a study is needed of a large cohort all born the same year who nevertheless vary on brain-age. In a population-representative 1972-73 birth cohort we measured brain-age at age 45, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N=869). In this cohort, all chronological age 45 years, brain-age was measured reliably (ICC=.81) and ranged from 24 to 72 years. Those with older midlife brain-ages tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brain-ages had an accelerated pace of biological aging, older facial appearance and early signs of cognitive decline from childhood to midlife. These findings help to validate brain-age as a potential surrogate biomarker for midlife intervention studies that seek to measure treatment response to dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brain-age scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.

neuroscience↗

bioRxiv2019

White matter hyperintensities are common in midlife and already associated with cognitive decline

White matter hyperintensities (WMHs) proliferate as the brain ages and are associated with increased risk for cognitive decline as well as Alzheimers disease and related dementias. As such, WMHs have been targeted as a surrogate biomarker in intervention trials with older adults. However, it is unclear at what stage of aging WMHs begin to relate to cognition and if they may be a viable target for early prevention. In a population-representative birth cohort of 843 45-year-olds we measured WMHs using T2-weighted MRI, and we assessed cognitive decline from childhood to midlife. We found that WMHs were common at age 45 and that WMH volume was modestly associated with both lower childhood ({beta}=-0.08, p=0.013) and adult IQ ({beta}=-0.15, p<0.001). Moreover, WMH volume was associated with greater cognitive decline from childhood to midlife ({beta}=-0.09, p<0.001). Our results demonstrate that a link between WMHs and early signs of cognitive decline is detectable decades before clinical symptoms of dementia emerge. Thus, WMHs may be a useful surrogate biomarker for identifying individuals in midlife at risk for future accelerated cognitive decline and selecting participants for dementia prevention trials.

neuroscience↗

bioRxiv2019

Poor test-retest reliability of task-fMRI: New empirical evidence and a meta-analysis

Identifying brain biomarkers of disease risk is a growing priority in neuroscience. The ability to identify meaningful biomarkers is limited by measurement reliability; unreliable measures are unsuitable for predicting clinical outcomes. Measuring brain activity using task-fMRI is a major focus of biomarker development; however, the reliability of task-fMRI has not been systematically evaluated. We present converging evidence demonstrating poor reliability of task-fMRI measures. First, a meta-analysis of 90 experiments (N=1,008) revealed poor overall reliability (mean ICC=.397). Second, the test-retest reliabilities of activity in a priori regions of interest across 11 common fMRI tasks collected in the context of the Human Connectome Project (N=45) and the Dunedin Study (N=20) were poor (ICCs=.067-.485). Collectively, these findings demonstrate that common task-fMRI measures are not currently suitable for brain biomarker discovery or individual differences research. We review how this state of affairs came to be and highlight avenues for improving task-fMRI reliability.

neuroscience↗

bioRxiv2019

Reproducibility of Structural Brain Alterations Associated with Transdiagnostic Risk for Mental Illness: Evidence from a Population-Representative Birth Cohort

Transdiagnostic research has identified a general psychopathology factor - often called the p factor - that accounts for shared variation across internalizing, externalizing, and thought disorders in diverse samples. It has been argued that the p factor may reflect dysfunctional thinking present in serious mental illness. In support of this, we previously used a theory-free, data-driven multimodal neuroimaging approach to find that higher p factor scores are associated with structural alterations within a cerebello-thalamo-cortical circuit (CTCC) and visual association cortex, both of which are important for monitoring and coordinating information processing in the service of executive control. Here we attempt to replicate these associations by conducting region-of-interest analyses of CTCC and visual association cortex using data from 875 members of the Dunedin Longitudinal Study, a five-decade study of a population-representative birth cohort now 45 years old. We further sought to replicate a more recent report that p factor scores can be predicted by patterns of distributed cerebellar morphology as estimated through independent component analysis. We successfully replicated associations between higher p factor scores and both reduced grey matter volume of the visual association cortex and fractional anisotropy of pontine white matter pathways within the CTCC. In contrast, we failed to replicate prior associations between cerebellar structure and p factor scores. Collectively, our findings encourage further focus on the CTCC and visual association cortex as core neural substrates and potential biomarkers of general psychopathology.

neuroscience↗

bioRxiv2019

No Evidence for Associations Between the Big Five Personality Traits and Variability in Brain Gray or White Matter

Attempts to link the Big Five personality traits of Openness-to-Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism with variability in trait-like features of brain structure have produced inconsistent results. Small sample sizes and heterogeneous methodology have been suspected in driving these inconsistencies. Here, we tested for associations between the Big Five personality traits and multiple measures of brain structure using data from 1,107 university students (636 women, mean age 19.69{+/-}1.24 years) representing the largest attempt to date. In addition to replication analyses based on a prior study, we conducted exploratory whole-brain analyses. Four supplementary analyses were also conducted to examine 1) possible associations with lower-order facets of personality; 2) modulatory effects of sex; 3) effect of controlling for non-target personality traits; and 4) parcellation scheme effects. The analyses failed to identify any significant associations between the Big Five personality traits and variability in measures of cortical thickness, surface area, subcortical volume, or white matter microstructural integrity, except for an association between greater surface area of the superior temporal gyrus and lower scores on conscientiousness that explained 0.44% of the morphometric measures variance. Notably however, the latter association is largely not supported by previous studies. The supplementary analyses mirrored these largely null findings, suggesting they were not substantively biased by our choice of analytic model. Collectively, these results indicate that if there are direct associations between the Big Five personality traits and variability in brain structure, they are of likely very small effect sizes and will require very large samples for reliable detection.

neuroscience↗

bioRxiv2019

Corticolimbic circuit structure moderates an association between early life stress and later trait anxiety

Childhood adversity is associated with a wide range of negative behavioral and neurodevelopmental consequences. However, individuals vary substantially in their sensitivity to such adversity. Here, we examined how individual variability in structural features of the corticolimbic circuit, which plays a key role in emotional reactivity, moderates the association between childhood adversity and later trait anxiety in 798 young adult university students. Consistent with prior research, higher self-reported childhood adversity was significantly associated with higher self-reported trait anxiety. However, this association was attenuated in participants with higher microstructural integrity of the uncinate fasciculus and greater thickness of the orbitofrontal cortex. These structural properties of the corticolimbic circuit may capture a neural profile of relative resiliency to early life stress, especially against the negative effects of childhood adversity on later trait anxiety. More generally, our findings highlight the potential utility in the simultaneous consideration of qualitatively different brain structural measures in explaining complex behavioral associations in future research.

neuroscience↗

bioRxiv2019

Maternal Protection in Childhood is Associated with Amygdala Reactivity and Structural Connectivity in Adulthood

Recently, we reported that variability in early-life caregiving experiences maps onto individual differences in threat-related brain function. Specifically, we found that greater familial affective responsiveness is associated with increased amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. Here, we conceptually replicate and extend on our previous work to provide further evidence that subtle variability in specific features of early caregiving shapes structural and functional connectivity between the amygdala and medial prefrontal cortex (mPFC) in a cohort of 312 young adult volunteers. Multiple regression analyses revealed that participants who reported higher maternal but not paternal protection exhibited increased amygdala reactivity to explicit signals of interpersonal threat (i.e., angry facial expressions) but not implicit signals of broad environmental threat (i.e., fearful facial expressions). While amygdala functional connectivity with regulatory regions of the mPFC was not significantly associated with maternal protection, participants who reported higher maternal protection exhibited relatively decreased structural integrity of the uncinate fasciculus (UF), a white matter tract connecting these same brain regions. The observed associations were independent of the potential confounding influences of participant sex, socioeconomic status, and self-reported childhood trauma. There were no significant associations between structural or functional brain measures and either maternal or paternal care ratings. These findings suggest that an over controlling parenting style in mothers during childhood is associated with functional and structural alterations of brain regions involved in generating and regulating responses to threat in young adulthood.

neuroscience↗

bioRxiv2019

A GWAS-Derived Polygenic Score for Interleukin-1β is Associated with Hippocampal Volume in Two Samples

Accumulating research suggests that the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we use an imaging genetics strategy to test an association between an IL-1{beta} polygenic score, derived from summary statistics of a recent genome-wide association study (GWAS) of circulating cytokines, and hippocampal volume, in two independent samples. In the first sample of 512 non-Hispanic Caucasian university students (274 women, mean age 19.78 {+/-} 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between higher polygenic scores, which presumably reflect higher circulating IL-1{beta} levels, and average hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63{+/-}7.45 years) from the UK Biobank. Collectively, our results suggest that a functional GWAS-derived score of IL-1{beta} blood circulating levels affects hippocampal volume, and lend further support in humans, to the link between IL-1{beta} and the structure of the hippocampus.

neuroscience↗

bioRxiv2018

General Functional Connectivity: shared features of resting-state and task fMRI drive reliable individual differences in functional brain networks

Intrinsic connectivity, measured using resting-state fMRI, has emerged as a fundamental tool in the study of the human brain. However, due to practical limitations, many studies do not collect enough resting-state data to generate reliable measures of intrinsic connectivity necessary for studying individual differences. Here we present general functional connectivity (GFC) as a method for leveraging shared features across resting-state and task fMRI and demonstrate in the Human Connectome Project and the Dunedin Study that GFC offers better test-retest reliability than intrinsic connectivity estimated from the same amount of resting-state data alone. Furthermore, at equivalent scan lengths, GFC displays higher heritability on average than resting-state functional connectivity. We also show that predictions of cognitive ability from GFC generalize across datasets, performing as well or better than resting-state or task data alone. Collectively, our work suggests that GFC can improve the reliability of intrinsic connectivity estimates in existing datasets and, subsequently, the opportunity to identify meaningful correlates of individual differences in behavior. Given that task and resting-state data are often collected together, many researchers can immediately derive more reliable measures of intrinsic connectivity through the adoption of GFC rather than solely using resting-state data. Moreover, by better capturing heritable variation in intrinsic connectivity, GFC represents a novel endophenotype with broad applications in clinical neuroscience and biomarker discovery.

neuroscience↗

bioRxiv2018

Microstructural integrity of white matter moderates an association between childhood adversity and adult trait anger

Amongst a number of negative life sequelae associated with childhood adversity is the later expression of a higher dispositional tendency to experience anger and frustration to a wide range of situations (i.e., trait anger). We recently reported that an association between childhood adversity and trait anger is moderated by individual differences in both threat-related amygdala activity and executive control-related dorsolateral prefrontal cortex (dlPFC) activity, wherein individuals with relatively low amygdala and high dlPFC activity do not express higher trait anger even when having experienced childhood adversity. Here, we examine possible structural correlates of this functional dynamic using diffusion magnetic resonance imaging data from 647 young adult men and women volunteers. Specifically, we tested whether the degree of white matter microstructural integrity as indexed by fractional anisotropy modulated the association between childhood adversity and trait anger. Our analyses revealed that higher microstructural integrity of multiple pathways was associated with an attenuated link between childhood adversity and adult trait anger. Amongst these pathways was the uncinate fasciculus, which not only provides a major anatomical link between the amygdala and prefrontal cortex but also is associated with individual differences in regulating negative emotion through top-down cognitive reappraisal. These findings suggest that higher microstructural integrity of distributed white matter pathways including but not limited to the uncinate fasciculus may represent an anatomical foundation serving to buffer against the expression of childhood adversity as later trait anger, which is itself associated with multiple negative health outcomes.

neuroscience↗

bioRxiv2018

Convergent evidence for predispositonal effects of brain volume on alcohol consumption

BackgroundAlcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors and/or causal consequences of alcohol use remains poorly understood.\n\nMethodsData came from 3 neuroimaging samples (total n=2,423), spanning childhood/adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use, and/or a causal consequence of alcohol use. Finally, we evaluated whether GWAS-defined genomic risk for alcohol consumption is enriched for genes preferentially expressed in regions identified in our neuroimaging analyses, using heritability and gene-set enrichment, and transcriptome-wide association study (TWAS) approaches.\n\nResultsSmaller right dorsolateral prefrontal cortex (DLPFC; i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene-sets preferentially expressed in the DLPFC and associated with differential expression of C16orf93, CWF19L1, and C18orf8 in the DLPFC.\n\nConclusionsThese data suggest that smaller DLPFC and insula GMV plausibly represent predispositional risk factors for, as opposed to consequences of, alcohol use. Alcohol use, particularly when heavy, may potentiate these predispositional risk factors. DLPFC and insula GMV represent promising biomarkers for alcohol consumption liability and related psychiatric and behavioral phenotypes.

neuroscience↗