Agatha D. Lee

Genetics of Brain Fiber Architecture and Intellectual Performance

The study is the first to analyze genetic and environmental factors that affect brain fiber architecture and its genetic linkage with cognitive function. We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4 Tesla), in 92 identical and fraternal twins. White matter integrity, quantified using fractional anisotropy (FA), was used to fit structural equation models (SEM) at each point in the brain, generating three-dimensional maps of heritability. We visualized the anatomical profile of correlations between white matter integrity and full-scale, verbal, and performance intelligence quotients (FIQ, VIQ, and PIQ). White matter integrity (FA) was under strong genetic control and was highly heritable in bilateral frontal (a2 = 0.55, p = 0.04, left; a2 = 0.74, p = 0.006, right), bilateral parietal (a2 = 0.85, p < 0.001, left; a2 = 0.84, p < 0.001, right), and left occipital (a2 = 0.76, p = 0.003) lobes, and was correlated with FIQ and PIQ in the cingulum, optic radiations, superior fronto-occipital fasciculus, internal capsule, callosal isthmus, and the corona radiata (p = 0.04 for FIQ and p = 0.01 for PIQ, corrected for multiple comparisons). In a cross-trait mapping approach, common genetic factors mediated the correlation between IQ and white matter integrity, suggesting a common physiological mechanism for both, and common genetic determination. These genetic brain maps reveal heritable aspects of white matter integrity and should expedite the discovery of single-nucleotide polymorphisms affecting fiber connectivity and cognition.

Abnormal Cortical Complexity and Thickness Profiles Mapped in Williams Syndrome

We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of ∼20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 × 192 × 124 volumes) of 42 subjects with genetically confirmed WS (mean ± SD, 29.2 ± 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 ± 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.

Greater cortical gray matter density in lithium-treated patients with bipolar disorder.

BACKGROUND The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures. METHODS We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 +/- 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 +/- 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations. RESULTS Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8). CONCLUSIONS These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.

3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry.

UNLABELLED Williams syndrome (WS) is a neurodevelopmental disorder associated with deletion of approximately 20 contiguous genes in chromosome band 7q11.23. Individuals with WS exhibit mild to moderate mental retardation, but are relatively more proficient in specific language and musical abilities. We used tensor-based morphometry (TBM) to visualize the complex pattern of gray/white matter reductions in WS, based on fluid registration of structural brain images. METHODS 3D T1-weighted brain MRIs of 41 WS subjects (age [mean+/-SD]: 29.2+/-9.2 years; 23F/18M) and 39 age-matched healthy controls (age: 27.5+/-7.4 years; 23F/16M) were fluidly registered to a minimum deformation target. Fine-scale volumetric differences were mapped between diagnostic groups. Local regions were identified where regional structure volumes were associated with diagnosis, and with intelligence quotient (IQ) scores. Brain asymmetry was also mapped and compared between diagnostic groups. RESULTS WS subjects exhibited widely distributed brain volume reductions (approximately 10-15% reduction; P<0.0002, permutation test). After adjusting for total brain volume, the frontal lobes, anterior cingulate, superior temporal gyrus, amygdala, fusiform gyrus and cerebellum were found to be relatively preserved in WS, but parietal and occipital lobes, thalamus and basal ganglia, and midbrain were disproportionally decreased in volume (P<0.0002). These regional volumes also correlated positively with performance IQ in adult WS subjects (age > or = 30 years, P = 0.038). CONCLUSION TBM facilitates 3D visualization of brain volume reductions in WS. Reduced parietal/occipital volumes may be associated with visuospatial deficits in WS. By contrast, frontal lobes, amygdala, and cingulate gyrus are relatively preserved or even enlarged, consistent with unusual affect regulation and language production in WS.

Acute and Chronic Changes in Diffusivity Measures after Sports Concussion

Despite negative neuroimaging findings in concussed athletes, studies indicate that the acceleration and deceleration of the brain after concussive impacts result in metabolic and electrophysiological alterations that may be attributable to changes in white matter resulting from biomechanical strain. In the present study we investigated the effects of sports concussion on white matter using three different diffusion tensor imaging (DTI) measures: fractional anisotropy (FA), mean diffusivity (MD), and axial diffusivity (AD). We compared a group of 10 non-concussed athletes with a group of 18 concussed athletes of the same age (mean age 22.5 years) and education (mean 16 years) using a voxel-based approach (VBA) in both the acute and chronic post-injury phases. All concussed athletes were scanned 1-6 days post-concussion and again 6 months later in a 3T Siemens Trio(™) MRI. Three 2×2 repeated-measures analyses of variance (ANOVAs) were conducted, one for each measure of DTI used in the current study. There was a main group effect of FA, which was increased in dorsal regions of both corticospinal tracts (CST) and in the corpus callosum in concussed athletes at both time points. There was a main group effect of AD in the right CST, where concussed athletes showed elevated values relative to controls at both time points. MD values were decreased in concussed athletes, in whom analyses revealed significant group differences in the CST and corpus callosum at both time points. Although the use of VBA does limit the analyses to large tracts, and it has clinical limitations with regard to individual analyses, our results nevertheless indicate that sports concussions do result in changes in diffusivity in the corpus callosum and CST that are not detected using conventional neuroimaging techniques.

Statistical Properties of Jacobian Maps and the Realization of Unbiased Large-Deformation Nonlinear Image Registration

Maps of local tissue compression or expansion are often computed by comparing magnetic resonance imaging (MRI) scans using nonlinear image registration. The resulting changes are commonly analyzed using tensor-based morphometry to make inferences about anatomical differences, often based on the Jacobian map, which estimates local tissue gain or loss. Here, we provide rigorous mathematical analyses of the Jacobian maps, and use them to motivate a new numerical method to construct unbiased nonlinear image registration. First, we argue that logarithmic transformation is crucial for analyzing Jacobian values representing morphometric differences. We then examine the statistical distributions of log-Jacobian maps by defining the Kullback-Leibler (KL) distance on material density functions arising in continuum-mechanical models. With this framework, unbiased image registration can be constructed by quantifying the symmetric KL-distance between the identity map and the resulting deformation. Implementation details, addressing the proposed unbiased registration as well as the minimization of symmetric image matching functionals, are then discussed and shown to be applicable to other registration methods, such as inverse consistent registration. In the results section, we test the proposed framework, as well as present an illustrative application mapping detailed 3-D brain changes in sequential magnetic resonance imaging scans of a patient diagnosed with semantic dementia. Using permutation tests, we show that the symmetrization of image registration statistically reduces skewness in the log-Jacobian map.

In vivo neuropathology of the hippocampal formation in AD: A radial mapping MR-based study

Early involvement of the hippocampal formation is the biological basis of the typical learning deficit in Alzheimers disease (AD). However, the hippocampal formation is unevenly affected by AD pathology, deposits of plaques and tangles being particularly dense in the CA1 field and subiculum. The aim of the study was to locate in vivo the structural changes within the hippocampal formation in AD patients of mild to moderate severity. A group of 28 AD patients and 40 cognitively intact persons (age 74 +/- 9 and 71 +/- 7 years) underwent T1-weighted high-resolution MR scans. The hippocampal formation was isolated by manually tracing on 35 coronal slices the outlines of the hippocampus proper and subiculum after registration to a common stereotactic space. Group differences were assessed with algorithms developed ad hoc that make use of three-dimensional parametric surface mesh models. In AD patients, significant atrophic changes amounting to tissue loss of 20% or more were found in regions of the hippocampal formation corresponding to the CA1 field and part of the subiculum. Regions corresponding to the CA2-3 fields were remarkably spared. We conclude that the regions of the hippocampal formation that we found atrophic in AD patients are those known to be affected from pathological studies. This study supports the possibility of carrying out in vivo macroscopic neuropathology of the hippocampus with MR imaging in the neurodegenerative dementias.

Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium

Previous structural neuroimaging studies of bipolar disorder have reported conflicting findings in limbic structures. Medication heterogeneity of patient samples may have contributed to these inconsistencies. Using structural magnetic resonance imaging we assessed whether lithium treatment was associated with differences in amygdala and hippocampal volumes in a sample of bipolar adults. A total of 49 magnetic resonance imaging scans were collected from patients who were currently treated with or without lithium. Amygdala and hippocampal volumes were analyzed using tensor-based morphometry. Statistical between-group comparisons of deformation maps showed that patients treated with lithium exhibited significantly increased volumes of the amygdala and hippocampus compared with patients who were not taking lithium. Our findings may help to explain previous inconsistencies in the bipolar literature.

GENETIC INFLUENCES ON BRAIN ASYMMETRY: A DTI STUDY OF 374 TWINS AND SIBLINGS

Brain asymmetry, or the structural and functional specialization of each brain hemisphere, has fascinated neuroscientists for over a century. Even so, genetic and environmental factors that influence brain asymmetry are largely unknown. Diffusion tensor imaging (DTI) now allows asymmetry to be studied at a microscopic scale by examining differences in fiber characteristics across hemispheres rather than differences in structure shapes and volumes. Here we analyzed 4Tesla DTI scans from 374 healthy adults, including 60 monozygotic twin pairs, 45 same-sex dizygotic pairs, and 164 mixed-sex DZ twins and their siblings; mean age: 24.4years+/-1.9 SD). All DTI scans were nonlinearly aligned to a geometrically-symmetric, population-based image template. We computed voxel-wise maps of significant asymmetries (left/right differences) for common diffusion measures that reflect fiber integrity (fractional and geodesic anisotropy; FA, GA and mean diffusivity, MD). In quantitative genetic models computed from all same-sex twin pairs (N=210 subjects), genetic factors accounted for 33% of the variance in asymmetry for the inferior fronto-occipital fasciculus, 37% for the anterior thalamic radiation, and 20% for the forceps major and uncinate fasciculus (all L>R). Shared environmental factors accounted for around 15% of the variance in asymmetry for the cortico-spinal tract (R>L) and about 10% for the forceps minor (L>R). Sex differences in asymmetry (men>women) were significant, and were greatest in regions with prominent FA asymmetries. These maps identify heritable DTI-derived features, and may empower genome-wide searches for genetic polymorphisms that influence brain asymmetry.

Increased local gyrification mapped in Williams syndrome

Applying a recently developed method to analyze gyrification with excellent spatial resolution across thousands of points across the lateral and medial cortical surface, we mapped differences in cortical surface anatomy between subjects with Williams syndrome (WS; n=42) and an age-matched sample of healthy subjects (n=40). WS subjects showed increased gyrification bilaterally in occipital regions and over the cuneus. Differences were more pronounced in the left hemisphere than in the right, with additional regions of increased gyrification in WS in the left precuneus, posterior and anterior cingulate, paracentral and mesial frontal lobe. No cortical area was significantly more convoluted in healthy subjects relative to the WS subjects. On the lateral surfaces, the direction and pattern of gyrification asymmetries were similar in WS subjects and controls; posterior brain regions had greater gyrification in the left hemisphere, while anterior brain regions showed greater gyrification in the right hemisphere. On the medial surfaces, control subjects and WS individuals differed considerably with respect to the degree but also direction of gyrification asymmetry. Our findings confirm and extend previous studies measuring cortical complexity at the global whole-brain or hemispheric levels. The observed gyrification abnormalities in individuals with WS might be related to dysfunctions in neuronal circuits and consequently contribute to the distinct cognitive and behavioral profile accompanying the disorder.