Rebecca A. Dutton

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.

Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline

HIV/AIDS infection is the fourth leading cause of death worldwide, and one in every 100 adults aged 15–49 years is HIV-infected. Forty percent of AIDS patients suffer from neurological symptoms, but the selective profile of damage caused by HIV in the brain is not well understood. Here, we report 3D maps revealing how AIDS affects the human cerebral cortex, identifying the most vulnerable regions and where deficits link with cognitive decline and immune-system suppression. With high-resolution brain MRI scans, we created composite maps of cortical gray-matter thickness in 26 AIDS patients and 14 healthy controls to establish the selective pattern of brain deficits in AIDS. In AIDS, primary sensory, motor, and premotor cortices were 15% thinner. Thinner frontopolar and language cortex correlated with immune system deterioration measured through blood levels of CD4+ T lymphocytes. Prefrontal and parietal tissue loss correlated with cognitive/motor deficits. T cell depletion and cognitive impairment are, therefore, associated with specific 3D brain-deficit patterns visualized with MRI. These quantitative MRI-based maps reveal that HIV selectively damages the cortex. They provide an approach to gauge the impact of AIDS on the living brain and show that the brain is still vulnerable to infection even when patients are receiving antiretroviral therapy.

Mapping Corpus Callosum Deficits in Autism: An Index of Aberrant Cortical Connectivity

BACKGROUND Volumetric studies have reported reductions in the size of the corpus callosum (CC) in autism, but the callosal regions contributing to this deficit have differed among studies. In this study, a computational method was used to detect and map the spatial pattern of CC abnormalities in male patients with autism. METHODS Twenty-four boys with autism (aged 10.0 +/- 3.3 years) and 26 control boys (aged 11.0 +/- 2.5 years) underwent a magnetic resonance imaging (MRI) scan at 3 Tesla. Total and regional areas of the CC were determined using traditional morphometric methods. Three-dimensional (3D) surface models of the CC were also created from the MRI scans. Statistical maps were created to visualize morphologic variability of the CC and to localize regions of callosal thinning in autism. RESULTS Traditional morphometric methods detected a significant reduction in the total callosal area and in the anterior third of the CC in patients with autism; however, 3D maps revealed significant reductions in both the splenium and genu of the CC in patients. CONCLUSIONS Statistical maps of the CC revealed callosal deficits in autism with greater precision than traditional morphometric methods. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism.

Tracking Alzheimer's Disease

Abstract:  Population‐based brain mapping provides great insight into the trajectory of aging and dementia, as well as brain changes that normally occur over the human life span. We describe three novel brain mapping techniques, cortical thickness mapping, tensor‐based morphometry (TBM), and hippocampal surface modeling, which offer enormous power for measuring disease progression in drug trials, and shed light on the neuroscience of brain degeneration in Alzheimers disease (AD) and mild cognitive impairment (MCI). We report the first time‐lapse maps of cortical atrophy spreading dynamically in the living brain, based on averaging data from populations of subjects with Alzheimers disease and normal subjects imaged longitudinally with MRI. These dynamic sequences show a rapidly advancing wave of cortical atrophy sweeping from limbic and temporal cortices into higher‐order association and ultimately primary sensorimotor areas, in a pattern that correlates with cognitive decline. A complementary technique, TBM, reveals the 3D profile of atrophic rates, at each point in the brain. A third technique, hippocampal surface modeling, plots the profile of shape alterations across the hippocampal surface. The three techniques provide moderate to highly automated analyses of images, have been validated on hundreds of scans, and are sensitive to clinically relevant changes in individual patients and groups undergoing different drug treatments. We compare time‐lapse maps of AD, MCI, and other dementias, correlate these changes with cognition, and relate them to similar time‐lapse maps of childhood development, schizophrenia, and HIV‐associated brain degeneration. Strengths and weaknesses of these different imaging measures for basic neuroscience and drug trials are discussed.

Generalized Tensor-Based Morphometry of HIV/AIDS Using Multivariate Statistics on Deformation Tensors

This paper investigates the performance of a new multivariate method for tensor-based morphometry (TBM). Statistics on Riemannian manifolds are developed that exploit the full information in deformation tensor fields. In TBM, multiple brain images are warped to a common neuroanatomical template via 3-D nonlinear registration; the resulting deformation fields are analyzed statistically to identify group differences in anatomy. Rather than study the Jacobian determinant (volume expansion factor) of these deformations, as is common, we retain the full deformation tensors and apply a manifold version of Hotellings test to them, in a Log-Euclidean domain. In 2-D and 3-D magnetic resonance imaging (MRI) data from 26 HIV/AIDS patients and 14 matched healthy subjects, we compared multivariate tensor analysis versus univariate tests of simpler tensor-derived indices: the Jacobian determinant, the trace, geodesic anisotropy, and eigenvalues of the deformation tensor, and the angle of rotation of its eigenvectors. We detected consistent, but more extensive patterns of structural abnormalities, with multivariate tests on the full tensor manifold. Their improved power was established by analyzing cumulative-value plots using false discovery rate (FDR) methods, appropriately controlling for false positives. This increased detection sensitivity may empower drug trials and large-scale studies of disease that use tensor-based morphometry.

3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry.

UNLABELLED 35% of HIV-infected patients have cognitive impairment, but the profile of HIV-induced brain damage is still not well understood. Here we used tensor-based morphometry (TBM) to visualize brain deficits and clinical/anatomical correlations in HIV/AIDS. To perform TBM, we developed a new MRI-based analysis technique that uses fluid image warping, and a new alpha-entropy-based information-theoretic measure of image correspondence, called the Jensen-Rényi divergence (JRD). METHODS 3D T1-weighted brain MRIs of 26 AIDS patients (CDC stage C and/or 3 without HIV-associated dementia; 47.2+/-9.8 years; 25M/1F; CD4+ T-cell count: 299.5+/-175.7/microl; log10 plasma viral load: 2.57+/- 1.28 RNA copies/ml) and 14 HIV-seronegative controls (37.6+/-12.2 years; 8M/6F) were fluidly registered by applying forces throughout each deforming image to maximize the JRD between it and a target image (from a control subject). The 3D fluid registration was regularized using the linearized Cauchy-Navier operator. Fine-scale volumetric differences between diagnostic groups were mapped. Regions were identified where brain atrophy correlated with clinical measures. RESULTS Severe atrophy ( approximately 15-20% deficit) was detected bilaterally in the primary and association sensorimotor areas. Atrophy of these regions, particularly in the white matter, correlated with cognitive impairment (P = 0.033) and CD4+ T-lymphocyte depletion (P = 0.005). CONCLUSION TBM facilitates 3D visualization of AIDS neuropathology in living patients scanned with MRI. Severe atrophy in frontoparietal and striatal areas may underlie early cognitive dysfunction in AIDS patients, and may signal the imminent onset of AIDS dementia complex.

Structural Correlates of Apathy in Alzheimer’s Disease

Background: Apathy is the most common noncognitive symptom inAlzheimer’s disease (AD). The structural correlates of apathy in AD have not yet been described. Methods: We analyzed magnetic resonance imaging data of 35 AD patients with and without apathy. Results: There was a significant linear association between apathy severity and cortical gray matter atrophy in the bilateral anterior cingulate [Brodmann area (BA) 24; r = 0.39–0.42, p = 0.01] and left medial frontal cortex (BA 8 and 9; r = 0.4, p < 0.02). Left mean cingulate cortical thinning predicted the presence/absence of apathy at the trend level of significance. Conclusion: Our study demonstrates a strong association between apathy and the integrity of medial frontal regions in AD.

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.

Three-Dimensional Mapping of Hippocampal Anatomy in Unmedicated and Lithium-Treated Patients with Bipolar Disorder

Declarative memory impairments are common in patients with bipolar illness, suggesting underlying hippocampal pathology. However, hippocampal volume deficits are rarely observed in bipolar disorder. Here we used surface-based anatomic mapping to examine hippocampal anatomy in bipolar patients treated with lithium relative to matched control subjects and unmedicated patients with bipolar disorder. High-resolution brain magnetic resonance images were acquired from 33 patients with bipolar disorder (21 treated with lithium and 12 unmedicated), and 62 demographically matched healthy control subjects. Three-dimensional parametric mesh models were created from manual tracings of the hippocampal formation. Total hippocampal volume was significantly larger in lithium-treated bipolar patients compared with healthy controls (by 10.3%; p=0.001) and unmedicated bipolar patients (by 13.9%; p=0.003). Statistical mapping results, confirmed by permutation testing, revealed localized deficits in the right hippocampus, in regions corresponding primarily to cornu ammonis 1 subfields, in unmedicated bipolar patients, as compared to both normal controls (p=0.01), and in lithium-treated bipolar patients (p=0.03). These findings demonstrate the sensitivity of these anatomic mapping methods for detecting subtle alterations in hippocampal structure in bipolar disorder. The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness. Moreover, increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent, a possibility warranting further study in longitudinal investigations.

3D mapping of ventricular and corpus callosum abnormalities in HIV/AIDS

OBJECTIVE 40 million people worldwide are now infected with HIV/AIDS, an illness that often leads to rapidly progressing dementia and death. Even so, little is known about how AIDS affects the brain. Using computational anatomy techniques, we mapped how AIDS impacts the corpus callosum (CC) and ventricular system, two systems that show prominent changes on MRI. We (1) identified regions with greatest differences between AIDS patients and healthy controls and (2) correlated specific 3D patterns of structural differences with measures of immune system deterioration and cognitive decline. METHODS 51 3D brain MRI scans from 30 non-demented AIDS patients (age: 43.4 years +/- 7.6 SD) and 21 HIV-seronegative controls (age: 39.5 years +/- 12.2) were aligned to ICBM standard space. 3D surface mesh reconstructions of the lateral ventricles and CC were spatially averaged and compared across diagnostic groups. Structural alterations were correlated with viral load, T cell counts, and cognitive impairment. RESULTS Statistical maps revealed the 3D profile of ventricular expansion and callosal thinning in AIDS. Specific 3D ventricular changes were linked with immune system decline (CD4+ T cell counts; P < 0.001) and cognitive impairment (P < 0.009), but not viral load. Frontal horn maps distinguished AIDS patients from controls better than occipital and temporal horn measures. T cell decline linked with callosal thinning in anterior regions connecting frontal areas with greatest cortical atrophy. CONCLUSION These maps (1) reveal how brain changes in HIV/AIDS relate to immune decline and impaired cognition, and, after further validation and testing, (2) may offer possible neuroimaging markers for anti-viral drug trials, which gauge how well treatments oppose disease progression in the brain.