Contributors: Megan Laurance, UCSF:CIND, UCSF
... Abstract This dataset contains a re-analysis of the raw microarray data originally published by Petrich AM et al in 2012 (citation details are provided through the link to the GEO record). We were interested in re-analyzing the data because the list of differentially expressed genes that were identified when comparing rapamycin resistant DLBCL cell lines to rapamycin sensitive cell lines was not included in the original article or supplemental materials. We were interested in validating and expanding upon the findings from the original article by reevaluating the raw microarray data. Our reanalysis identified over 200 genes that were significantly differentially expressed between rapamycin resistant and sensitive cells. Importantly, our analysis highlighted a gene that was highly upregulated in rapamycin resistant cells, CD247, that was not the focus on the original publication, and is the target of a drug currently in clinical trials for refractory DLBCL. Our reanalysis also highlighted the role of SYK, a kinase upregulated in rapamycin resistant cell lines, that has a direct molecular relationship with CD247, and is a potential biomarker of drug response in DLBCL. Methods The methods used to generate the original microarray data are described in the GEO record where the data were originally published: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE27255 We downloaded the raw Affymetrix data (CEL files) from GEO for renalysis. Statistical and quality analysis was performed using the data analysis pipeline in iReport (http://www.ingenuity.com/products/ireport) which utilizes packages such as RMA and Limma from Bioconductor, in the R programming language. A full description of the analysis packages used by this pipeline are included in the word document "GSE27255 stats and QC details" included in this DataShare record. Analysis of microarray data in iReport identified 229 differentially expressed genes (DEGs) with a p-value 1.5. These DEGs were then uploaded and analyzed in Ingenuity Pathway Analysis (www.ingenuity.com) for functional enrichment, pathway analysis, and drug target/biomarker analysis. Our novel findings with respect to the role of CD247 and SYK in rapamycin resistant DLBCL cell lines is depicted in the pathway image fine "Rap resist network with CD247" which is included in this DataShare record. SeriesInformation The original microarray data that was used for this reanalysis use case is described in the GEO record GSE27255. SeriesInformation http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE27255
Contributors: McDaniel, Patricia A, Malone, Ruth E, UCSF
... Abstract This dataset contains the transcripts of 15 focus groups conducted in California, New York state, and Ohio from 2009-2013 concerning retailers that had voluntarily discontinued tobacco sales. Transcripts are grouped by state: FG1-8 are the California groups, FG9-13 are the New York groups, and FG14-15 are the Ohio groups. Methods Focus groups with one moderator, and, in California, one note-taker who occasionally asked questions. All but one of the focus groups in California were conducted by the same person. All of the New York and Ohio focus groups were conducted by the same person. SeriesInformation McDaniel PA, Malone RE. Why California retailers stop selling tobacco products, and what their customers and employees think about it when they do: case studies. BMC Public Health. 2011 Nov 8;11(1):848. SeriesInformation McDaniel PA, Malone RE. “People over Profits”: Retailers Who Voluntarily Ended Tobacco Sales. PLoS ONE 2014 9(1): e85751.
Contributors: Greninger, Alexander, DeRisi, Joseph, UCSF
... Abstract This dataset corresponds to the data presented in "The complete genome of klassevirus – a novel picornavirus in pediatric stool" by Greninger et al (http://www.ncbi.nlm.nih.gov/pubmed/19538752). Methods 141 diarrhea samples were prepared, pooled, and pyrosequenced on the Roche Genome Sequence FLX as described in "The complete genome of klassevirus – a novel picornavirus in pediatric stool" by Greninger et al (http://www.ncbi.nlm.nih.gov/pubmed/19538752). A novel member of the Picornaviridae viral family, Human klassevirus 1, was discovered in the 540,412 unique reads with an average length of 240 nt. The reads were stripped of sequences mapping with 90% or greater identity to known diarrhea-causing viruses: 6,959 reads mapped to the Adenoviridae and Caliciviridae viral families by translated BLAST. Of the remaining 533,453 unique reads, 483 derived from Human klassevirus 1. The data are provided in FASTA format. SeriesInformation The complete genome of klassevirus a novel picornavirus in pediatric stool. Greninger AL, Runckel C, Chiu CY, Haggerty T, Parsonnet J, Ganem D, DeRisi JL. Virol J. 2009 Jun 18;6:82. doi: 10.1186/1743-422X-6-82. PMID: 19538752
Contributors: Gansky, Stuart, Early Childhood Caries Collaborating Centers, UCSF, National Institutes of Health, National Institutes of Health, National Institutes of Health, National Institutes of Health, National Institutes of Health
... Abstract OBJECTIVES: To summarize diagnostic criteria and examiner training and calibration of the National Institute of Dental and Craniofacial Research-funded Early Childhood Caries Collaborating Centers (EC4) and report examiner calibration results from 2010 to 2014. The EC4 at Boston University, University of Colorado, and University of California San Francisco are performing randomized controlled early childhood caries (ECC) prevention trials with caries as the main outcome measure. METHODS: The EC4 with University of Iowa consultants developed standardized tooth and tooth surface status examination criteria for use in field conditions, examiner training materials, and examiner calibration and re-calibration methodologies. Calibration and re-calibration were performed with 1- to 5-year-old children in the San Francisco Mission District in which assessments from each examiner to be calibrated were compared with those from a single gold standard examiner from 2010 to 2014. Cohen's kappa statistic was used to determine inter-examiner agreement. RESULTS: A total of seven examiners were successfully (re)calibrated during that period, examining a total of 231 children. Overall unweighted Cohen's kappas for 10 surface conditions exceeded the criterion of 0.70. However, separate agreement for assessment of noncavitated lesions, as in other studies, was lower. CONCLUSIONS: An experienced multidisciplinary and multi-institutional team was able to develop criteria and training materials to anticipate situations and field conditions the main trials would encounter. Examiners were successfully trained and (re)calibrated. Other Please cite NIH grant numbers in any publications using this dataset. Other Data were created with funding from National Institutes of Health under grant(s) U54DE019275. Other Data were created with funding from National Institutes of Health under grant(s) R21DE018650. Other Data were created with funding from National Institutes of Health under grant(s) U54DE014251. Other Data were created with funding from National Institutes of Health under grant(s) U54DE019259. Other Data were created with funding from National Institutes of Health under grant(s) U54DE019285.
Contributors: Dr. David Wang, UCSF
... Abstract Nucleic acid from two nematode species, C. elegans JU1580 (isolated from a rotting apple in Orsay, France) and C. briggsae JU1264 (isolated from a snail on a rotting grape in Santeuil, France) were prepared and pyrosequenced on the Roche Titanium Genome Sequencer. Raw sequence reads were filtered for quality and repetitive sequences as described in "Natural and experimental infection of Caenorhabditis nematodes by novel viruses related to nodaviruses" by F?©lix et al (http://www.ncbi.nlm.nih.gov/pubmed/21283608). Two novel members of the Nodaviridae viral family, Orsay nodavirus and Santeuil nodavirus, were discovered in the the 15933 and 20,787 reads, respectively. 1046 Orsay nodavirus reads were found in the C. elegans samples while 2492 Santeuil nodavirus reads were identified in in the C. briggsae sample. The data are provided in FASTA format. Methods This is a 454 dataset corresponding to the raw reads from Felix et al., 2011 SeriesInformation Félix M-A, Ashe A, Piffaretti J, Wu G, Nuez I, et al. (2011) Natural and Experimental Infection of Caenorhabditis Nematodes by Novel Viruses Related to Nodaviruses. PLoS Biol 9: e1000586. doi:10.1371/journal.pbio.1000586. PMC3026760
Contributors: Weiner, Michael W., Chui, Helena, UCSF Center for Imaging of Neurodegenerative Diseases
... Abstract The overall goal of this project was to determine the extent to which subcortical ischemia and infaraction, and Alzheimer's disease, contribute to dementia. This project aimed to provide a greater understanding of the pathogenesis of dementia in patients with SIVD and AD. Methods Data were acquired at several sites: ABS = Aging Brain San Francisco (SFVAMC), ABD = Aging Brain UC Davis, and ABL = Aging Brain Los Angeles (USC).
Contributors: Zhang, Yu, Schuff, Norbert, Du, An-Tao, Rosen, Howard J., Kramer, Joel H., Gorno-Tempini, Maria Luisa, Miller, Bruce L., Weiner, Michael W., Memory and Aging Center, UCSF Center for Imaging of Neurodegenerative Diseases
... Abstract Frontotemporal dementia (FTD) and Alzheimer's disease are sometimes difficult to differentiate clinically because of overlapping symptoms. Using diffusion tensor imaging (DTI) measurements of fractional anisotropy (FA) can be useful in distinguishing the different patterns of white matter degradation between the two dementias. In this study, we performed MRI scans in a 4 Tesla MRI machine including T1-weighted structural images and diffusion tensor images in 18 patients with FTD, 18 patients with Alzheimer's disease and 19 cognitively normal (CN) controls. FA was measured selectively in specific fibre tracts (including corpus callosum, cingulum, uncinate and corticospinal tracts) as well as globally in a voxel-by-voxel analysis. Patients with FTD were associated with reductions of FA in frontal and temporal regions including the anterior corpus callosum (P < 0.001), bilateral anterior (left P < 0.001; right P = 0.005), descending (left P < 0.001; right P = 0.003) cingulum tracts, and uncinate tracts (left P < 0.001; right P = 0.005), compared to controls. Patients with Alzheimer's disease were associated with reductions of FA in parietal, temporal and frontal regions including the left anterior (P = 0.003) and posterior (P = 0.002) cingulum tracts, bilateral descending cingulum tracts (P < 0.001) and left uncinate tracts (P < 0.001) compared to controls. When compared with Alzheimer's disease, FTD was associated with greater reductions of FA in frontal brain regions, whereas no region in Alzheimer's disease showed greater reductions of FA when compared to FTD. In conclusion, the regional patterns of anisotropy reduction in FTD and Alzheimer's disease compared to controls suggest a characteristic distribution of white matter degradation in each disease. Moreover, the white matter degradation seems to be more prominent in FTD than in Alzheimer's disease. Taken together, the results suggest that white matter degradation measured with DTI may improve the diagnostic differentiation between FTD and Alzheimer's disease. Methods The dataset available here consists of Fractional Anisotropy (FA) and Mean Diffusivity (MD) images in Analyze format. There are FA & MD images for 55 subjects (some subjects have two timepoints, as indicated by a -1 or -2 following subject ID in the filename, please disregard timepoint 2 at this time), and a spreadsheet describing each subject’s age (at time of scan), gender, diagnosis (Normal Control, Alzheimer’s Dissease, or Frontotemporal Dementia), ApoE alleles, and Mini-Mental State Exam score. Data Acquisition Location: San Francisco VA Medical Center; Scanner Type: Siemens Bruker 4T, equipped with a birdcage transmit and eight channel receive coil. DTI was based on a dual spin-echo echo-planar imaging (EPI) sequence supplemented with parallel imaging acceleration (GRAPPA) with a factor 2 to reduce susceptibility distortions. Other imaging parameters were: TR/TE = 6000/77 ms; field of view 256 × 224 cm; 128 × 112 matrix size, yielding 2 × 2 mm2 in-plane resolution; 40 continuous 3 mm slices. A reference image (no diffusion gradient b = 0) and six diffusion-weighted images (b = 800 s/mm2 along six non-collinear directions) were acquired. Four DTI scans were acquired and averaged after motion correction to boost signal-to-noise.
Associations between vascular risk factors, carotid atherosclerosis and cortical volume and thickness in older adults
Contributors: Cardenas, Valerie, Reed, Bruce, Chao, Linda, Chui, Helena, Sanossian, Nerses, DeCarli, Charles, Mack, Wendy, Kramer, Joel, Hodis, Howard, Yan, Mingzhu
... Abstract Data from healthy and cognitively impaired elderly, enriched for cerebrovascular disease. Background and Purpose: To investigate whether the Framingham Cardiovascular Risk Profile (FCRP) and carotid artery intima-media thickness (CIMT) are associated with cortical volume and thickness. Results: 152 subjects (82 men) were aged 78 (±7) years old, 94 had a CDR of 0, 58 had a clinical dementia rating (CDR) of 0.5 and the mean mini-mental status examination (MMSE) was 28 ±2. FCRP score was inversely associated with total gray matter (GM) volume, parietal and temporal GM volume (adjusted p<0.04). FCRP was inversely associated with parietal and total cerebral GM thickness (adjusted p<0.03). CIMT was inversely associated with thickness of parietal GM only (adjusted p=0.04). Including history of myocardial infarction or stroke and radiologic evidence of brain infarction, or apoE genotype did not alter relationships with FCRP or CIMT. Conclusions: Increased cardiovascular risk was associated with reduced GM volume and thickness in regions also affected by Alzheimer's disease (AD), independent of infarcts and apoE genotype. These results suggest a "double hit" toward developing dementia when someone with incipient AD also has high cardiovascular risk. Subjects: Consecutive subjects were identified from an ongoing, longitudinal, multi-institutional Aging Brain program project that recruits subjects with normal cognition to mild cognitive impairment, representing a spectrum of low to high vascular risk14. Most participants were acquired through community-based recruitment using a protocol designed to obtain a demographically diverse cohort, or through sources such as stroke clinics and support groups attended by people with high vascular risk factors. All participants gave written informed consent in accordance with the policies of each institutional review board. Inclusion criteria include age 60 or older, with cognitive function in the normal to mild cognitive impairment range (Clinical Dementia Rating [CDR] score of 0 or 0.5) 15. Persons with history of multiple vascular risk factors, coronary or carotid disease, myocardial infarction, or ischemic stroke were targeted for inclusion, although patients with very large strokes that interfered with estimation of cortical volume and thickness were excluded. Exclusion criteria included evidence of alcohol or substance abuse, head trauma with loss of consciousness lasting longer than 15 minutes, factors contraindicating MRI, and severe medical illness, neurologic or psychiatric disorders unrelated to AD or vascular dementia that could significantly affect brain structure (e.g., schizophrenia and other psychotic disorders, bipolar disorder, current major depression, post-traumatic stress disorder, obsessive-compulsive disorder, liver disease, multiple sclerosis, amyotrophic lateral sclerosis). Participant demographics by CDR are shown in Table 1. Measures of cardiovascular risk and carotid atherosclerosis: The FCRP uses empirically-derived ageand gender-adjusted weighting of categorical variables to predict the 10-year risk of coronary heart disease and is a weighted sum of: age, gender, active smoking, diabetes, systolic blood pressure (and/or use of hypertensive medications) and total cholesterol and high-density lipoprotein cholesterol levels13. Higher scores indicate greater coronary risk. CIMT was used as a measure of subclinical atherosclerosis. CIMT is a measures of the thickness of the inner two layers of the carotid artery; higher CIMT indicates greater atherosclerosis burden. High-resolution B-mode ultrasound images of the right and left common carotid arteries were obtained with a 7.5-MHz linear array transducer attached to an ATL Apogee ultrasound system (Bothell, WA). CIMT was determined as the average of 70 to 100 measurements between the intima-lumen and media-adventitia interfaces along a 1 cm length just proximal to the carotid artery bulb at the same point of the cardiac cycle using comperterized automated edge detection. Right and left CIMT were measured in each individual whenever possible. For individuals with CIMT measurements from both sides, the maximum of these two quantities was used in subsequent statistical analyses. Measure of AD risk: Blood was drawn with the subject's consent for apolipoprotein E genotyping. Genotyping was completed for 102 participants. Subjects with 3/4 or 4/4 combined alleles were classified as apoE e4 positive, and those with 3/3 alleles as apoE e4 negative. Because the 2/4 combined allele is associated with a lower risk of AD16, these subjects were not included in the APOE e4 positive group. Methods Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3T and 4T MRI at three sites. Freesurfer (v5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of FCRP and CIMT with cortical volume and thickness. MRI: acquisition: Structural T1-weighted MRI scans for participants were collected on 3T and 4T MRI systems. Forty-three participants were scanned at the University of Southern California using a 3T General Electric Signal HDx system with an 8-channel head coil. Acquired images included a T1-weighted volumetric SPGR (TR = 7 ms, TE = 2.9 ms, TI= 650 ms, 1 mm3 isotropic resolution). Fifty-four participants were scanned at the University of California, Davis research center. Nine participants were scanned using a 3T Siemens Magnetom Trio Syngo System with an 8-channel head coil. Forty-five were scanned using a 3T Siemens Magnetom TrioTim system with an 8-channel head coil. Acquired images for all 54 participants included a T1-weighted volumetric MP-RAGE (TR = 2500, TE = 2.98, TI = 1100, 1 mm3 isotropic resolution). Thirty-three participants were scanned at the San Francisco Veterans Administration Medical Center using a 4T Siemens MedSpec Syngo System with an 8-channel head coil. A T1-weighted volumetric MP-RAGE scan (TR = 2300, TE = 2.84, TI = 950, 1 mm3 isotropic resolution) was acquired. Twenty-two participants were scanned at the University of California, San Francisco Neuroscience Imaging Center using a 3T Siemens Magnetom TrioTim system with a 12-channel head coil. Acquired images included a T1-weighted volumetric MP-RAGE (TR = 2500, TE = 2.98, TI = 1100, 1 mm3 isotropic resolution). MRI: processing: The publicly available Freesurfer v5.1 (http://surfer.nmr.mgh.harvard.edu/) volumetric segmentation and cortical surface reconstruction methods were used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). The reconstructed cortical surface models for each participant were manually inspected to ensure segmentation accuracy; regions with poor segmentation accuracy due to poor image quality or misregistration were excluded from further statistical analyses. Cortical surfaces were automatically parcellated17 and combined to create average cortical thickness and volume for total GM and for frontal, temporal, parietal, and occipital lobar regions. Region of interest volumes and thicknesses by cognitive status are shown in Table 2.
Voxel-wise co-analysis of macro- and microstructural brain alteration in Mild Cognitive Impairment and Alzheimer's disease using anatomical and diffusion MRI
Contributors: Cardenas, Valerie ; Tosun, Duygu ; Chao, Linda ; Fletcher, P. Thomas ; Joshi, Sarang; Weiner, Michael; Schuff, Norbert
Voxel-wise co-analysis of macro- and microstructural brain alteration in Mild Cognitive Impairment and Alzheimer's disease using anatomical and diffusion MRI
Contributors: Cardenas, Valerie, Tosun, Duygu, Chao, Linda, Fletcher, P. Thomas, Joshi, Sarang, Joshi, Sarang, Weiner, Michael W., Schuff, Norbert, UCSF Center for Imaging of Neurodegenerative Diseases
... Abstract Structural and diffusion data from cognitively normal elderly and those with mild cognitive impairment. Background and Purpose: To determine if a voxel-wise "co-analysis" of structural and diffusion tensor magnetic resonance imaging (MRI) together reveals additional brain regions affected in mild cognitive impairment (MCI) and Alzheimer's Disease (AD) than voxel-wise analysis of the individual MRI modalities alone. Conclusion: These results suggest that in corpus callosum and temporal regions macroand microstructural variations in MCI can be congruent, providing potentially new insight into the mechanisms of brain tissue degeneration. Methods Methods: Twenty-one patients with MCI, 21 patients with AD, and 21 cognitively normal healthy elderly were studied with MRI. Maps of deformation and fractional anisotropy (FA) were computed and used as dependent variables in univariate and multivariate statistical models. Results: Univariate voxel-wise analysis of macrostructural changes in MCI showed atrophy in the right anterior temporal lobe, left posterior parietal/precuneus region, WM adjacent to the cingulate gyrus, and dorsolateral prefrontal regions, consistent with prior research. Univariate voxel-wise analysis of microstructural changes in MCI showed reduced FA in the left posterior parietal region extending into the corpus callosum, consistent with previous work. The multivariate analysis, which provides more information than univariate tests when structural and FA measures are correlated, revealed additional MCI-related changes in corpus callosum and temporal lobe. Participants: Participants were recruited by advertisements in the community or referred by one of several memory clinics in the San Francisco Bay Area, including the Memory Disorders Clinic at the San Francisco Veterans Affairs Medical Center, the Memory and Aging Center at the University of California, San Francisco, and the Memory Disorders Clinic at the California Pacific Medical Center, for inclusion in one of several studies. Study procedures include a neurological exam, structural MRI, diffusion MRI, and comprehensive neuropsychological testing. In compliance with the Code of Ethics of the World Medical Association and the Declaration of Helsinki, study procedures were approved by review boards of the University of California San Francisco and the San Francisco VA Medical Center, explained to all participants, written informed consent was obtained. From the larger population studied, only participants with artifact-free structural and diffusion MRI were included. Twenty-one patients met Petersen's criteria for MCI, age: 71 ± 8 yrs, 11 women, MMSE (Mini-Mental State Examination): 29 ± 2. These patients were gender matched with 21 cognitively normal healthy elderly controls (CN), age: 70 ± 7 yrs, 11 women, MMSE 29 ± 1. The MCI patients were also gender matched with 21 patients who met AD criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA), age: 69 ± 9, 11 women, MMSE 21 ± 7. As evidenced by the high MMSE scores, the MCI patients were in an early stage of cognitive deficits and far less impaired than the AD patients. Magnetic resonance imaging (MRI) acquisition: All scans were performed on a 4 Tesla (Bruker/Siemens) MRI system with a birdcage transmit and 8 channel receive coil arranged in the same housing. The scans included T1-weighted and T2-weighted structural MRI data for measurements of brain macro-structure and diffusion tensor MRI for measurement of micro-structure. T1-weighted images were obtained with a 3D volumetric magnetization prepared rapid gradient echo (MPRAGE) sequence, TR/TE/TI=2300/3/950 ms, timing; 7º flip angle; 1.0 x 1.0 x 1.0 mm3 resolution; 157 continuous sagittal slices; acquisition time of 5 min. T2-weighted images were acquired with a variable flip (VFL) angle turbo spin-echo sequence with TR/TE = 4000/30 ms and with the same resolution matrix and field of view of MPRAGE. DTI was based on a dual spin-echo refocused echo-planar imaging (EPI) sequence supplemented with parallel imaging acceleration (GRAPPA) (Griswold et al., 2002) with a factor 2 to reduce susceptibility distortions. Other imaging parameters were: TR/TE=6000/77 ms; 2 x 2 mm2 in-plane resolution; 40 continuous 3 mm slices. A reference image (no diffusion gradient b=0) and six diffusion-weighted images (b=800s/mm2 along six non-collinear direction) were acquired. Four DTI scans were acquired and averaged after motion correction to boost signal-to-noise. The total acquisition time of DTI was 4 min. MRI pre-processing: An expectation maximization segmentation (EMS) algorithm including correction for intensity inhomogeneity 30,31 was applied to T1 weighted MRI, separating skull, scalp, extra-cranial tissue from the rest of brain image volume. Each individual skull-stripped and bias field corrected brain image volume was affine registered to a reference brain image to adjust for global differences in brain positioning and scale across individuals. For this study, an unbiased average brain image was used as the reference. The unbiased average brain was generated from 10 healthy elderly individual brains (i.e., age of 50 to 70) that were not part of the CN group using an unbiased atlas formation technique based on large deformations mapping 32. A large deformation diffeomorphic mapping algorithm using fluid-flow registration 33 was used to register individual scans to standard image space of the unbiased atlas brain. The Jacobian determinant of this transformation was computed at each voxel (resolution 1x1x1 mm3), giving the pattern of volume change required to force the individual anatomy to conform to the reference. The Jacobian images were log transformed to achieve a more normal distribution and then smoothed using a Gaussian filter (FWHM=10 mm) to create tissue volume maps (JAC), where the value at each voxel represents the tissue volume relative to the reference (e.g., a voxel value of 0.06 denotes a volume volrefx100.06, or about 15 percent greater than the reference voxel) DTI pre-processing: The pre-processing pipeline aims to align a set of DTI images with the corresponding structural data through the following steps. Diffusion tensor images were corrected for eddy currents and head motion 34. Based on a mutual information metric, the T2-weighted image was rigidly aligned to the B0 image, which is a DTI maps without diffusion sensing gradients (b=0 s/mm2). A variational image-based approach was used to calculate a deformation field from the B0 image to the rigidly aligned T2-weighted image to correct for susceptibility artifacts (i.e., nonlinear geometric distortion in DTI) 35. We selected a variational approach for EPI distortion correction over the conventional field map approach, because studies have shown that the local deformations in EPI are best handled with a dense displacement field (i.e. high order deformations) 35. In contrast, field maps can fail to completely correct geometric distortions, presumably due to limits in the physical model 36. Concatenated eddy current transformation and the deformation field for nonlinear distortion correction were applied to all DTIs. Diffusion tensors were estimated for each subject from the diffusion tensor images using weighted least squares tensor estimation 37. The T2-weighted image was rigidly aligned to the T1-weighted image and the transformation was concatenated with the inverse rigid transformation from B0 image to T2-weighted image. The resulting rigid transformation was applied to the FA image to map onto the T1-weighted structural image space of the subject. The FA image was then mapped onto the standard image space by applying the diffeomorphic mapping estimated in MRI pre-processing. FA images were then smoothed using a Gaussian filter (FWHM=10 mm) in the standard image space.