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Ming T. Tsuang

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13 papers
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13

YNICL Journal 2021 Journal Article

Discriminatory experiences predict neuroanatomical changes and anxiety among healthy individuals and those at clinical high risk for psychosis

  • Meghan A. Collins
  • Yoonho Chung
  • Jean Addington
  • Carrie E. Bearden
  • Kristin S. Cadenhead
  • Barbara A. Cornblatt
  • Daniel H. Mathalon
  • Thomas H. McGlashan

Individuals face discrimination based on characteristics including race/ethnicity, gender, age, and disability. Discriminatory experiences (DE) are associated with poor psychological health in the general population and with worse outcomes among individuals at clinical high risk for psychosis (CHR). Though the brain is sensitive to stress, and brain structural change is a well-documented precursor to psychosis, potential relationships between DE and brain structure among CHR or healthy individuals are not known. This report assessed whether lifetime DE are associated with cortical thinning and clinical outcomes across time, after controlling for discrimination-related demographic factors among CHR individuals who ultimately do (N = 57) and do not convert to psychosis (N = 451), and healthy comparison (N = 208) participants in the North American Prodrome Longitudinal Study 2. Results indicate that DE are associated with thinner cortex across time in several cortical areas. Thickness in several right hemisphere regions partially mediates associations between DE and subsequent anxiety symptoms, but not attenuated positive symptoms of psychosis. This report provides the first evidence to date of an association between DE and brain structure in both CHR and healthy comparison individuals. Results also suggest that thinner cortex across time in areas linked with DE may partially explain associations between DE and cross-diagnostic indicators of psychological distress.

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YNIMG Journal 2017 Journal Article

Multisite reliability of MR-based functional connectivity

  • Stephanie Noble
  • Dustin Scheinost
  • Emily S. Finn
  • Xilin Shen
  • Xenophon Papademetris
  • Sarah C. McEwen
  • Carrie E. Bearden
  • Jean Addington

Recent years have witnessed an increasing number of multisite MRI functional connectivity (fcMRI) studies. While multisite studies provide an efficient way to accelerate data collection and increase sample sizes, especially for rare clinical populations, any effects of site or MRI scanner could ultimately limit power and weaken results. Little data exists on the stability of functional connectivity measurements across sites and sessions. In this study, we assess the influence of site and session on resting state functional connectivity measurements in a healthy cohort of traveling subjects (8 subjects scanned twice at each of 8 sites) scanned as part of the North American Prodrome Longitudinal Study (NAPLS). Reliability was investigated in three types of connectivity analyses: (1) seed-based connectivity with posterior cingulate cortex (PCC), right motor cortex (RMC), and left thalamus (LT) as seeds; (2) the intrinsic connectivity distribution (ICD), a voxel-wise connectivity measure; and (3) matrix connectivity, a whole-brain, atlas-based approach to assessing connectivity between nodes. Contributions to variability in connectivity due to subject, site, and day-of-scan were quantified and used to assess between-session (test-retest) reliability in accordance with Generalizability Theory. Overall, no major site, scanner manufacturer, or day-of-scan effects were found for the univariate connectivity analyses; instead, subject effects dominated relative to the other measured factors. However, summaries of voxel-wise connectivity were found to be sensitive to site and scanner manufacturer effects. For all connectivity measures, although subject variance was three times the site variance, the residual represented 60–80% of the variance, indicating that connectivity differed greatly from scan to scan independent of any of the measured factors (i. e. , subject, site, and day-of-scan). Thus, for a single 5min scan, reliability across connectivity measures was poor (ICC=0. 07–0. 17), but increased with increasing scan duration (ICC=0. 21–0. 36 at 25min). The limited effects of site and scanner manufacturer support the use of multisite studies, such as NAPLS, as a viable means of collecting data on rare populations and increasing power in univariate functional connectivity studies. However, the results indicate that aggregation of fcMRI data across longer scan durations is necessary to increase the reliability of connectivity estimates at the single-subject level.

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YNIMG Journal 2016 Journal Article

Is bigger always better? The importance of cortical configuration with respect to cognitive ability

  • Eero Vuoksimaa
  • Matthew S. Panizzon
  • Chi-Hua Chen
  • Mark Fiecas
  • Lisa T. Eyler
  • Christine Fennema-Notestine
  • Donald J. Hagler
  • Carol E. Franz

General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical “bigger is better” view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions.

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YNIMG Journal 2015 Journal Article

Does degree of gyrification underlie the phenotypic and genetic associations between cortical surface area and cognitive ability?

  • Anna R. Docherty
  • Donald J. Hagler
  • Matthew S. Panizzon
  • Michael C. Neale
  • Lisa T. Eyler
  • Christine Fennema-Notestine
  • Carol E. Franz
  • Amy Jak

The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA–GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N=512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA–GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA.

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YNIMG Journal 2014 Journal Article

Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: Analysis from the North American Prodrome Longitudinal Study

  • Jennifer K. Forsyth
  • Sarah C. McEwen
  • Dylan G. Gee
  • Carrie E. Bearden
  • Jean Addington
  • Brad Goodyear
  • Kristin S. Cadenhead
  • Heline Mirzakhanian

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n =8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0. 81 for left dorsolateral prefrontal cortex, 0. 95 for left superior parietal cortex). In the second study sample (n =154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i. e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular.

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YNIMG Journal 2012 Journal Article

Genetic and environmental influences of white and gray matter signal contrast: A new phenotype for imaging genetics?

  • Matthew S. Panizzon
  • Christine Fennema-Notestine
  • Thomas S. Kubarych
  • Chi-Hua Chen
  • Lisa T. Eyler
  • Bruce Fischl
  • Carol E. Franz
  • Michael D. Grant

The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer's disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (. 50), and lowest in the cingulate cortex (. 24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from −. 11 to −. 54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from −. 16 to −. 34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics.

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YNIMG Journal 2012 Journal Article

Genetic influences on hippocampal volume differ as a function of testosterone level in middle-aged men

  • Matthew S. Panizzon
  • Richard L. Hauger
  • Lindon J. Eaves
  • Chi-Hua Chen
  • Anders M. Dale
  • Lisa T. Eyler
  • Bruce Fischl
  • Christine Fennema-Notestine

The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55. 8years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor.

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YNIMG Journal 2010 Journal Article

Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study

  • William S. Kremen
  • Elizabeth Prom-Wormley
  • Matthew S. Panizzon
  • Lisa T. Eyler
  • Bruce Fischl
  • Michael C. Neale
  • Carol E. Franz
  • Michael J. Lyons

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51–59 years old, and were similar to U. S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0. 00–0. 75) as compared with subcortical and ventricular ROIs (0. 48–0. 85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

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YNIMG Journal 2010 Journal Article

Salivary cortisol and prefrontal cortical thickness in middle-aged men: A twin study

  • William S. Kremen
  • Robert C. O'Brien
  • Matthew S. Panizzon
  • Elizabeth Prom-Wormley
  • Lindon J. Eaves
  • Seth A. Eisen
  • Lisa T. Eyler
  • Richard L. Hauger

Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51–59 years old. Small but significant negative phenotypic associations were found between cortisol levels and the thickness of left dorsolateral (superior frontal gyrus, left rostral middle frontal gyrus) and ventrolateral (pars opercularis, pars triangularis, pars orbitalis) prefrontal regions, and right dorsolateral (superior frontal gyrus) and medial orbital frontal cortex. Most of the associations remained significant after adjusting for general cognitive ability, cardiovascular risk factors, and depression. Bivariate genetic analyses suggested that some of the associations were primarily accounted for by shared genetic influences; that is, some of the genes that tend to result in increased cortisol levels also tend to result in reduced prefrontal cortical thickness. Aging has been associated with reduced efficiency of hypothalamic–pituitary–adrenal function, frontal lobe shrinkage, and increases in health problems, but our present data do not allow us to determine the direction of effects. Moreover, the degree or the direction of the observed associations and the extent of their shared genetic underpinnings may well change as these individuals age. Longitudinal assessments are underway to elucidate the direction of the associations and the genetic underpinnings of longitudinal phenotypes for changes in cortisol and brain morphology.

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v2026.09.13