Michael J. Lyons

YNICL Journal 2025 Journal Article

Associations of history of traumatic brain injury with markers of brain health among older men in the Vietnam Era Twin Study of Aging

• Alexander Ivan B. Posis
• Jeremy A. Elman
• John E. Alcaraz
• Humberto Parada
• Aladdin H. Shadyab
• Christine Fennema-Notestine
• Donald J. Hagler
• Michael J. Lyons

BACKGROUND: Traumatic brain injury (TBI) is associated with increased risk of dementia, but it is unclear how earlier life TBI is related to brain health in older age. METHODS: This cross-sectional study compared 517 male Vietnam Era Twin Study of Aging participants with and without a history of TBI (34 % with TBI; median age = 68 [range = 61-72] years). Validated brain age models were used to calculate predicted brain age difference (PBAD and Brain-PAD) scores. A multichannel segmentation approach was used to quantify abnormal white matter signal intensities (AWM). Restriction spectrum imaging (RSI) was used to model multishell diffusion in restricted (intracellular) and free water compartments. Multivariable linear mixed-effects models estimated associations of TBI with PBAD, Brain-PAD, AWM, and RSI outcomes. We assessed moderation in associations of TBI with PBAD, Brain-PAD, AWM, and RSI outcomes by apolipoprotein E epsilon 4 (APOE-ε4) status, depressive and posttraumatic stress symptom severity, and loneliness. RESULTS: PBAD, Brain-PAD, AWM, and global white matter RSI measures did not differ by TBI status but those with history of TBI showed lower restricted diffusion in the inferior longitudinal fasciculus bilaterally and the left inferior occipital fasciculus compared to those without TBI, after adjusting for age and scanner (p-values < 0.05). Results did not differ by APOE-ε4 status, psychiatric symptoms, or loneliness for any primary outcome. CONCLUSIONS: There may be subtle white matter microstructural changes after a TBI event that persist even after over four decades after initial injury. Further research is needed to determine if these differences relate to increased TBI-associated risk of dementia.

YNIMG Journal 2025 Journal Article

Image-based meta- and mega-analysis (IBMMA): A unified framework for large-scale, multi-site, neuroimaging data analysis

• Nick Steele
• Ashley A. Huggins
• Rajendra A. Morey
• Ahmed Hussain
• Courtney Russell
• Benjamin Suarez-Jimenez
• Elena Pozzi
• Hadis Jameei

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA successfully analyzed a large-n dataset of several thousand participants and revealed findings in brain regions that some traditional software overlooked due to missing voxel-data resulting in gaps in brain coverage. IBMMA has the potential to accelerate discoveries in neuroscience and enhance the clinical utility of neuroimaging findings.

YNICL Journal 2023 Journal Article

Associations among executive function Abilities, free Water, and white matter microstructure in early old age

• Daniel E. Gustavson
• Derek B. Archer
• Jeremy A. Elman
• Olivia K. Puckett
• Christine Fennema-Notestine
• Matthew S. Panizzon
• Niranjana Shashikumar
• Timothy J. Hohman

BACKGROUND: ). METHOD: . RESULTS: , including the triangularis portion of the inferior frontal gyrus. There was no evidence that cognitive reserve (i.e., general cognitive ability assessed in early adulthood) moderated these associations between executive function and FW or FA. DISCUSSION: ). Moderation analyses suggested cognitive reserve does not play a strong role in these associations, at least in this sample of non-demented men.

YNIMG Journal 2019 Journal Article

Predominantly global genetic influences on individual white matter tract microstructure

• Daniel E. Gustavson
• Sean N. Hatton
• Jeremy A. Elman
• Matthew S. Panizzon
• Carol E. Franz
• Donald J. Hagler
• Christine Fennema-Notestine
• Lisa T. Eyler

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50. 1% and 62. 5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38. 4% and 47. 0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.

YNICL Journal 2018 Journal Article

Alcohol intake and brain white matter in middle aged men: Microscopic and macroscopic differences

• Linda K. McEvoy
• Christine Fennema-Notestine
• Jeremy A. Elman
• Lisa T. Eyler
• Carol E. Franz
• Donald J. Hagler
• Sean N. Hatton
• Michael J. Lyons

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56-66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9-28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage.

YNIMG Journal 2017 Journal Article

Genetic and environmental influences on cortical mean diffusivity

• Jeremy A. Elman
• Matthew S. Panizzon
• Donald J. Hagler
• Christine Fennema-Notestine
• Lisa T. Eyler
• Nathan A. Gillespie
• Michael C. Neale
• Michael J. Lyons

Magnetic resonance imaging (MRI) has become an important tool in the early detection of age-related and neuropathological brain changes. Recent studies suggest that changes in mean diffusivity (MD) of cortical gray matter derived from diffusion MRI scans may be useful in detecting early effects of Alzheimer's disease (AD), and that these changes may be detected earlier than alterations associated with standard structural MRI measures such as cortical thickness. Thus, due to its potential clinical relevance, we examined the genetic and environmental influences on cortical MD in middle-aged men to provide support for the biological relevance of this measure and to guide future gene association studies. It is not clear whether individual differences in cortical MD reflect neuroanatomical variability similarly detected by other MRI measures, or whether unique features are captured. For instance, variability in cortical MD may reflect morphological variability more commonly measured by cortical thickness. Differences among individuals in cortical MD may also arise from breakdowns in myelinated fibers running through the cortical mantle. Thus, we investigated whether genetic influences on variation in cortical MD are the same or different from those influencing cortical thickness and MD of white matter (WM) subjacent to the cortical ribbon. Univariate twin analyses indicated that cortical MD is heritable in the majority of brain regions; the average of regional heritability estimates ranged from 0. 38 in the cingulate cortex to 0. 66 in the occipital cortex, consistent with the heritability of other MRI measures of the brain. Trivariate analyses found that, while there was some shared genetic variance between cortical MD and each of the other two measures, this overlap was not complete (i. e. , the correlation was statistically different from 1). A significant amount of distinct genetic variance influences inter-individual variability in cortical MD; therefore, this measure could be useful for further investigation in studies of neurodegenerative diseases and gene association studies.

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.

YNICL Journal 2016 Journal Article

White matter disease in midlife is heritable, related to hypertension, and shares some genetic influence with systolic blood pressure

• Christine Fennema-Notestine
• Linda K. McEvoy
• Randy Notestine
• Matthew S. Panizzon
• Wai-Ying Wendy Yau
• Carol E. Franz
• Michael J. Lyons
• Lisa T. Eyler

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61. 9±2. 6years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E-ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age (t =1. 9, p =0. 05) and hypertension (t =2. 9, p =0. 004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled (t =3. 0, p =0. 003) and normotensive (t =4. 0, p =0. 0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a2 =0. 81) and shared some genetic influences with systolic blood pressure (rA =0. 26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery.

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.

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.

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.

YNIMG Journal 2010 Journal Article

Corrigendum to “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

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.

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.