Lisa T. Eyler

Distinct Genetic Influences on Cortical Surface Area and Cortical Thickness

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51-59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease

Objective: To determine whether APOE genotype influences brain response and whether nonverbal stimuli generate findings comparable with those of previous studies that used verbal stimuli. The relationship between APOE genotype and blood oxygenation level dependent (BOLD) brain response was examined during a picture-encoding task in nondemented older adults. Methods: Twenty nondemented participants with normal episodic memory function were divided into two groups based on the presence (n = 10) or absence (n = 10) of the APOE ε4 allele. Picture learning was completed during functional MRI in a blocked design alternating between experimental (novel pictures) and control (repeated picture) conditions. Results: Nondemented older adults with an APOE ε4 allele showed greater magnitude and extent of BOLD brain response during learning of new pictures relative to their matched ε3 counterparts. Different patterns and directions of association between hippocampal activity and learning and memory performance were also demonstrated. Conclusions: The results suggest that brain response differences are not due to poorer general memory abilities, differential atrophy, or brain response during control conditions, but instead appear to be directly influenced by APOE genotype. Results are consistent with a compensatory hypothesis wherein older adults at genetic risk for Alzheimer disease by virtue of the APOE ε4 allele appear to require additional cognitive effort to achieve comparable performance levels on tests of episodic memory encoding.

Hierarchical Genetic Organization of Human Cortical Surface Area

Building the Brain Brain connectivity is often described as a network of discrete independent cables analogous to a switchboard, but how is the physical structure of the brain constructed (see the Perspective by Zilles and Amunts)? Wedeen et al. (p. 1628) used high-resolution diffusion tensor imaging in humans and four species of nonhuman primates to identify and compare the geometric structure of large fiber tracts in the brain. Fiber tracts followed a highly constrained and regular geometry, which may provide an efficient solution for pathfinding during ontogenetic development. Much of development occurs through elaboration and assembly of semiautonomous building blocks. Chen et al. (p. 1634) applied statistical analysis to the form of the human cortex in brain-imaging studies that compared more than 400 di- and mono-zygotic twins. The findings suggest that the structure of the human cortex is defined by genetics. Human brain structure is genetically controlled in a hierarchical, modular, and symmetric fashion. Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non–genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.

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

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.

A failure of left temporal cortex to specialize for language is an early emerging and fundamental property of autism

Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small sample (n = 12) of sleeping 2-3 year olds with autism in contrast to typically developing children, a finding also reported in autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample, and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was used in which brain activity was measured in a large sample of toddlers (n = 80) during the presentation of a bedtime story during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between 12-48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to language; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of language in autism across two separate samples, including a large sample of young infants who later are diagnosed with autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism.

Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response☆

Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE epsilon4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-epsilon4 and 12 epsilon4 subjects. The epsilon4 group displayed greater activation than the non-epsilon4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE epsilon4-related deficiencies associated with verbal episodic memory encoding and consolidation.

A preliminary study of functional magnetic resonance imaging response during verbal encoding among adolescent binge drinkers

Binge alcohol use is common among teenagers with 28% of 12th graders reporting getting drunk in the past month. Chronic heavy drinking has been associated with verbal learning and memory deficits in adolescents and adults, yet verbal encoding in less frequently drinking teens has not yet been studied. Here, we examined functional magnetic resonance imaging (fMRI) response during verbal encoding among adolescent binge drinkers. Participants recruited from local high schools were of ages 16-18 and consisted of 12 binge drinkers and 12 demographically similar nondrinkers. Participants were all nonsmokers, and drinkers were abstinent from alcohol for an average of 33 days at the time of scanning. Participants performed a verbal paired associates learning task during fMRI acquisition. Drinkers recalled marginally fewer words than nondrinkers (P=.07). Compared with nondrinkers, bingers showed more response in right superior frontal and bilateral posterior parietal cortices but less response in occipital cortex during novel encoding (Ps<.05, clusters >1,512microL). In addition, controls showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. Adolescent binge drinkers demonstrated (1) more response than nondrinkers in frontal and parietal regions, which could suggest greater engagement of working memory systems during encoding; (2) no hippocampal activation to novel word pairs; and (3) slightly poorer word pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope. Longitudinal studies will be needed to ascertain the degree to which emergence of binge drinking is linked temporally to these brain response patterns.

A Review of Functional Brain Imaging Correlates of Successful Cognitive Aging

Preserved cognitive performance is a key feature of successful aging. Several theoretical models have been proposed to explain the putative underlying relationship between brain function and performance. We aimed to review imaging studies of the association between brain functional response and cognitive performance among healthy younger and older adults to understand the neural correlates of successful cognitive aging. MEDLINE-indexed articles published between January 1989 and December 2009 and bibliographies of these articles and related reviews were searched. Studies that measured brain function with functional magnetic resonance imaging or positron emission tomography, evaluated cognitive performance, analyzed how cognitive performance related to brain response, and studied healthy older individuals were included. Eighty of 550 articles met these criteria. Seventy percent of the studies reported some brain regions in which greater activation related to better cognitive performance among older participants. This association was not universal, however, and was seen mainly in frontal cortex brain response and seemed to be more common among older compared with younger individuals. This review supports the notion of compensatory increases in brain activity in old age resulting in better cognitive performance, as suggested by hemispheric asymmetry reduction and posterior-anterior shift models of functional brain aging. However, a simple model of bigger structure → greater brain response → better cognitive performance might not be accurate. Suggestions for future research are discussed.

Cortical Thickness Is Influenced by Regionally Specific Genetic Factors

BACKGROUND Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally specific sets of genes. METHODS We mapped the heritability of cortical thickness throughout the brain using three-dimensional structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface. RESULTS There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions. CONCLUSIONS These results provide strong evidence of regionally specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders and normal and pathological cognitive aging.

Genetic topography of brain morphology

Significance How diverse functional cortical regions develop is an important neuroscience question. Animal experiments show that regional differentiation is controlled by genes that express in a graded and regionalized pattern; however, such investigation in humans is scarce. Using noninvasive imaging techniques to acquire brain structure data of genetically related subjects (i.e., twins), we estimated the spatial pattern of genetic influences on cortical structure. We developed a genetic parcellation of cortical thickness to delineate the boundaries of cortical divisions that are—within each division—maximally under control of shared genetic influences. We also found differences in genetic influences on cortical surface area and thickness along two orthogonal axes. The concept of gradations is crucial for understanding the organization of the human brain. Animal data show that cortical development is initially patterned by genetic gradients largely along three orthogonal axes. We previously reported differences in genetic influences on cortical surface area along an anterior-posterior axis using neuroimaging data of adult human twins. Here, we demonstrate differences in genetic influences on cortical thickness along a dorsal-ventral axis in the same cohort. The phenomenon of orthogonal gradations in cortical organization evident in different structural and functional properties may originate from genetic gradients. Another emerging theme of cortical patterning is that patterns of genetic influences recapitulate the spatial topography of the cortex within hemispheres. The genetic patterning of both cortical thickness and surface area corresponds to cortical functional specializations. Intriguingly, in contrast to broad similarities in genetic patterning, two sets of analyses distinguish cortical thickness and surface area genetically. First, genetic contributions to cortical thickness and surface area are largely distinct; there is very little genetic correlation (i.e., shared genetic influences) between them. Second, organizing principles among genetically defined regions differ between thickness and surface area. Examining the structure of the genetic similarity matrix among clusters revealed that, whereas surface area clusters showed great genetic proximity with clusters from the same lobe, thickness clusters appear to have close genetic relatedness with clusters that have similar maturational timing. The discrepancies are in line with evidence that the two traits follow different mechanisms in neurodevelopment. Our findings highlight the complexity of genetic influences on cortical morphology and provide a glimpse into emerging principles of genetic organization of the cortex.