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1.  White Matter Microstructure Changes Induced by Motor Skill Learning Utilizing a Body Machine Interface 
NeuroImage  2013;0:32-40.
The purpose of this study is to identify white matter microstructure changes following bilateral upper extremity motor skill training to increase our understanding of learning-induced structural plasticity and enhance clinical strategies in physical rehabilitation. Eleven healthy subjects performed two visuo-spatial motor training tasks over 9 sessions (2–3 sessions per week). Subjects controlled a cursor with bilateral simultaneous movements of the shoulders and upper arms using a body machine interface. Before the start and within 2 days of the completion of training, whole brain diffusion tensor MR imaging data were acquired. Motor training increased fractional anisotropy (FA) values in the posterior and anterior limbs of the internal capsule, the corona radiata, and the body of the corpus callosum by 4.19% on average indicating white matter microstructure changes induced by activity-dependent modulation of axon number, axon diameter, or myelin thickness. These changes may underlie the functional reorganization associated with motor skill learning.
PMCID: PMC4016193  PMID: 24220038
motor skill learning; diffusion tensor imaging; fractional anisotropy; white matter plasticity
2.  White Matter in Aging and Cognition: A Cross-sectional Study of Microstructure in Adults Aged Eighteen to Eighty-Three 
Developmental neuropsychology  2010;35(3):257-277.
Structural brain change and concomitant cognitive decline are the seemingly unavoidable escorts of aging. Despite accumulating studies detailing the effects of age on the brain and cognition, the relationship between white matter features and cognitive function in aging have only recently received attention and remain incompletely understood. White matter microstructure can be measured with diffusion tensor imaging (DTI), but whether DTI can provide unique information on brain aging that is not explained by white matter volume is not known. In the current study, the relationship between white matter microstructure, age and neuropsychological function was assessed using DTI in a statistical framework that employed white matter volume as a voxel-wise covariate in a sample of 120 healthy adults across a broad age range (18–83). Memory function and executive function were modestly correlated with the DTI measures while processing speed showed the greatest extent of correlation. The results suggest that age-related white matter alterations underlie age-related declines in cognitive function. Mean diffusivity and fractional anisotropy in several white matter brain regions exhibited a non-linear relationship with age, while white matter volume showed a primarily linear relationship with age. The complex relationships between cognition, white matter microstructure, and white matter volume still require further investigation.
PMCID: PMC2895988  PMID: 20446132
3.  Alterations in White Matter Microstructure in Neurofibromatosis-1 
PLoS ONE  2012;7(10):e47854.
Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well–characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.
PMCID: PMC3477133  PMID: 23094098
4.  Diffusion Tensor Imaging in Autism Spectrum Disorder: A Review 
Lay Abstract
White matter tracts are like the “highways” of the brain, allowing for fast and efficient communication among diverse brain regions. The purpose of this paper is to review the results of autism studies that have used Diffusion Tensor Imaging (DTI), which is a neuroimaging method that allows us to examine the structure and integrity of these white matter tracts. From the 48 studies we reviewed, persons with ASD tended to have decreased white matter integrity spanning across many regions of the brain but most consistently in regions such as the corpus callosum (connecting the left and right hemispheres and associated with motor skill and complex information processing), the cingulum bundles (connecting regions along the middle-line of the brain with important frontal projections and associated with executive function), and white matter tracts that pass through the temporal lobe (connecting temporal lobe regions with other brain regions and associated with social functioning). The pattern of results in these studies suggests that the white matter tracts may be atypical in persons with ASD. Additionally, the review suggests that people with ASD may not exhibit the typical left-greater-than-right-brain asymmetry in white matter integrity compared to people with typical development. White matter alterations in persons with ASD are a target of emerging interventions and may help identify the brain basis of individual differences in this population.
Scientific Abstract
White matter tracts of the brain allow neurons and neuronal networks to communicate and function with high efficiency. The aim of this review is to briefly introduce Diffusion Tensor Imaging (DTI) methods that examine white matter tracts and then to give an overview of the studies that have investigated white matter integrity in the brains of individuals with Autism Spectrum Disorder (ASD). From the 48 studies we reviewed, persons with ASD tended to have decreased fractional anisotropy and increased mean diffusivity in white matter tracts spanning many regions of the brain but most consistently in regions such as the corpus callosum, cingulum, and aspects of the temporal lobe. This decrease in fractional anisotropy was often accompanied by increased radial diffusivity. Additionally, the review suggests possible atypical lateralization in some white matter tracts of the brain and a possible atypical developmental trajectory of white matter microstructure in persons with ASD. Clinical implications and future research directions are discussed.
PMCID: PMC3474893  PMID: 22786754
Diffusion Tensor Imaging; Neuroimaging; Autism; White Matter
5.  Experience-dependent plasticity in white matter microstructure: reasoning training alters structural connectivity 
Diffusion tensor imaging (DTI) techniques have made it possible to investigate white matter plasticity in humans. Changes in DTI measures, principally increases in fractional anisotropy (FA), have been observed following training programs as diverse as juggling, meditation, and working memory. Here, we sought to test whether three months of reasoning training could alter white matter microstructure. We recruited participants (n = 23) who were enrolled in a course to prepare for the Law School Admission Test (LSAT), a test that places strong demands on reasoning skills, as well as age- and IQ-matched controls planning to take the LSAT in the future (n = 22). DTI data were collected at two scan sessions scheduled three months apart. In trained participants but not controls, we observed decreases in radial diffusivity (RD) in white matter connecting frontal cortices, and in mean diffusivity (MD) within frontal and parietal lobe white matter. Further, participants exhibiting larger gains on the LSAT exhibited greater decreases in MD in the right internal capsule. In summary, reasoning training altered multiple measures of white matter structure in young adults. While the cellular underpinnings are unknown, these results provide evidence of experience-dependent white matter changes that may not be limited to myelination.
PMCID: PMC3424489  PMID: 22936899
cognitive training; fluid reasoning; plasticity; diffusion-weighted imaging; test preparation
6.  Longitudinal Assessment of Gray and White Matter in Chronic Schizophrenia: A Combined Diffusion-Tensor and Structural Magnetic Resonance Imaging Study 
Previous studies have reported continued focal gray matter loss after the clinical onset of schizophrenia. Longitudinal assessments in chronic illness, of white matter in particular, have been less conclusive.
We used diffusion-tensor and structural magnetic resonance imaging in 16 healthy subjects and 49 chronic schizophrenia patients, subdivided into good-outcome (n=23) and poor-outcome (n=26) groups, scanned twice 4 years apart. Fractional anisotropy, gray matter and white matter volumes were parcellated into the Brodmann’s areas and entered into multiway ANCOVAs.
At baseline, schizophrenia patients had 1) lower anisotropy in frontoparietal white matter, 2) larger posterior frontal white matter volumes, and 3) smaller frontal, temporal, and parietal gray matter volumes. On follow-up, healthy subjects showed a more pronounced 1) decline in anisotropy, 2) expansion of regional white matter volumes, and 3) reduction in regional gray matter volumes than schizophrenia patients. Good-outcome patients showed a more pronounced decline in white matter anisotropy and a less pronounced increase in white matter volumes than poor-outcome patients. Poor-outcome patients displayed a greater gray matter loss throughout the brain than good-outcome patients.
In the chronic phase of the illness, longitudinal changes in both gray and white matter are in the direction of an effacement of between-group differences among schizophrenia patients and healthy subjects. Similarly, preexisting white matter differences between good-outcome and poor-outcome patients diminish over time. In contrast, gray matter volumes in poor-outcome patients continue to decline more rapidly than in patients with good outcome. These patterns are consistent with earlier onset of aging-associated changes in schizophrenia.
PMCID: PMC2700015  PMID: 19547667
Kraepelinian schizophrenia; poor outcome; anisotropy; white matter; illness progression.
7.  Diffusion tensor tractography findings in schizophrenia across the adult lifespan 
Brain  2010;133(5):1494-1504.
In healthy adult individuals, late life is a dynamic time of change with respect to the microstructural integrity of white matter tracts. Yet, elderly individuals are generally excluded from diffusion tensor imaging studies in schizophrenia. Therefore, we examined microstructural integrity of frontotemporal and interhemispheric white matter tracts in schizophrenia across the adult lifespan. Diffusion tensor imaging data from 25 younger schizophrenic patients (≤55 years), 25 younger controls, 25 older schizophrenic patients (≥56 years) and 25 older controls were analysed. Patients with schizophrenia in each group were individually matched to controls. Whole-brain tractography and clustering segmentation were employed to isolate white matter tracts. Groups were compared using repeated measures analysis of variance with 12 within-group measures of fractional anisotropy: (left and right) uncinate fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, inferior occipito-frontal fasciculus, cingulum bundle, and genu and splenium of the corpus callosum. For each white matter tract, fractional anisotropy was then regressed against age in patients and controls, and correlation coefficients compared. The main effect of group (F3,92 = 12.2, P < 0.001), and group by tract interactions (F26,832 = 1.68, P = 0.018) were evident for fractional anisotropy values. Younger patients had significantly lower fractional anisotropy than younger controls (Bonferonni-corrected alpha = 0.0042) in the left uncinate fasciculus (t48 = 3.7, P = 0.001) and right cingulum bundle (t48 = 3.6, P = 0.001), with considerable effect size, but the older groups did not differ. Schizophrenic patients did not demonstrate accelerated age-related decline compared with healthy controls in any white matter tract. To our knowledge, this is the first study to examine the microstructural integrity of frontotemporal white matter tracts across the adult lifespan in schizophrenia. The left uncinate fasciculus and right cingulum bundle are disrupted in younger chronic patients with schizophrenia compared with matched controls, suggesting that these white matter tracts are related to frontotemporal disconnectivity. The absence of accelerated age-related decline, or differences between older community-dwelling patients and controls, suggests that these patients may possess resilience to white matter disruption.
PMCID: PMC2859148  PMID: 20237131
schizophrenia; diffusion tensor; ageing; white matter fibre pathways
8.  Structural Brain Correlates Associated with Professional Handball Playing 
PLoS ONE  2015;10(4):e0124222.
There is no doubt that good bimanual performance is very important for skilled handball playing. The control of the non-dominant hand is especially demanding since efficient catching and throwing needs both hands.
We investigated training-induced structural neuroplasticity in professional handball players using several structural neuroimaging techniques and analytic approaches and also provide a review of the literature about sport-induced structural neuroplastic alterations. Structural brain adaptations were expected in regions relevant for motor and somatosensory processing such as the grey matter (GM) of the primary/secondary motor (MI/supplementary motor area, SMA) and somatosensory cortex (SI/SII), basal ganglia, thalamus, and cerebellum and in the white matter (WM) of the corticospinal tract (CST) and corpus callosum, stronger in brain regions controlling the non-dominant left hand.
Increased GM volume in handball players compared with control subjects were found in the right MI/SI, bilateral SMA/cingulate motor area, and left intraparietal sulcus. Fractional anisotropy (FA) and axial diffusivity were increased within the right CST in handball players compared with control women. Age of handball training commencement correlated inversely with GM volume in the right and left MI/SI and years of handball training experience correlated inversely with radial diffusivity in the right CST. Subcortical structures tended to be larger in handball players. The anatomical measures of the brain regions associated with handball playing were positively correlated in handball players, but not interrelated in control women.
Training-induced structural alterations were found in the somatosensory-motor network of handball players, more pronounced in the right hemisphere controlling the non-dominant left hand. Correlations between handball training-related measures and anatomical differences suggest neuroplastic adaptations rather than a genetic predisposition for a ball playing affinity. Investigations of neuroplasticity specifically in sportsmen might help to understand the neural mechanisms of expertise in general.
PMCID: PMC4411074  PMID: 25915906
9.  Competing physiological pathways link individual differences in weight and abdominal adiposity to white matter microstructure 
NeuroImage  2013;79:129-137.
Being overweight or obese is associated with reduced white matter integrity throughout the brain. It is not yet clear which physiological systems mediate the association between inter-individual variation in adiposity and white matter. We tested whether composite indicators of cardiovascular, lipid, glucose, and inflammatory factors would mediate the adiposity-related variation in white matter microstructure, measured with diffusion tensor imaging on a group of neurologically healthy adults (N=155). A composite factor representing adiposity (comprised of body mass index and waist circumference) was negatively associated fractional anisotropy, and increased radial diffusivity, throughout the brain, a pattern linked to myelin structure changes in non-human animal models. A similar global negative association was found for factors representing inflammation and, to a lesser extent, glucose regulation. In contrast, factors for blood pressure and dyslipidemia had positive associations with white matter in isolated brain regions. Taken together, these competing influences on the diffusion signal were significant mediators linking adiposity to white matter and explained up to fifty-percent of the adiposity-white matter variance. These results provide the first evidence for contrasting physiological pathways, a globally distributed immunity-linked negative component and a more localized vascular-linked positive component, that associate adiposity to individual differences in the microstructure of white matter tracts in otherwise healthy adults.
PMCID: PMC3752776  PMID: 23639257
adiposity; inflammation; obesity; metabolic syndrome; white matter
10.  Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy 
Early adverse experiences, especially those involving disruption of the mother-infant relationship, are detrimental for proper socioemotional development in primates. Humans with histories of childhood maltreatment are at high risk for developing psychopathologies including depression, anxiety, substance abuse, and behavioral disorders. However, the underlying neurodevelopmental alterations are not well understood. Here we used a nonhuman primate animal model of infant maltreatment to study the long-term effects of this early life stress on brain white matter integrity during adolescence, its behavioral correlates, and the relationship with early levels of stress hormones.
Diffusion tensor imaging and tract based spatial statistics were used to investigate white matter integrity in 9 maltreated and 10 control animals during adolescence. Basal plasma cortisol levels collected at one month of age (when abuse rates were highest) were correlated with white matter integrity in regions with group differences. Total aggression was also measured and correlated with white matter integrity.
We found significant reductions in white matter structural integrity (measured as fractional anisotropy) in the corpus callosum, occipital white matter, external medullary lamina, as well as in the brainstem of adolescent rhesus monkeys that experienced maternal infant maltreatment. In most regions showing fractional anisotropy reductions, opposite effects were detected in radial diffusivity, without changes in axial diffusivity, suggesting that the alterations in tract integrity likely involve reduced myelin. Moreover, in most regions showing reduced white matter integrity, this was associated with elevated plasma cortisol levels early in life, which was significantly higher in maltreated than in control infants. Reduced fractional anisotropy in occipital white matter was also associated with increased social aggression.
These findings highlight the long-term impact of infant maltreatment on brain white matter structural integrity, particularly in tracts involved in visual processing, emotional regulation, and somatosensory and motor integration. They also suggest a relationship between elevations in stress hormones detected in maltreated animals during infancy and long-term brain white matter structural effects.
PMCID: PMC3880213  PMID: 24289263
Early life stress; Adolescence; Rhesus monkeys; Diffusion tensor imaging
11.  Microstructure Abnormalities in Adolescents with Internet Addiction Disorder 
PLoS ONE  2011;6(6):e20708.
Recent studies suggest that internet addiction disorder (IAD) is associated with structural abnormalities in brain gray matter. However, few studies have investigated the effects of internet addiction on the microstructural integrity of major neuronal fiber pathways, and almost no studies have assessed the microstructural changes with the duration of internet addiction.
Methodology/Principal Findings
We investigated the morphology of the brain in adolescents with IAD (N = 18) using an optimized voxel-based morphometry (VBM) technique, and studied the white matter fractional anisotropy (FA) changes using the diffusion tensor imaging (DTI) method, linking these brain structural measures to the duration of IAD. We provided evidences demonstrating the multiple structural changes of the brain in IAD subjects. VBM results indicated the decreased gray matter volume in the bilateral dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the orbitofrontal cortex (OFC), the cerebellum and the left rostral ACC (rACC). DTI analysis revealed the enhanced FA value of the left posterior limb of the internal capsule (PLIC) and reduced FA value in the white matter within the right parahippocampal gyrus (PHG). Gray matter volumes of the DLPFC, rACC, SMA, and white matter FA changes of the PLIC were significantly correlated with the duration of internet addiction in the adolescents with IAD.
Our results suggested that long-term internet addiction would result in brain structural alterations, which probably contributed to chronic dysfunction in subjects with IAD. The current study may shed further light on the potential brain effects of IAD.
PMCID: PMC3108989  PMID: 21677775
12.  Characteristics of diffusion-tensor imaging for healthy adult rhesus monkey brains 
Neural Regeneration Research  2013;8(31):2951-2961.
Diffusion-tensor imaging can be used to observe the microstructure of brain tissue. Fractional sotropy reflects the integrity of white matter fibers. Fractional anisotropy of a young adult brain is low in gray matter, high in white matter, and highest in the splenium of the corpus callosum. Thus, we selected the anterior and posterior limbs of the internal capsule, head of the caudate nucleus, semioval center, thalamus, and corpus callosum (splenium and genu) as regions of interest when using diffusion-tensor imaging to observe fractional anisotropy of major white matter fiber tracts and the deep gray matter of healthy rhesus monkeys aged 4–8 years. Results showed no laterality ferences in fractional anisotropy values. Fractional anisotropy values were low in the head of date nucleus and thalamus in gray matter. Fractional anisotropy values were highest in the splenium of corpus callosum in the white matter, followed by genu of the corpus callosum and the posterior limb of the internal capsule. Fractional anisotropy values were lowest in the semioval center and posterior limb of internal capsule. These results suggest that fractional anisotropy values in major white matter fibers and the deep gray matter of 4–8-year-old rhesus monkeys are similar to those of healthy young people.
PMCID: PMC4146173  PMID: 25206616
neural regeneration; neuroimaging; rhesus monkey; fractional anisotropy; brain; white matter; gray matter; MRI; diffusion-tensor imaging; grants-supported paper; neuroregeneration
13.  Midlife measurements of white matter microstructure predict subsequent regional white matter atrophy in healthy adults 
Human brain mapping  2013;35(5):2044-2054.
While age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a four-year interval.
Experimental design
Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor Based Morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, while gray and white matter atrophy rates as indexed by Tensor Based Morphometry were the dependent variables.
Principal observations
Over a four-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (p<0.05, corrected for multiple comparisons). Baseline FA in entorhinal white matter, genu, and splenium, was associated with longitudinal rates of atrophy in regions that included the superior longitudinal fasciculus, anterior corona radiata, temporal stem, and white matter of the inferior temporal gyrus (p<0.001, uncorrected for multiple comparisons).
Brain change with aging is characterized by extensive shrinkage of white matter. Baseline white matter microstructure as indexed by DTI was associated with some of the observed regional volume loss. The findings suggest that both white matter volume loss and microstructural alterations should be considered more prominently in models of aging and neurodegenerative diseases.
PMCID: PMC3895105  PMID: 23861348
aging; fractional anisotropy; microstructure; atrophy; longitudinal; diffusion tensor imaging; tensor-based morphometry
14.  Altered Myelination and axonal integrity in Adults with Childhood Lead Exposure: A Diffusion Tensor Imaging Study 
Neurotoxicology  2009;30(6):867-875.
Childhood lead exposure is associated with adverse cognitive, neurobehavioral and motor outcomes, suggesting altered brain structure and function. The purpose of this work was to assess the long-term impact of childhood lead exposure on white matter integrity in young adults. We hypothesized that childhood lead exposure would alter adult white matter architecture via deficits in axonal integrity and myelin organization. Adults (22.9 ± 1.5 years, range 20.0 to 26.1 years) from the Cincinnati Lead Study were recruited to undergo a study employing diffusion tensor imaging (DTI). The anatomic regions of association between water diffusion characteristics in white matter and mean childhood blood lead level were determined for ninety-one participants (52 female). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured on an exploratory voxel-wise basis. In adjusted analyses, mean childhood blood lead levels were associated with decreased FA throughout white matter. Regions of the corona radiata demonstrated highly significant lead-associated decreases in FA and AD and increases in MD and RD. The genu, body, and splenium of the corpus callosum demonstrated highly significant lead-associated decreases in RD, smaller and less significant decreases in MD, and small areas with increases in AD. The results of this analysis suggest multiple insults appear as distinct patterns of white matter diffusion abnormalities in the adult brain. Neurotoxic insults from the significant lead burden the participants experienced throughout childhood affect neural elements differently and may be related to the developmental stage of myelination at periods of exposure. This study indicates that childhood lead exposure is associated with a significant and persistent impact on white matter microstructure as quantified with diffusivity changes suggestive of altered myelination and axonal integrity.
PMCID: PMC2789851  PMID: 19619581
myelination; internal capsule; corona radiata; corpus callosum
15.  Diffusion tensor imaging of deep gray matter brain structures: Effects of age and iron concentration 
Neurobiology of aging  2008;31(3):482.
Diffusion tensor imaging (DTI) of the brain has become a mainstay in the study of normal aging of white matter, and only recently has attention turned to the use of DTI to examine aging effects in gray matter structures. Of the many changes in the brain that occur with advancing age is increased presence of iron, notable in selective deep gray matter structures. In vivo detection and measurement of iron deposition is possible with magnetic resonance imaging (MRI) because of iron's effect on signal intensity. In the process of a DTI study, a series of diffusion-weighted images (DWI) is collected, and while not normally considered as a major dependent variable in research studies, they are used clinically and they reveal striking conspicuity of the globus pallidus and putamen caused by signal loss in these structures, presumably due to iron accumulation with age. These iron deposits may in turn influence DTI metrics, especially of deep gray matter structures. The combined imaging modality approach has not been previously used in the study of normal aging. The present study used legacy DTI data collected in 10 younger (22–37 years) and 10 older (65–79 years) men and women at 3.0 T and fast spin-echo (FSE) data collected at 1.5 T and 3.0 T to derive an estimate of the field-dependent relaxation rate increase (the “FDRI estimate”) in the putamen, caudate nucleus, globus pallidus, thalamus, and a frontal white matter sample comparison region. The effect of age on the diffusion measures in the deep gray matter structures was distinctly different from that reported in white matter. In contrast to lower anisotropy and higher diffusivity typical in white matter of older relative to younger adults observed with DTI, both anisotropy and diffusivity were higher in the older than younger group in the caudate nucleus and putamen; the thalamus showed little effect of age on anisotropy or diffusivity. Signal intensity measured with DWI was lower in the putamen of elderly than young adults, whereas the opposite was observed for the white matter region and thalamus. As a retrospective study based on legacy data, the FDRI estimates were based on FSE sequences, which underestimated the classical FDRI index of brain iron. Nonetheless, the differential effects of age on DTI metrics in subcortical gray matter structures compared with white matter tracts appears to be related, at least in part, to local iron content, which in the elderly of the present study was prominent in the FDRI estimate of the putamen and visibly striking in the diffusion-weighted image of the basal ganglia structures.
PMCID: PMC2815127  PMID: 18513834
Brain; Aging; Iron; DTI; DWI; MRI; Diffusion
16.  Motor skill learning is associated with diffusion characteristics of white matter in individuals with chronic stroke 
Background and Purpose
Imaging advances allow investigation of white matter following stroke; a growing body of literature has shown links between diffusion-based measures of white matter microstructure and motor function. However, the relationship between these measures and motor skill learning has not been considered in individuals with stroke. The aim of this study was to investigate the relationships between post-training white matter microstructural status, as indexed by diffusion tensor imaging (DTI) within the ipsilesional posterior limb of the internal capsule (PLIC) and learning of a novel motor task in individuals with chronic stroke.
Thirteen participants with chronic stroke and nine healthy controls practiced a visuomotor pursuit task across five sessions. Change in motor behavior associated with learning was indexed by comparing baseline performance with a delayed retention test. Fractional anisotropy (FA) indexed at the retention test was the primary DTI-derived outcome measure.
In individuals with chronic stroke, we discovered an association between post-training ipsilesional PLIC FA and the magnitude of change associated with motor learning; hierarchical multiple linear regression analyses revealed that the combination of age, time post stroke and ipsilesional PLIC FA post-training was associated with motor learning related change (R2=0.649, p=0.02). Baseline motor performance was not related to post-training ipsilesional PLIC FA.
Discussion and Conclusions
Diffusion characteristics of post-training ipsilesional PLIC were linked to magnitude of change in skilled motor behavior. These results imply that the microstructural properties of regional white matter indexed by diffusion behavior may be an important factor to consider when determining potential response to rehabilitation in persons with stroke. Video Abstract available (See Video, Supplemental Digital Content 1.) for more insights from the authors.
PMCID: PMC3918251  PMID: 23934017
Motor behavior; Diffusion tensor imaging; Cerebrovascular accident; Posterior limb of the internal capsule; Rehabilitation
17.  Depressive symptoms and neuroanatomical structures in community-dwelling women: A combined voxel-based morphometry and diffusion tensor imaging study with tract-based spatial statistics 
NeuroImage : Clinical  2014;4:481-487.
Depressive symptoms, even at a subclinical level, have been associated with structural brain abnormalities. However, previous studies have used regions of interest or small sample sizes, limiting the ability to generalize the results. In this study, we examined neuroanatomical structures of both gray matter and white matter associated with depressive symptoms across the whole brain in a large sample. A total of 810 community-dwelling adult participants underwent measurement of depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D). The participants were not demented and had no neurological or psychiatric history. To examine the gray and white matter volume, we used structural MRI scans and voxel-based morphometry (VBM); to examine the white matter integrity, we used diffusion tensor imaging with tract-based spatial statistics (TBSS). In female participants, VBM revealed a negative correlation between bilateral anterior cingulate gray matter volume and the CES-D score. TBSS showed a CES-D-related decrease in fractional anisotropy and increase in radial and mean diffusivity in several white matter regions, including the right anterior cingulum. In male participants, there was no significant correlation between gray or white matter volume or white matter integrity and the CES-D score. Our results indicate that the reduction in gray matter volume and differences in white matter integrity in specific brain regions, including the anterior cingulate, are associated with depressive symptoms in women.
•We studied neuroanatomical structures associated with subclinical depression.•The analysis was performed across the whole brain in a large sample.•Anterior cingulate gray matter volume reduction was revealed by VBM.•Broad white matter integrity differences were revealed by DTI with TBSS.•Both changes were seen only in females but not in males.
PMCID: PMC3984445  PMID: 24818074
Anterior cingulate gyrus; Voxel-based morphometry; Diffusion tensor imaging; Tract-based spatial statistics; Subclinical depression; CES-D, Center for Epidemiologic Studies Depression Scale; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; RD, radial diffusivity; TBSS, tract-based spatial statistics; VBM, voxel-based morphometry
18.  Longitudinal regression analysis of spatial-temporal growth patterns of geometrical diffusion measures in early postnatal brain development with diffusion tensor imaging 
Neuroimage  2011;58(4):993-1005.
Although diffusion tensor imaging (DTI) has provided substantial insights into early brain development, most DTI studies based on fractional anisotropy (FA) and mean diffusivity (MD) may not capitalize on the information derived from the three principal diffusivities (e.g. eigenvalues). In this study, we explored the spatial and temporal evolution of white matter structures during early brain development using two geometrical diffusion measures, namely, linear (Cl) and planar (Cp) diffusion anisotropies, from 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects. The growth trajectories were estimated with generalized estimating equations (GEE) using linear fitting with logarithm of age (days). The presence of the white matter structures in Cl and Cp was observed in neonates, suggesting that both the cylindrical and fanning or crossing structures in various white matter regions may already have been formed at birth. Moreover, we found that both Cl and Cp evolved in a temporally nonlinear and spatially inhomogeneous manner. The growth velocities of Cl in central white matter were significantly higher when compared to peripheral, or more laterally located, white matter: central growth velocity Cl = 0.0465±0.0273/log(days), versus peripheral growth velocity Cl=0.0198±0.0127/log(days), p<10−6. In contrast, the growth velocities of Cp in central white matter were significantly lower than that in peripheral white matter: central growth velocity Cp= 0.0014±0.0058/log(days), versus peripheral growth velocity Cp = 0.0289±0.0101/log(days), p<10−6. Depending on the underlying white matter site which is analyzed, our findings suggest that ongoing physiologic and microstructural changes in the developing brain may exert different effects on the temporal evolution of these two geometrical diffusion measures. Thus, future studies utilizing DTI with correlative histological analysis in the study of early brain development are warranted.
PMCID: PMC3299497  PMID: 21784163
early brain development; DTI; longitudinal analysis; GEE; geometrical diffusion measures; brain growth
19.  Selective Alterations of White Matter Associated with Visuospatial and Sensorimotor Dysfunction in Turner Syndrome 
Turner syndrome (TS) is a neurogenetic disorder characterized by impaired spatial, numerical, and motor functioning but relatively spared verbal ability. Results from previous neuroimaging studies suggest that gray matter alterations in parietal and frontal regions may contribute to atypical visuospatial and executive functioning in TS. Recent findings in TS also indicate variations in the shape of parietal gyri and white matter microstructural anomalies of the temporal lobe. Diffusion tensor imaging and structural imaging methods were used to determine whether 10 females with TS and 10 age- and gender-matched control subjects exhibited differences in fractional anisotropy, white matter density, and local brain shape. Relative to controls, females with TS had lower fractional anisotropy (FA) values in the deep white matter of the left parietal-occipital region extending anteriorly along the superior longitudinal fasciculus into the deep white matter of the frontal lobe. In addition, decreased FA values were located bilaterally in the internal capsule extending into the globus pallidus and in the right prefrontal region. Voxel-based morphometry (VBM) analysis showed corresponding white matter density differences in the internal capsules and left centrum semiovale. Tensor-based morphometry analysis indicated that the FA and VBM results were not attributable to differences in the local shape of brain structures. Compared with controls, females with TS had increases in FA values and white matter density in language-related areas of the inferior parietal and temporal lobes. These complementary analyses provide evidence for alterations in white matter pathways that subserve affected and preserved cognitive functions in TS.
PMCID: PMC3063771  PMID: 16807330
DTI; MRI; voxel-based morphometry; Turner syndrome; visual spatial; white matter; sensory motor
20.  What’s special about task in dystonia? A voxel-based morphometry and diffusion weighted imaging study 
Numerous brain imaging studies have demonstrated structural changes in the basal ganglia, thalamus, sensorimotor cortex and cerebellum across different forms of primary dystonia. However, our understanding of brain abnormalities contributing to the clinically well-described phenomenon of task-specificity in dystonia remained limited.
We used high-resolution MRI with voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics of fractional anisotropy to examine gray and white matter organization in two task-specific dystonia forms, writer’s cramp and laryngeal dystonia, and two non-task-specific dystonia forms, cervical dystonia and blepharospasm.
A direct comparison between the both dystonia forms revealed that characteristic gray matter volumetric changes in task-specific dystonia involve the brain regions responsible for sensorimotor control during writing and speaking, such as primary somatosensory cortex, middle frontal gyrus, superior/inferior temporal gyrus, middle/posterior cingulate cortex, occipital cortex as well as the striatum and cerebellum (lobules VI-VIIa). These gray matter changes were accompanied by white matter abnormalities in the premotor cortex, middle/inferior frontal gyrus, genu of the corpus callosum, anterior limb/genu of the internal capsule, and putamen. Conversely, gray matter volumetric changes in non-task-specific group were limited to the left cerebellum (lobule VIIa) only, while white matter alterations were found to underlie the primary sensorimotor cortex, inferior parietal lobule and middle cingulate gyrus.
Distinct microstructural patterns in task-specific and non-task-specific dystonias may represent neuroimaging markers and provide evidence that these two dystonia subclasses likely follow divergent pathophysiological mechanisms precipitated by different triggers.
PMCID: PMC4139455  PMID: 24925463
brain imaging; task specificity; focal dystonia
21.  Tract-Based Spatial Statistics of Diffusion Tensor Imaging in Adults with Dyslexia 
Diffusion tensor imaging is a tool that can be used to study white matter microstructure in dyslexia. We tested the hypothesis that dyslexics have a white matter structural change (as measured by directional diffusion of water, which can be affected by disruption in white matter tracts) between brain regions that previous functional connectivity studies showed were associated with phonologic processing.
Diffusion tensor imaging (DTI) scans were acquired from 7 healthy adult normal readers and from 14 adults with dyslexia on a 1.5T scanner. Voxelwise statistical analysis of the fractional anisotropy data were carried out by using Tract-Based Spatial Statistics to compare dyslexic subjects versus control subjects in white matter tracts.
Significant group difference map clusters (comparing adults with and without dyslexia) occurred in specific bilateral white matter tracts within the frontal lobe, temporal lobe, occipital lobe, and parietal lobe.
The DTI fractional anisotropy results in the bilateral white matter showing higher fractional anisotropy in adult control subjects compared with adults with dyslexia (relating to white matter fiber tract integrity) are consistent with our previous functional connectivity results from seed points in the bilateral inferior frontal gyrus.
PMCID: PMC2435068  PMID: 18467520
22.  Surface based laminar analysis of diffusion abnormalities in cortical and white matter layers in neocortical epilepsy 
Epilepsia  2013;54(4):667-677.
Microstructural alterations seen in the epileptic cortex have been implicated as a cause and also result of multiple seizure activity. In the present study, we evaluated water diffusion changes at different cortical thickness fractions and in the underlying white matter of the epileptic cortex and compared them with electrographically normal cortex and also with corresponding cortical regions of healthy controls.
We selected 18 children with normal MRI who underwent two-stage epilepsy surgery to control seizures of neocortical origin, and compared their MR images with those of 18 age-matched healthy controls. First, delineation of the grey-white and grey-pial intersection surfaces was performed on high-resolution volumetric T1 MR images. Using the delineated surfaces as reference, diffusion values were measured at different cortical thickness fractions and in the underlying white matter at various depths, using diffusion tensor imaging (DTI). Cortical regions representing seizure onset and electrographically normal cortex were differentiated by electrocorticography in the epilepsy patients.
Key findings
We observed different patterns of diffusion abnormalities in both the seizure onset and electrographically normal cortical regions when compared to healthy controls. In the seizure onset regions, a marked increase in diffusivity was noted in the cortical grey matter and this increase was most pronounced in the outer fraction of the grey matter. Similarly, increased diffusivity was noted in the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to the controls. The white matter underlying the electrographically normal cortex did not show any difference in diffusivity between the epileptic children and controls. Finally, both the cortical grey matter and the underlying white matter regions showed decreased anisotropy in epileptic as well as electrographically normal regions when compared to controls.
Our results suggest specific patterns of diffusion changes in the cortical fractions and the underlying white matter of the epileptic region compared to electrographically normal and normal control regions. The abnormal increase in diffusivity of the superficial cortex might be associated with microstructural abnormalities commonly seen in layers II through IV of epileptic cortex. Such combined use of a high-resolution structural image to extract the laminar diffusion values, which are highly sensitive to microstructural alterations, could be of clinical value in localizing epileptogenic cortex.
PMCID: PMC3618513  PMID: 23448199
epilepsy; diffusion; surface; seizure; DTI
23.  Individual Differences in Expert Motor Coordination Associated with White Matter Microstructure in the Cerebellum 
Cerebral Cortex (New York, NY)  2012;23(10):2282-2292.
Recent investigations into the neural basis of elite sporting performance have focused on whether cortical activity might characterize individual differences in ability. However, very little is understood about how changes in brain structure might contribute to individual differences in expert motor control. We compared the behavior and brain structure of healthy controls with a group of karate black belts, an expert group who are able to perform rapid, complex movements that require years of training. Using 3D motion tracking, we investigated whether the ability to control ballistic arm movements was associated with differences in white matter microstructure. We found that karate experts are better able than novices to coordinate the timing of inter-segmental joint velocities. Diffusion tensor imaging revealed significant differences between the groups in the microstructure of white matter in the superior cerebellar peduncles (SCPs) and primary motor cortex—brain regions that are critical to the voluntary control of movement. Motor coordination, the amount of experience, and the age at which training began were all associated with individual differences in white matter integrity in the cerebellum within the karate groups. These findings suggest a role for the white matter pathways of the SCPs in motor expertise.
PMCID: PMC3767954  PMID: 22892425
cerebellum; diffusion tensor imaging; expertise; individual differences; motor control
24.  White Matter Microstructure Alterations: A Study of Alcoholics with and without Post-Traumatic Stress Disorder 
PLoS ONE  2013;8(11):e80952.
Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. Therefore, understanding and differentiating these effects would be very important in characterizing alcoholism and PTSD. Alcoholics are known to have neurocognitive deficits in decision-making, particularly in decisions related to emotionally-motivated behavior, while individuals with PTSD have deficits in emotional regulation and enhanced fear response. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. In addition, previous studies have shown cortico-limbic fiber degradation through fiber tracking in alcoholism. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure, possibly indicating white matter integrity. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in healthy volunteers (HV) and alcohol dependent subjects without PTSD (ALC) and with PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD.
PMCID: PMC3832443  PMID: 24260518
25.  Topographical relationships between arcuate fasciculus connectivity and cortical thickness 
Human brain mapping  2010;32(11):1788-1801.
The arcuate fasciculus (AF) connects cortical regions important in language processing, but how fiber coherence and organization relates to gray matter macrostructure remains uncharacterized. We used high-resolution structural and 30-direction diffusion imaging data from 36 healthy adults (24 male/12 female; mean age: 30.5±9.8 years) to establish the relationships between AF microstructure and regional variations in cortical gray matter within language networks. Cortical pattern matching algorithms were used to measure gray matter thickness at high spatial density, and a validated diffusion tractography method was used to reconstruct the AF in the left and right hemisphere of each subject. Relationships between imaging measures and neuropsychological scores of verbal fluency were additionally assessed. Results revealed positive and highly topographical associations between arcuate fractional anisotropy and cortical thickness within anterior and posterior language regions and surrounding cortices, more prominently in the left hemisphere. These regional cortical thickness/fractional anisotropy relationships were primarily attributable to variations in radial diffusivity. Associations between cortical thickness and verbal fluency were observed in perisylvian language-related regions. Language scores associated with left hemisphere AF axial diffusivity, but not with AF fractional anisotropy or radial diffusivity. These findings thus suggest that particular components of white matter microstructure and regional increases in cortical thickness benefit aspects of language processing. Further, the topographical relationships between independent measures of white matter and gray matter integrity suggest that rich developmental or environmental interactions influence brain structure and function where the presence and strength of such associations may elucidate pathophysiological processes influencing language systems.
PMCID: PMC3071430  PMID: 20886580
Diffusion Tensor Imaging; Magnetic Resonance Imaging; white matter; gray matter; language; neuroanatomy; tractography; superior longitudinal fasciculus; fractional anisotropy

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