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Adolf Pfefferbaum

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23 papers

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YNICL Journal 2024 Journal Article

Aging, HIV infection, and alcohol exert synergist effects on regional thalamic volumes resulting in functional impairment

Adolf Pfefferbaum
Natalie M. Zahr
Stephanie A. Sassoon
Rosemary Fama
Manojkumar Saranathan
Kilian M. Pohl
Edith V. Sullivan

OBJECTIVE: Pharmacologically-treated people living with HIV infection have near-normal life spans with more than 50 % living into at-risk age for dementia and a disproportionate number relative to uninfected people engaging in unhealthy drinking. Accelerated aging in HIV occurs in some brain structures including the multinucleated thalamus. Unknown is whether aging with HIV affects thalamic nuclei and associated functions differentially and whether the common comorbidity of alcohol use disorder (AUD) + HIV accelerates aging. METHODS: This mixed cross-sectional/longitudinal design examined 216 control, 69 HIV, and 74 HIV + AUD participants, age 25-75 years old at initial visit, examined 1-8 times. MRI thalamic volumetry, parcellated using THalamus Optimized Multi-Atlas Segmentation (THOMAS), identified 10 nuclei grouped into 4 functional regions for correlation with age and measures of neuropsychological, clinical, and hematological status. RESULTS: Aging in the control group was best modeled with quadratic functions in the Anterior and Ventral regions and with linear functions in the Medial and Posterior regions. Relative to controls, age-related decline was even steeper in the Anterior and Ventral regions of the HIV group and in the Anterior region of the comorbid group. Anterior volumes of each HIV group declined significantly faster after age 50 (HIV = -2.4 %/year; HIV + AUD = -2.8 %/year) than that of controls (-1.8 %/year). Anterior and Ventral volumes were significantly smaller in the HIV + AUD than HIV-only group when controlling for infection factors. Although compared with controls HIV + AUD declined faster than HIV alone, the two HIV groups did not differ significantly from each other in aging rates. Declining Attention/Working Memory and Motor Skills performance correlated with Anterior and Posterior volume declines in the HIV + AUD group. CONCLUSIONS: Regional thalamic volumetry detected normal aging declines, differential and accelerated volume losses in HIV, relations between age-related nuclear and performance declines, and exacerbation of volume declines in comorbid AUD contributing to functional deficits.

JBHI Journal 2021 Journal Article

Longitudinal Pooling & Consistency Regularization to Model Disease Progression From MRIs

Jiahong Ouyang
Qingyu Zhao
Edith V. Sullivan
Adolf Pfefferbaum
Susan F. Tapert
Ehsan Adeli
Kilian M. Pohl

Many neurological diseases are characterized by gradual deterioration of brain structure andfunction. Large longitudinal MRI datasets have revealed such deterioration, in part, by applying machine and deep learning to predict diagnosis. A popular approach is to apply Convolutional Neural Networks (CNN) to extract informative features from each visit of the longitudinal MRI and then use those features to classify each visit via Recurrent Neural Networks (RNNs). Such modeling neglects the progressive nature of the disease, which may result in clinically implausible classifications across visits. To avoid this issue, we propose to combine features across visits by coupling feature extraction with a novel longitudinal pooling layer and enforce consistency of the classification across visits in line with disease progression. We evaluate the proposed method on the longitudinal structural MRIs from three neuroimaging datasets: Alzheimer's Disease Neuroimaging Initiative (ADNI, $N=404$ ), a dataset composed of 274 normal controls and 329 patients with Alcohol Use Disorder (AUD), and 255 youths from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). In allthree experiments our method is superior to other widely used approaches for longitudinal classification thus making a unique contribution towards more accurate tracking of the impact of conditions on the brain. The code is available at https://github.com/ouyangjiahong/longitudinal-pooling.

YNIMG Journal 2020 Journal Article

Deep learning identifies morphological determinants of sex differences in the pre-adolescent brain

Ehsan Adeli
Qingyu Zhao
Natalie M. Zahr
Aimee Goldstone
Adolf Pfefferbaum
Edith V. Sullivan
Kilian M. Pohl

The application of data-driven deep learning to identify sex differences in developing brain structures of pre-adolescents has heretofore not been accomplished. Here, the approach identifies sex differences by analyzing the minimally processed MRIs of the first 8144 participants (age 9 and 10 years) recruited by the Adolescent Brain Cognitive Development (ABCD) study. The identified pattern accounted for confounding factors (i. e. , head size, age, puberty development, socioeconomic status) and comprised cerebellar (corpus medullare, lobules III, IV/V, and VI) and subcortical (pallidum, amygdala, hippocampus, parahippocampus, insula, putamen) structures. While these have been individually linked to expressing sex differences, a novel discovery was that their grouping accurately predicted the sex in individual pre-adolescents. Another novelty was relating differences specific to the cerebellum to pubertal development. Finally, we found that reducing the pattern to a single score not only accurately predicted sex but also correlated with cognitive behavior linked to working memory. The predictive power of this score and the constellation of identified brain structures provide evidence for sex differences in pre-adolescent neurodevelopment and may augment understanding of sex-specific vulnerability or resilience to psychiatric disorders and presage sex-linked learning disabilities.

YNICL Journal 2019 Journal Article

Convergence of three parcellation approaches demonstrating cerebellar lobule volume deficits in Alcohol Use Disorder

Edith V. Sullivan
Natalie M. Zahr
Manojkumar Saranathan
Kilian M. Pohl
Adolf Pfefferbaum

Recent advances in robust and reliable methods of MRI-derived cerebellar lobule parcellation volumetry present the opportunity to assess effects of Alcohol Use Disorder (AUD) on selective cerebellar lobules and relations with indices of nutrition and motor functions. In pursuit of this opportunity, we analyzed high-resolution MRI data acquired in 24 individuals with AUD and 20 age- and sex-matched controls with a 32-channel head coil using three different atlases: the online automated analysis pipeline volBrain Ceres, SUIT, and the Johns Hopkins atlas. Participants had also completed gait and balance examination and hematological analysis of nutritional and liver status, enabling testing of functional meaningfulness of each cerebellar parcellation scheme. Compared with controls, each quantification approach yielded similar patterns of group differences in regional volumes: All three approaches identified AUD-related deficits in total tissue and total gray matter, but only Ceres identified a total white matter volume deficit. Convergent volume differences occurred in lobules I-V, Crus I, VIIIB, and IX. Coefficients of variation (CVs) were <20% for 46 of 56 regions measured and in general were graded: Ceres<SUIT<Hopkins. The most robust correlations were identified between poorer stability in balancing on one leg and smaller lobule VI and Crus I volumes from the Ceres atlas. Lower values of two essential vitamins-thiamine (vitamin B1) and serum folate (vitamin B9)-along with lower red blood cell count, which are dependent on adequate levels of B vitamins, correlated with smaller gray matter volumes of lobule VI and Crus I. Higher γ-glutamyl transferase (GGT) levels, possibly reflecting compromised liver function, correlated with smaller volumes of lobules VI and X. These initial results based on high resolution data produced with clinically practical imaging procedures hold promise for expanding our knowledge about the relevance of focal cerebellar morphology in AUD and other neuropsychiatric conditions.

YNICL Journal 2019 Journal Article

Hippocampal subfield CA2+3 exhibits accelerated aging in Alcohol Use Disorder: A preliminary study

Natalie M. Zahr
Kilian M. Pohl
Manojkumar Saranathan
Edith V. Sullivan
Adolf Pfefferbaum

The profile of brain structural dysmorphology of individuals with Alcohol Use Disorders (AUD) involves disruption of the limbic system. In vivo imaging studies report hippocampal volume loss in AUD relative to controls, but only recently has it been possible to articulate different regions of this complex structure. Volumetric analysis of hippocampal regions rather than total hippocampal volume may augment differentiation of disease processes. For example, damage to hippocampal subfield cornu ammonis 1 (CA1) is often reported in Alzheimer's disease (AD), whereas deficits in CA4/dentate gyrus are described in response to stress and trauma. Two previous studies explored the effects of chronic alcohol use on hippocampal subfields: one reported smaller volume of the CA2+3 in alcohol-dependent subjects relative to controls, associated with years of alcohol consumption; the other, smaller volumes of presubiculum, subiculum, and fimbria in alcohol-dependent relative to control men. The current study, conducted in 24 adults with DSM5-diagnosed AUD (7 women, 53.7 ± 8.8) and 20 controls (7 women, 54.1 ± 9.3), is the first to use FreeSurfer 6.0, which provides state-of-the art hippocampal parcellation, to explore the sensitivity of hippocampal sufields to alcoholism. T1- and T2- images were collected on a GE MR750 system with a 32-channel Nova head coil. FreeSurfer 6.0 hippocampal subfield analysis produced 12 subfields: parasubiculum; presubiculum; subiculum; CA1; CA2+3; CA4; GC-ML-DG (Granule Cell (GC) and Molecular Layer (ML) of the Dentate Gyrus (DG)); molecular layer; hippocampus-amygdala-transition-area (HATA); fimbria; hippocampal tail; hippocampal fissure; and whole volume for left and right hippocampi. A comprehensive battery of neuropsychological tests comprising attention, memory and learning, visuospatial abilities, and executive functions was administered. Multiple regression analyses of raw volumetric data for each subfields by group, age, sex, hemisphere, and supratentorial volume (svol) showed significant effects of svol (p < .04) on nearly all structures (excluding tail and fissure). Volumes corrected for svol showed effects of age (fimbria, fissure) and group (subiculum, CA1, CA4, GC-ML-DG, HATA, fimbria); CA2+3 showed a diagnosis-by-age interaction indicating older AUD individuals had a smaller volume than would be expected for their age. There were no selective relations between hippocampal subfields and performance on neuropsychological tests, likely due to lack of statistical power. The current results concur with the previous study identifying CA2+3 as sensitive to alcoholism, extend them by identifying an alcoholism-age interaction, and suggest an imaging phenotype distinguishing AUD from AD and stress/trauma.

YNIMG Journal 2019 Journal Article

Image processing and analysis methods for the Adolescent Brain Cognitive Development Study

Donald J. Hagler
SeanN. Hatton
M. Daniela Cornejo
Carolina Makowski
Damien A. Fair
Anthony Steven Dick
Matthew T. Sutherland
B.J. Casey

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.

YNIMG Journal 2018 Journal Article

Chained regularization for identifying brain patterns specific to HIV infection

Ehsan Adeli
Dongjin Kwon
Qingyu Zhao
Adolf Pfefferbaum
Natalie M. Zahr
Edith V. Sullivan
Kilian M. Pohl

Human Immunodeficiency Virus (HIV) infection continues to have major adverse public health and clinical consequences despite the effectiveness of combination Antiretroviral Therapy (cART) in reducing HIV viral load and improving immune function. As successfully treated individuals with HIV infection age, their cognition declines faster than reported for normal aging. This phenomenon underlines the importance of improving long-term care, which requires a better understanding of the impact of HIV on the brain. In this paper, automated identification of patients and brain regions affected by HIV infection are modeled as a classification problem, whose solution is determined in two steps within our proposed Chained-Regularization framework. The first step focuses on selecting the HIV pattern (i. e. , the most informative constellation of brain region measurements for distinguishing HIV infected subjects from healthy controls) by constraining the search for the optimal parameter setting of the classifier via group sparsity ( ℓ 2, 1 -norm). The second step improves classification accuracy by constraining the parameterization with respect to the selected measurements and the Euclidean regularization ( ℓ 2 -norm). When applied to the cortical and subcortical structural Magnetic Resonance Images (MRI) measurements of 65 controls and 65 HIV infected individuals, this approach is more accurate in distinguishing the two cohorts than more common models. Finally, the brain regions of the identified HIV pattern concur with the HIV literature that uses traditional group analysis models.

YNIMG Journal 2016 Journal Article

Harmonizing DTI measurements across scanners to examine the development of white matter microstructure in 803 adolescents of the NCANDA study

Kilian M. Pohl
Edith V. Sullivan
Torsten Rohlfing
Weiwei Chu
Dongjin Kwon
B. Nolan Nichols
Yong Zhang
Sandra A. Brown

Neurodevelopment continues through adolescence, with notable maturation of white matter tracts comprising regional fiber systems progressing at different rates. To identify factors that could contribute to regional differences in white matter microstructure development, large samples of youth spanning adolescence to young adulthood are essential to parse these factors. Recruitment of adequate samples generally relies on multi-site consortia but comes with the challenge of merging data acquired on different platforms. In the current study, diffusion tensor imaging (DTI) data were acquired on GE and Siemens systems through the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a multi-site study designed to track the trajectories of regional brain development during a time of high risk for initiating alcohol consumption. This cross-sectional analysis reports baseline Tract-Based Spatial Statistic (TBSS) of regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), and radial diffusivity (LT) from the five consortium sites on 671 adolescents who met no/low alcohol or drug consumption criteria and 132 adolescents with a history of exceeding consumption criteria. Harmonization of DTI metrics across manufacturers entailed the use of human-phantom data, acquired multiple times on each of three non-NCANDA participants at each site's MR system, to determine a manufacturer-specific correction factor. Application of the correction factor derived from human phantom data measured on MR systems from different manufacturers reduced the standard deviation of the DTI metrics for FA by almost a half, enabling harmonization of data that would have otherwise carried systematic error. Permutation testing supported the hypothesis of higher FA and lower diffusivity measures in older adolescents and indicated that, overall, the FA, MD, and L1 of the boys were higher than those of the girls, suggesting continued microstructural development notable in the boys. The contribution of demographic and clinical differences to DTI metrics was assessed with General Additive Models (GAM) testing for age, sex, and ethnicity differences in regional skeleton mean values. The results supported the primary study hypothesis that FA skeleton mean values in the no/low-drinking group were highest at different ages. When differences in intracranial volume were covaried, FA skeleton mean reached a maximum at younger ages in girls than boys and varied in magnitude with ethnicity. Our results, however, did not support the hypothesis that youth who exceeded exposure criteria would have lower FA or higher diffusivity measures than the no/low-drinking group; detecting the effects of excessive alcohol consumption during adolescence on DTI metrics may require longitudinal study.

YNIMG Journal 2013 Journal Article

Fiber tract-driven topographical mapping (FTTM) reveals microstructural relevance for interhemispheric visuomotor function in the aging brain

Tilman Schulte
Mahnaz Maddah
Eva M. Müller-Oehring
Torsten Rohlfing
Adolf Pfefferbaum
Edith V. Sullivan

We present a novel approach – DTI-based fiber tract-driven topographical mapping (FTTM) – to map and measure the influence of age on the integrity of interhemispheric fibers and challenge their selective functions with measures of interhemispheric integration of lateralized information. This approach enabled identification of spatially specific topographical maps of scalar diffusion measures and their relation to measures of visuomotor performance. Relative to younger adults, older adults showed lower fiber integrity indices in anterior than posterior callosal fibers. FTTM analysis identified a dissociation in the microstructural–function associates between age groups: in younger adults, genu fiber integrity correlated with interhemispheric transfer time, whereas in older adults, body fiber integrity was correlated with interhemispheric transfer time with topographical specificity along left-lateralized callosal fiber trajectories. Neural co-activation from redundant targets was evidenced by fMRI-derived bilateral extrastriate cortex activation in both groups, and a group difference emerged for a pontine activation cluster that was differently modulated by response hand in older than younger adults. Bilateral processing advantages in older but not younger adults further correlated with fiber integrity in transverse pontine fibers that branch into the right cerebellar cortex, thereby supporting a role for the pons in interhemispheric facilitation. In conclusion, in the face of compromised anterior callosal fibers, older adults appear to use alternative pathways to accomplish visuomotor interhemispheric information transfer and integration for lateralized processing. This shift from youthful associations may indicate recruitment of compensatory mechanisms involving medial corpus callosum fibers and subcortical pathways.

YNIMG Journal 2013 Journal Article

Variation in longitudinal trajectories of regional brain volumes of healthy men and women (ages 10 to 85years) measured with atlas-based parcellation of MRI

Adolf Pfefferbaum
Torsten Rohlfing
Margaret J. Rosenbloom
Weiwei Chu
Ian M. Colrain
Edith V. Sullivan

Numerous cross-sectional MRI studies have characterized age-related differences in regional brain volumes that differ with structure and tissue type. The extent to which cross-sectional assumptions about change are accurate depictions of actual longitudinal measurement remains controversial. Even longitudinal studies can be limited by the age range of participants, sex distribution of the samples, and scan intervals. To address these issues, we calculated trajectories of regional brain volume changes from T1-weighted (SPGR) MRI data, quantified with our automated, unsupervised SRI24 atlas-based registration and parcellation method. Longitudinal MRIs were acquired at 3T in 17 boys and 12 girls, age 10 to 14years, and 41 men and 41 women, age 20 to 85years at first scan. Application of a regression-based correction function permitted merging of data acquired at 3T field strength with data acquired at 1. 5T from additional subjects, thereby expanding the sample to a total of 55 men and 67 women, age 20 to 85years at first scan. Adjustment for individual supratentorial volume removed regional volume differences between men and women due to sex-related differences in head size. Individual trajectories were computed from data collected on 2 to 6 MRIs at a single field strength over a ~1 to 8year interval. Using linear mixed-effects models, the pattern of trajectories over age indicated: rises in ventricular and Sylvian fissure volumes, with older individuals showing faster increases than younger ones; declines in selective cortical volumes with faster tissue shrinkage in older than younger individuals; little effect of aging on volume of the corpus callosum; more rapid expansion of CSF-filled spaces in men than women after age 60years; and evidence for continued growth in central white matter through early adulthood with accelerated decline in senescence greater in men than women.

YNIMG Journal 2012 Journal Article

Combining atlas-based parcellation of regional brain data acquired across scanners at 1.5T and 3.0T field strengths

Adolf Pfefferbaum
Torsten Rohlfing
Margaret J. Rosenbloom
Edith V. Sullivan

Longitudinal brain morphometric studies designed for data acquisition at a single MRI field strength can be seriously limited by system replacements from lower to higher field strength. Merging data across field strengths has not been endorsed for a variety of reasons, yet the ability to combine such data would broaden longitudinal investigations. To determine whether structural T1-weighted MRI data acquired across MR field strengths could be merged, parcellations of archival SPGR data acquired in 114 individuals at 1. 5T and at 3. 0T within 3weeks of each other were compared. The first set of analyses examined 1) the correspondence between regional tissue volumes derived from data collected at 1. 5T and 3. 0T and 2) whether there were systematic differences for which a correction factor could be determined and applied to improve measurement agreement. Comparability of regional volume determination at 1. 5T and 3. 0T was assessed with intraclass correlation (ICC) computed on volumes derived from the automated and unsupervised SRI24 atlas registration and parcellation method. A second set of analyses measured the reliability of the registration and quantification using the same approach on longitudinal data acquired in 69 healthy adults at a single field strength, 1. 5T, at an interval <2years. The mainstay of the analyses was based on the SRI24 method; to examine the potential of merging data across field strengths and across image analysis packages, a secondary set of analyses used FreeSurfer instead of the SRI24 method. For both methods, a regression-based linear correction function significantly improved correspondence. The results indicated high correspondence between most selected cortical, subcortical, and CSF-filled spaces; correspondence was lowest in the globus pallidus, a region rich in iron, which in turn has a considerable field-dependent effect on signal intensity. Thus, the application of a regression-based correction function that improved the correspondence in regional volume estimations argues well for the proposition that selected T1-weighted regional anatomical brain data can be reliably combined across 1. 5T and 3. 0T field strengths with the application of an appropriate correction procedure.

YNIMG Journal 2012 Journal Article

MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping

Berkin Bilgic
Adolf Pfefferbaum
Torsten Rohlfing
Edith V. Sullivan
Elfar Adalsteinsson

Quantifying tissue iron concentration in vivo is instrumental for understanding the role of iron in physiology and in neurological diseases associated with abnormal iron distribution. Herein, we use recently-developed Quantitative Susceptibility Mapping (QSM) methodology to estimate the tissue magnetic susceptibility based on MRI signal phase. To investigate the effect of different regularization choices, we implement and compare ℓ1 and ℓ2 norm regularized QSM algorithms. These regularized approaches solve for the underlying magnetic susceptibility distribution, a sensitive measure of the tissue iron concentration, that gives rise to the observed signal phase. Regularized QSM methodology also involves a pre-processing step that removes, by dipole fitting, unwanted background phase effects due to bulk susceptibility variations between air and tissue and requires data acquisition only at a single field strength. For validation, performances of the two QSM methods were measured against published estimates of regional brain iron from postmortem and in vivo data. The in vivo comparison was based on data previously acquired using Field-Dependent Relaxation Rate Increase (FDRI), an estimate of MRI relaxivity enhancement due to increased main magnetic field strength, requiring data acquired at two different field strengths. The QSM analysis was based on susceptibility-weighted images acquired at 1. 5T, whereas FDRI analysis used Multi-Shot Echo-Planar Spin Echo images collected at 1. 5T and 3. 0T. Both datasets were collected in the same healthy young and elderly adults. The in vivo estimates of regional iron concentration comported well with published postmortem measurements; both QSM approaches yielded the same rank ordering of iron concentration by brain structure, with the lowest in white matter and the highest in globus pallidus. Further validation was provided by comparison of the in vivo measurements, ℓ1-regularized QSM versus FDRI and ℓ2-regularized QSM versus FDRI, which again yielded perfect rank ordering of iron by brain structure. The final means of validation was to assess how well each in vivo method detected known age-related differences in regional iron concentrations measured in the same young and elderly healthy adults. Both QSM methods and FDRI were consistent in identifying higher iron concentrations in striatal and brain stem ROIs (i. e. , caudate nucleus, putamen, globus pallidus, red nucleus, and substantia nigra) in the older than in the young group. The two QSM methods appeared more sensitive in detecting age differences in brain stem structures as they revealed differences of much higher statistical significance between the young and elderly groups than did FDRI. However, QSM values are influenced by factors such as the myelin content, whereas FDRI is a more specific indicator of iron content. Hence, FDRI demonstrated higher specificity to iron yet yielded noisier data despite longer scan times and lower spatial resolution than QSM. The robustness, practicality, and demonstrated ability of predicting the change in iron deposition in adult aging suggest that regularized QSM algorithms using single-field-strength data are possible alternatives to tissue iron estimation requiring two field strengths.

YNIMG Journal 2011 Journal Article

Developmental change in regional brain structure over 7 months in early adolescence: Comparison of approaches for longitudinal atlas-based parcellation

Edith V. Sullivan
Adolf Pfefferbaum
Torsten Rohlfing
Fiona C. Baker
Mayra L. Padilla
Ian M. Colrain

Early adolescence is a time of rapid change in neuroanatomy and sexual development. Precision in tracking changes in brain morphology with structural MRI requires image segmentation with minimal error. Here, we compared two approaches to achieve segmentation by image registration with an atlas to quantify regional brain structural development over a 7-month interval in normal, early adolescent boys and girls. Adolescents were scanned twice (average interval=7. 3months), yielding adequate data for analysis in 16 boys (baseline age 10. 9 to 13. 9years; Tanner Stage=1 to 4) and 12 girls (baseline age=11. 2 to 13. 7years; Tanner Stage=3 to 4). Brain volumes were derived from T1-weighted (SPGR) images and dual-echo Fast Spin-Echo (FSE) images collected on a GE 3T scanner with an 8-channel phased-array head coil and analyzed by registration-based parcellation using the SRI24 atlas. The “independent” method required two inter-subject registrations: both baseline (MRI 1) to atlas and follow-up (MRI 2) to the atlas. The “sequential” method required one inter-subject registration, which was MRI 1 to the atlas, and one intra-subject registration, which was MRI 2 to MRI 1. Gray matter/white matter/CSF were segmented in both MRI-1 and MRI-2 using FSL FAST with tissue priors also based on the SRI24 atlas. Gray matter volumes were derived for 10 cortical regions, gray+white matter volumes for 5 subcortical structures, and CSF volumes for 4 ventricular regions and the cortical sulci. Across the 15 tissue regions, the coefficient of variation (CV) of change scores across individuals was significantly lower for the sequential method (CV=3. 02), requiring only one inter-subject registration, than for the independent method (CV=9. 43), requiring two inter-subject registrations. Volume change based on the sequential method revealed that total supratentorial and CSF volumes increased, while cortical gray matter volumes declined significantly (p <0. 01) in anterior (lateral and medial frontal, anterior cingulate, precuneus, and parietal) but not posterior (occipital, calcarine) cortical regions. These volume changes occurred in all boys and girls who advanced a step in Tanner staging. Subcortical structures did not show consistent changes. Thus, longitudinal MRI assessment using robust registration methods is sufficiently sensitive to identify significant regional brain changes over a 7-month interval in boys and girls in early adolescence. Increasing the temporal resolution of the retest interval in longitudinal developmental studies could increase accuracy in timing of peak growth of regional brain tissue and refine our understanding of the neural mechanisms underlying the dynamic changes in brain structure throughout adolescence.

YNIMG Journal 2009 Journal Article

Double dissociation between action-driven and perception-driven conflict resolution invoking anterior versus posterior brain systems

Tilman Schulte
Eva M. Müller-Oehring
Shara Vinco
Fumiko Hoeft
Adolf Pfefferbaum
Edith V. Sullivan

The ability to select and integrate relevant information in the presence of competing irrelevant information can be enhanced by advance information to direct attention and guide response selection. Attentional preparation can reduce perceptual and response conflict, yet little is known about the neural source of conflict resolution, whether it is resolved by modulating neural responses for perceptual selection to emphasize task-relevant information or for action selection to inhibit pre-potent responses to interfering information. We manipulated perceptual information that either matched or did not match the relevant color feature of an upcoming Stroop stimulus and recorded hemodynamic brain responses to these events. Longer reaction times to incongruent than congruent color–word Stroop stimuli indicated conflict; however, conflict was even greater when a color cue correctly predicted the Stroop target's color (match) than when it did not (nonmatch). A predominantly anterior network was activated for Stroop-match and a predominantly posterior network was activated for Stroop-nonmatch. Thus, when a stimulus feature did not match the expected feature, a perceptually-driven posterior attention system was engaged, whereas when interfering, automatically-processed semantic information required inhibition of pre-potent responses, an action-driven anterior control system was engaged. These findings show a double dissociation of anterior and posterior cortical systems engaging in different types of control for perceptually-driven and action-driven conflict resolution.

YNIMG Journal 2009 Journal Article

MRI estimates of brain iron concentration in normal aging: Comparison of field-dependent (FDRI) and phase (SWI) methods

Adolf Pfefferbaum
Elfar Adalsteinsson
Torsten Rohlfing
Edith V. Sullivan

Different brain structures accumulate iron at different rates throughout the adult life span. Typically, striatal and brain stem structures are higher in iron concentrations in older than younger adults, whereas cortical white matter and thalamus have lower concentrations in the elderly than young adults. Brain iron can be measured in vivo with MRI by estimating the relaxivity increase across magnetic field strengths, which yields the Field-Dependent Relaxation Rate Increase (FDRI) metric. The influence of local iron deposition on susceptibility, manifests as MR phase effects, forms the basis for another approach for iron measurement, Susceptibility-Weighted Imaging (SWI), for which imaging at only one field strength is sufficient. Here, we compared the ability of these two methods to detect and quantify brain iron in 11 young (5 men, 6 women; 21 to 29 years) and 12 elderly (6 men, 6 women; 64 to 86 years) healthy adults. FDRI was acquired at 1. 5 T and 3. 0 T, and SWI was acquired at 1. 5 T. The results showed that both methods detected high globus pallidus iron concentration regardless of age and significantly greater iron in putamen with advancing age. The SWI measures were more sensitive when the phase signal intensities themselves were used to define regions of interest, whereas FDRI measures were robust to the method of region of interest selection. Further, FDRI measures were more highly correlated than SWI iron estimates with published postmortem values and were more sensitive than SWI to iron concentration differences across basal ganglia structures. Whereas FDRI requires more imaging time than SWI, two field strengths, and across-study image registration for iron concentration calculation, FDRI appears more specific to age-dependent accumulation of non-heme brain iron than SWI, which is affected by heme iron and non-iron source effects on phase.

YNIMG Journal 2009 Journal Article

Problem solving, working memory, and motor correlates of association and commissural fiber bundles in normal aging: A quantitative fiber tracking study

Natalie M. Zahr
Torsten Rohlfing
Adolf Pfefferbaum
Edith V. Sullivan

Normal aging is accompanied by decline in selective cognitive and motor functions. A concurrent decline in regional white matter integrity, detectable with diffusion tensor imaging (DTI), potentially contributes to waning function. DTI analysis of white matter loci indicates an anterior-to-posterior gradient distribution of declining fractional anisotropy (FA) and increasing diffusivity with age. Quantitative fiber tracking can be used to determine regional patterns of normal aging of fiber systems and test the functional ramifications of the DTI metrics. Here, we used quantitative fiber tracking to examine age effects on commissural (genu and splenium), bilateral association (cingulate, inferior longitudinal fasciculus and uncinate), and fornix fibers in 12 young and 12 elderly healthy men and women and tested functional correlates with concurrent assessment of a wide range of neuropsychological abilities. Principal component analysis of cognitive and motor tests on which the elderly achieved significantly lower scores than the young group was used for data reduction and yielded three factors: Problem Solving, Working Memory, and Motor. Age effects – lower FA or higher diffusivity – in the elderly were prominent in anterior tracts, specifically, genu, fornix, and uncinate fibers. Differential correlations between FA or diffusivity in fiber tracts and scores on Problem Solving, Working Memory, or Motor factors provide convergent validity to the biological meaningfulness of the integrity of the fibers tracked. The observed pattern of relations supports the possibility that regional degradation of white matter fiber integrity is a biological source of age-related functional compromise and may have the potential to limit accessibility to alternative neural systems to compensate for compromised function.

YNIMG Journal 2007 Journal Article

In vivo fiber tracking in the rat brain on a clinical 3T MRI system using a high strength insert gradient coil

Dirk Mayer
Natalie M. Zahr
Elfar Adalsteinsson
Brian Rutt
Edith V. Sullivan
Adolf Pfefferbaum

In vivo neuroimaging methods permit longitudinal quantitative examination of the dynamic course of neurodegenerative conditions in humans and animal models and enable assessment of therapeutic efforts in mitigating disease effects on brain systems. The study of conditions affecting white matter, such as multiple sclerosis, demyelinating conditions, and drug and alcohol dependence, can be accomplished with diffusion tensor imaging (DTI), a technique uniquely capable of probing the microstructural integrity of white matter fibers in the living brain. We used a 3T clinical MR scanner equipped with an insert gradient coil that yields an order of magnitude increase in performance over the whole-body hardware to acquire in vivo DTI images of rat brain. The resolution allowed for fiber tracking evaluation of fractional anisotropy (FA) and apparent diffusion coefficients in the genu and splenium of the corpus callosum. A comparison of short (46 min) and long (92 min) acquisition time DTI protocols indicated low but adequate signal-to-noise ratio (SNR=6. 2) of the shorter protocol to conduct quantitative fiber tracking enhanced by multiple acquisitions. As observed in human studies, FA in the rat splenium was higher than in the genu. Advantages of this technology include the use of similar user interface, pulse sequences, and field strength for preclinical animal and clinical human research, enhancing translational capabilities. An additional benefit of scanning at lower field strength, such as 3 T, is the reduction of artifacts due to main field inhomogeneity relative to higher field animal systems.

YNIMG Journal 2006 Journal Article

Contribution of alcoholism to brain dysmorphology in HIV infection: Effects on the ventricles and corpus callosum

Adolf Pfefferbaum
Margaret J. Rosenbloom
Torsten Rohlfing
Elfar Adalsteinsson
Carol A. Kemper
Stanley Deresinski
Edith V. Sullivan

Nonrigid registration and atlas-based parcellation methods were used to compare the volume of the ventricular system and the cross-sectional area of the midsagittal corpus callosum on brain MRIs from 272 subjects in four groups: patients with HIV infection, with and without alcoholism comorbidity, alcoholics, and controls. Prior to testing group differences in regional brain metrics, each measure was corrected by regression analysis for significant correlations with supratentorial cranial volume and age, observed in 121 normal control men and women, whose age spanned six decades. Disregarding HIV disease severity, we observed a graded pattern of modest enlargement of the total ventricular system (0. 28 SD for uncomplicated HIV, 0. 65 SD for HIV comorbid with alcoholism, and 0. 72 SD for the alcoholism group). The pattern of callosal thinning showed a similar but small (∼0. 5 SD) graded effect. A different pattern emerged, however, when HIV severity in the context of alcoholism comorbidity was factored into the analysis. Substantially greater volume abnormalities were present in individuals with a history of an AIDS-defining event or low CD4+ T cell counts (≤200 mm3) irrespective of alcoholism comorbidity, and the effect of HIV severity was disproportionately exacerbated by alcoholism comorbidity, with 1 SD size deficit in the genu of corpus callosum and nearly 2 SD greater volume of the frontal and body regions of the ventricles for the AIDS + alcohol comorbid group. The differences in brain volumes between the AIDS groups with vs. without alcoholism could not be attributed to differences in HIV disease severity, defined by CD4+ count, viral load, or Karnofsky score. The substantial effect of the alcoholism–AIDS interaction on ventricular and callosal dysmorphology, in the context of the modest changes observed in non-AIDS, nonalcohol abusing HIV-infected individuals, highlight the need to consider alcohol use disorders as a major risk factor for neuropathology among HIV-infected persons.

YNIMG Journal 2005 Journal Article

Frontal circuitry degradation marks healthy adult aging: Evidence from diffusion tensor imaging

Adolf Pfefferbaum
Elfar Adalsteinsson
Edith V. Sullivan

In vivo study of white matter microstructural integrity through magnetic resonance diffusion tensor imaging (DTI) permits examination of degradation of axonal circuitry that may underlie functional decline of frontally-based processes in normal adult aging. Determination of the pattern of age-related degradation of white matter microstructure requires quantitative comparison of the rostral–caudal and superior–inferior extents of the brain's white matter. To date, this has not been accomplished, probably because of significant artifacts from spatial distortion and poor signal resolution that precludes accurate analysis in prefrontal and inferior brain regions. Here, we report a profile analysis of the integrity of white matter microstructure across the supratentorium and in selected focal regions using DTI data collected at high-field strength (3 T), with isotropic voxel acquisition, and an analysis based on a concurrently-acquired field map to permit accurate quantification of artifact-prone, anterior and inferior brain regions. The groups comprised 10 younger and 10 older individuals; all were high functioning, highly educated, and in excellent health. The DTI profile analysis revealed a robust frontal distribution of low white matter anisotropy and high bulk mean diffusivity in healthy older compared with younger adults. In contrast to frontal fiber systems, posterior systems were largely preserved with age. A second analysis, based on focal samples of FA, confirmed that the age-related FA decline was restricted to frontal regions, leaving posterior and inferior brain regions relatively intact. The selective decline of anterior anisotropy with advancing age provides evidence for the potential of a microstructural white matter mechanism for the commonly observed decline in frontally-based functions.

YNIMG Journal 2004 Journal Article

Postmortem MR imaging of formalin-fixed human brain

Adolf Pfefferbaum
Edith V. Sullivan
Elfar Adalsteinsson
Therese Garrick
Clive Harper

High-resolution postmortem neuroimaging of the brain can play a role in research programs by providing archival and reslicable images of brain specimens before permanent sectioning. These images can supplement evidence attained from both traditional neuropathological observations and in vivo neuroimaging. Differential brain tissue conspicuity, detectable with MRI, is determined by the density and mobility of water protons. Water content is about 70% in white matter, 80% in gray matter, and 99% in cerebrospinal fluid (CSF). To the extent that brain tissue contrast is determined by the number and microenvironment of water protons, timing parameters of MR image acquisition can interrogate this environment. Because the chemical environment of protons is different in living from dead tissue, optimal temporal imaging parameters, for example, for spin-echo imaging, commonly used for in vivo clinical and research study are different from those best for postmortem imaging. Here, we present a series of observations to identify relaxation times and optimal parameters for high-resolution structural imaging of formalin-fixed postmortem brain tissue using commercially available clinical scanners and protocols. Examples of high-resolution images and results from attempts at diffusion imaging are presented.

YNIMG Journal 2003 Journal Article

Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study

John E Desmond
S.H.Annabel Chen
Eve DeRosa
Michelle R Pryor
Adolf Pfefferbaum
Edith V Sullivan

Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.

YNIMG Journal 2002 Journal Article

Microstructural but Not Macrostructural Disruption of White Matter in Women with Chronic Alcoholism

Adolf Pfefferbaum
Edith V. Sullivan

The results of in vivo neuroimaging studies assessing whether and where brain white matter damage occurs in alcoholic women is controversial. To address this controversy, we examined regional white matter macrostructure and microstructure, the latter of which may be more sensitive to the detection of subtle fiber disruption than gross measures of size. Accordingly, we used conventional magnetic resonance imaging (MRI) to quantify regional callosal size and diffusion tensor imaging (DTI) to examine intravoxel coherence (fractional anisotropy, FA) and intervoxel coherence (C) of white matter of the genu and splenium of the corpus callosum and of the centrum semiovale in 12 detoxified alcoholic women and 18 control women. Additional analyses examined sex differences in FA and C in alcoholic women compared with alcoholic men. Despite absence of group differences in regional areas of callosal macrostructure, the alcoholic women had lower FA and C in genu and centrum semiovale than the control group of women. These measures also correlated with total lifetime consumption of alcohol and performance on a test of visual search in the alcoholic women. Sex comparisons revealed similar extents of FA abnormality in the genu and centrum semiovale in alcoholic men and women and differential effects in other DTI measures, with abnormalities present in splenium FA and C in the men and abnormalities present in centrum C in the women. These results provide in vivo evidence for disruption of white matter microstructure in alcoholic women not necessarily detectable with coarser measures of white matter mass and perhaps antedating its appearance.

YNIMG Journal 2001 Journal Article

Reorganization of Frontal Systems Used by Alcoholics for Spatial Working Memory: An fMRI Study

Adolf Pfefferbaum
John E. Desmond
Christopher Galloway
Vinod Menon
Gary H. Glover
Edith V. Sullivan

Chronic alcoholism is associated with impairment in sustained attention and visual working memory. Thus, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks, assumed to be subserved by regions of prefrontal cortex. To identify neural substrates associated with this impairment, we used functional MRI (fMRI) to determine whether alcoholics invoke the same or different brain systems as controls when engaged in working memory tasks that the two groups were able to perform at equivalent levels. The fMRI spatial working memory paradigm instructed subjects to respond with a button press when a target position was either in the center of the field (match to center) or matched the spatial position of one presented two items previously (match 2-back) or to rest. Using whole-brain fMRI, alcoholics showed diminished activation frontal cortical systems compared to controls (bilateral dorsolateral prefrontal cortex) when responding 2-back vs rest. In the center vs rest contrast, the control group compared with the alcoholic group activated a large expanse of prefrontal cortex (including Brodmann areas 9, 10, and 45), whereas there was significantly greater activation by the alcoholic group relative to the control group localized more posteriorly and inferiorly in the frontal cortex (area 47). Examination of within group activation patterns revealed two different patterns of activation: the control group exhibited activation of the dorsal (“Where? ”) stream for visual spatial working memory processing, whereas the alcoholic group exhibited activation of the ventral (“What? ”) stream and declarative memory systems to accomplish the spatial working memory task. The differences in the pattern of brain activations exhibited by the alcoholic and control groups, despite equivalence in behavioral performance, is consistent with a functional reorganization of the brain systems invoked by alcoholic individuals or invocation of an inappropriate brain system when engaged in a visual spatial task requiring working memory.