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1.  Diffusion Tensor Imaging of Parkinson’s Disease, Multiple System Atrophy and Progressive Supranuclear Palsy: A Tract-Based Spatial Statistics Study 
PLoS ONE  2014;9(11):e112638.
Although often clinically indistinguishable in the early stages, Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have distinct neuropathological changes. The aim of the current study was to identify white matter tract neurodegeneration characteristic of each of the three syndromes. Tract-based spatial statistics (TBSS) was used to perform a whole-brain automated analysis of diffusion tensor imaging (DTI) data to compare differences in fractional anisotropy (FA) and mean diffusivity (MD) between the three clinical groups and healthy control subjects. Further analyses were conducted to assess the relationship between these putative indices of white matter microstructure and clinical measures of disease severity and symptoms. In PSP, relative to controls, changes in DTI indices consistent with white matter tract degeneration were identified in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, superior cerebellar peduncle, medial lemniscus, retrolenticular and anterior limb of the internal capsule, cerebral peduncle and external capsule bilaterally, as well as the left posterior limb of the internal capsule and the right posterior thalamic radiation. MSA patients also displayed differences in the body of the corpus callosum corticospinal tract, cerebellar peduncle, medial lemniscus, anterior and superior corona radiata, posterior limb of the internal capsule external capsule and cerebral peduncle bilaterally, as well as the left anterior limb of the internal capsule and the left anterior thalamic radiation. No significant white matter abnormalities were observed in the PD group. Across groups, MD correlated positively with disease severity in all major white matter tracts. These results show widespread changes in white matter tracts in both PSP and MSA patients, even at a mid-point in the disease process, which are not found in patients with PD.
doi:10.1371/journal.pone.0112638
PMCID: PMC4236070  PMID: 25405990
2.  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.
doi:10.3969/j.issn.1673-5374.2013.31.008
PMCID: PMC4146173  PMID: 25206616
neural regeneration; neuroimaging; rhesus monkey; fractional anisotropy; brain; white matter; gray matter; MRI; diffusion-tensor imaging; grants-supported paper; neuroregeneration
3.  White matter compromise of callosal and subcortical fiber tracts in children with autism spectrum disorder: a diffusion tensor imaging study 
Objective
Autism spectrum disorder (ASD) is increasingly viewed as a disorder of functional networks, highlighting the importance of investigating white matter and interregional connectivity. We used diffusion tensor imaging (DTI) to examine white matter integrity for the whole brain and for corpus callosum, internal capsule, and middle cerebellar peduncle in children with ASD and typically developing (TD) children.
Method
DTI data were obtained from 26 children with ASD and 24 matched TD children. Fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusion were calculated for the whole brain, genu, body and splenium of the corpus callosum, genu, anterior and posterior limbs of the internal capsule, and middle cerebellar peduncle.
Results
Children with ASD had reduced FA and increased radial diffusion for whole brain white matter and all three segments of the corpus callosum and internal capsule, compared to TD children. Increased MD was found for the whole brain and anterior and posterior limbs of the internal capsule. Reduced axial diffusion was found for the body of corpus callosum. Reduced FA was also found for middle cerebellar peduncle.
Conclusions
Our findings suggest widespread white matter compromise in children with ASD. Abnormalities in the corpus callosum indicate impaired interhemispheric transfer. Results for internal capsule and middle cerebellar peduncle add to the currently limited DTI evidence on subcortico-cortical tracts in ASD. The robust impairment found in all three segments of the internal capsule is consistent with studies documenting impairment of elementary sensorimotor function in ASD.
doi:10.1016/j.jaac.2010.08.018
PMCID: PMC3346956  PMID: 21093776
Autism; diffusion tensor imaging; corpus callosum; internal Capsule; middle cerebellar peduncle
4.  Repeatability and variation of region-of-interest methods using quantitative diffusion tensor MR imaging of the brain 
BMC Medical Imaging  2012;12:30.
Background
Diffusion tensor imaging (DTI) is increasingly used in various diseases as a clinical tool for assessing the integrity of the brain’s white matter. Reduced fractional anisotropy (FA) and an increased apparent diffusion coefficient (ADC) are nonspecific findings in most pathological processes affecting the brain’s parenchyma. At present, there is no gold standard for validating diffusion measures, which are dependent on the scanning protocols, methods of the softwares and observers. Therefore, the normal variation and repeatability effects on commonly-derived measures should be carefully examined.
Methods
Thirty healthy volunteers (mean age 37.8 years, SD 11.4) underwent DTI of the brain with 3T MRI. Region-of-interest (ROI) -based measurements were calculated at eleven anatomical locations in the pyramidal tracts, corpus callosum and frontobasal area. Two ROI-based methods, the circular method (CM) and the freehand method (FM), were compared. Both methods were also compared by performing measurements on a DTI phantom. The intra- and inter-observer variability (coefficient of variation, or CV%) and repeatability (intra-class correlation coefficient, or ICC) were assessed for FA and ADC values obtained using both ROI methods.
Results
The mean FA values for all of the regions were 0.663 with the CM and 0.621 with the FM. For both methods, the FA was highest in the splenium of the corpus callosum. The mean ADC value was 0.727 ×10-3 mm2/s with the CM and 0.747 ×10-3 mm2/s with the FM, and both methods found the ADC to be lowest in the corona radiata. The CV percentages of the derived measures were < 13% with the CM and < 10% with the FM. In most of the regions, the ICCs were excellent or moderate for both methods. With the CM, the highest ICC for FA was in the posterior limb of the internal capsule (0.90), and with the FM, it was in the corona radiata (0.86). For ADC, the highest ICC was found in the genu of the corpus callosum (0.93) with the CM and in the uncinate fasciculus (0.92) with FM.
Conclusions
With both ROI-based methods variability was low and repeatability was moderate. The circular method gave higher repeatability, but variation was slightly lower using the freehand method. The circular method can be recommended for the posterior limb of the internal capsule and splenium of the corpus callosum, and the freehand method for the corona radiata.
doi:10.1186/1471-2342-12-30
PMCID: PMC3533516  PMID: 23057584
5.  Quantitative diffusion tensor imaging and intellectual outcomes in spina bifida 
Object
Patients with spina bifida (SB) have variable intellectual outcomes. The authors used diffusion tensor (DT) imaging to quantify whole-brain volumes of gray matter, white matter, and cerebrospinal fluid (CSF), and perform regional quantitative microstructural assessments of gray matter nuclei and white matter tracts in relation to intellectual outcomes in patients with SB.
Methods
Twenty-nine children with myelomeningoceles and 20 age- and sex-matched children with normal neural tube development underwent MR imaging with DT image acquisition and assessments of intelligence. The DT imaging-derived metrics were the fractional anisotropy (FA), axial (parallel), and transverse (perpendicular) diffusivities. These metrics were also used to segment the brain into white matter, gray matter, and CSF. A region-of-interest analysis was conducted of the white and gray matter structures implicated in hydrocephalus.
Results
The amount of whole-brain gray matter was decreased in patients with SB, with a corresponding increase in CSF (p < 0.0001). Regional transverse diffusivity in the caudate nucleus was decreased (p < 0.0001), and the corresponding FA was increased (p < 0.0001), suggesting reduced dendritic branching and connectivity. Fractional anisotropy in the posterior limb of the internal capsule increased in the myelomeningocele group (p = 0.02), suggesting elimination of some divergent fascicles; in contrast, the FA in several white matter structures (such as the corpus callosum genu [p < 0.001] and arcuate fasciculus) was reduced, suggesting disruption of myelination. Diffusion tensor imaging-metrics involving gray matter volume and the caudate nucleus, but not other structures, predicted variations in IQ (r = 0.37-0.50; p < 0.05).
Conclusions
Diffusion tensor imaging-derived metrics provide noninvasive neuronal surrogate markers of the pathogenesis of SB and predict variations in general intellectual outcomes in children with this condition.
doi:10.3171/PED/2008/2/7/075
PMCID: PMC3046025  PMID: 18590401
caudate nucleus; diffusion tensor imaging; IQ; myelomeningocele; neurodevelopment; spina bifida
6.  Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging 
Neurobiology of aging  2008;31(3):464.
The integrity of white matter, as measured in vivo with diffusion tensor imaging (DTI), is disrupted in normal aging. A current consensus is that in adults advancing age affects anterior brain regions disproportionately more than posterior regions; however, the mainstay of studies supporting this anterior-posterior gradient is based primarily on measures of the corpus callosum. Using our quantitative fiber tracking approach, we assessed fiber tract integrity of samples of major white matter cortical, subcortical, interhemispheric, and cerebellar systems (11 bilateral and 2 callosal) on DTI data collected at 1.5 T magnet strength. Participants were 55 men (age 20-78 years) and 65 women (age 28-81 years), deemed healthy and cognitively intact following interview and behavioral testing. Fiber integrity was measured as orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, which was quantified separately for longitudinal diffusivity (λL), an index of axonal length or number, and transverse diffusivity (λT), an index of myelin integrity. Aging effects were more evident in diffusivity than FA measures. Men and women, examined separately, showed similar age-related increases in longitudinal and transverse diffusivity in fibers of the internal and external capsules bilaterally and the fornix. FA was lower and diffusivity higher in anterior than posterior fibers of regional paired comparisons (genu versus splenium and frontal versus occipital forceps). Diffusivity with older age was generally greater or FA lower in the superior than inferior fiber systems (longitudinal fasciculi, cingulate bundles), with little to no evidence for age-related degradation in pontine or cerebellar systems. The most striking sex difference emerged for the corpus callosum, for which men showed significant decline in FA and increase in longitudinal and transverse diffusivity in the genu but not splenium. By contrast, in women the age effect was present in both callosal regions, albeit modestly more so in the genu than splenium. Functional meaningfulness of these age-related differences was supported by significant correlations between DTI signs of white matter degradation and poorer performance on cognitive or motor tests. This survey of multiple fiber systems throughout the brain revealed a differential pattern of age’s effect on regional FA and diffusivity and suggests mechanisms of functional degradation, attributed at least in part to compromised fiber microstructure affecting myelin and axonal morphology.
doi:10.1016/j.neurobiolaging.2008.04.007
PMCID: PMC2815144  PMID: 18495300
Brain; Aging; DTI; White matter; Fiber tracking; Diffusion
7.  Assessment of degradation of the selected projectile, commissural and association brain fibers in patients with Alzheimer’s disease on diffusion tensor MR imaging 
Polish Journal of Radiology  2010;75(2):7-14.
Summary
Background:
Pathological examinations and the increasingly popular diffusion tensor imaging (DTI) show that in Alzheimer’s disease (AD), the pathology involves not only the cortical and hippocampal structures, but also the white matter of the brain. DTI is a well recognized technique for evaluation of the integrity of white matter fibers. The aim of this study was to assess with the use of DTI some selected brain tracts in patients with AD, as well as to analyze the severity and distribution of the identified changes.
Material/Methods:
Thirty-five patients with AD (mean age of 71.6 years, MMSE 17.6), and a control group of 15 healthy volunteers (mean age of 69.1 years, MMSE 29.8) were enrolled in the study. All patients were subjected to a thorough psychiatric examination and psychological tests. DTI examinations (TE 8500, TR 100) were performed using a 1.5T MR scanner. Fractional anisotropy (FA) measurements in the selected areas of interest (ROI) of the white matter fibers were performed under the control of color FA maps. The following fibers were evaluated – the middle cerebellar peduncles (MCP), the inferior longitudinal fasciculi (ILF), inferior frontooccipital fasciculi (IFO), genu (GCC) and splenium of the corpus callosum (SCC), posterior limbs of internal capsules (PLIC), superior longitudinal fasciculi (SLF) and posterior cingula (CG).
Results:
There was a statistically significant decrease in FA in patients with AD, comparing to the control group. It was particularly strongly expressed in both CG (P<0.0001), followed by both ILF, right IFO, and left SLF. Less pronounced changes were found in GCC, SCC, and left IFO. In both PLICs and MCPs and in the right SLF, there was no significant change of FA.
Conclusions:
In Alzheimer’s disease, there is a significant decrease in FA, which suggests degradation of the majority of the assessed white matter tracts. Distribution of these changes is not uniform. They involve the selected association fibers mainly and, to a lesser extent, the commissural fibers, while they are not found in the pyramidal tracts or medial cerebellar peduncles. Definitely, the most pronounced changes were found in the posterior cingula, the assessment of which (in the process of AD diagnostics) seems to be particularly promising.
PMCID: PMC3389871  PMID: 22802770
Alzheimer’s disease; white matter; diffusion tensor imaging; fractional anisotropy
8.  Abnormal Integrity of Corticocortical Tracts in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study 
Journal of Korean Medical Science  2008;23(3):477-483.
Mild cognitive impairment (MCI) has been defined as a transitional state between normal aging and Alzheimer disease. Diffusion tensor imaging (DTI) can estimate the microstructural integrity of white matter tracts in MCI. We evaluated the microstructural changes in the white matter of MCI patients with DTI. We recruited 11 patients with MCI who met the working criteria of MCI and 11 elderly normal controls. The mean diffusivity (MD) and fractional anisotropy (FA) were measured in 26 regions of the brain with the regions of interest (ROIs) method. In the MCI patients, FA values were significantly decreased in the hippocampus, the posterior limb of the internal capsule, the splenium of corpus callosum, and in the superior and inferior longitudinal fasciculus compared to the control group. MD values were significantly increased in the hippocampus, the anterior and posterior limbs of the internal capsules, the splenium of the corpus callosum, the right frontal lobe, and in the superior and the inferior longitudinal fasciculus. Microstructural changes of several corticocortical tracts associated with cognition were identified in patients with MCI. FA and MD values of DTI may be used as novel biomarkers for the evaluation of neurodegenerative disorders.
doi:10.3346/jkms.2008.23.3.477
PMCID: PMC2526517  PMID: 18583886
Mild Cognitive Impairment; Alzheimer Disease; Diffusion Tensor Imaging; Mean Diffusivity; Fractional Anisotropy
9.  Associations between White Matter Hyperintensities and β Amyloid on Integrity of Projection, Association, and Limbic Fiber Tracts Measured with Diffusion Tensor MRI 
PLoS ONE  2013;8(6):e65175.
The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.
doi:10.1371/journal.pone.0065175
PMCID: PMC3675157  PMID: 23762308
10.  Performances of diffusion kurtosis imaging and diffusion tensor imaging in detecting white matter abnormality in schizophrenia 
NeuroImage : Clinical  2014;7:170-176.
Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI), exhibiting improved sensitivity and specificity in detecting developmental and pathological changes in neural tissues. However, little attention was paid to the performances of DKI and DTI in detecting white matter abnormality in schizophrenia. In this study, DKI and DTI were performed in 94 schizophrenia patients and 91 sex- and age-matched healthy controls. White matter integrity was assessed by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK) of DKI and FA, MD, AD and RD of DTI. Group differences in these parameters were compared using tract-based spatial statistics (TBSS) (P < 0.01, corrected). The sensitivities in detecting white matter abnormality in schizophrenia were MK (34%) > AK (20%) > RK (3%) and RD (37%) > FA (24%) > MD (21%) for DKI, and RD (43%) > FA (30%) > MD (21%) for DTI. DKI-derived diffusion parameters (RD, FA and MD) were sensitive to detect abnormality in white matter regions (the corpus callosum and anterior limb of internal capsule) with coherent fiber arrangement; however, the kurtosis parameters (MK and AK) were sensitive to reveal abnormality in white matter regions (the juxtacortical white matter and corona radiata) with complex fiber arrangement. In schizophrenia, the decreased AK suggests axonal damage; however, the increased RD indicates myelin impairment. These findings suggest that diffusion and kurtosis parameters could provide complementary information and they should be jointly used to reveal pathological changes in schizophrenia.
Highlights
•Kurtosis parameters are suitable to assess WM regions with complex fiber arrangement.•Diffusion parameters are suitable to assess WM regions with coherent fiber arrangement.•Increased RD suggests myelin abnormalities in schizophrenia.•Decreased AK indicates axonal abnormalities in schizophrenia.
doi:10.1016/j.nicl.2014.12.008
PMCID: PMC4300008  PMID: 25610778
Diffusion kurtosis imaging; Diffusion tensor imaging; Schizophrenia; White matter; Magnetic resonance imaging
11.  Thalamic integrity underlies executive dysfunction in traumatic brain injury 
Neurology  2010;74(7):558-564.
Objective:
To quantify the effects of traumatic brain injury on integrity of thalamocortical projection fibers and to evaluate whether damage to these fibers accounts for impairments in executive function in chronic traumatic brain injury.
Methods:
High-resolution (voxel size: 0.78 mm × 0.78 mm × 3 mm3) diffusion tensor MRI of the thalamus was conducted on 24 patients with a history of single, closed-head traumatic brain injury (TBI) (12 each of mild TBI and moderate to severe TBI) and 12 age- and education-matched controls. Detailed neuropsychological testing with an emphasis on executive function was also conducted. Fractional anisotropy was extracted from 12 regions of interest in cortical and corpus callosum structures and 7 subcortical regions of interest (anterior, ventral anterior, ventral lateral, dorsomedial, ventral posterior lateral, ventral posterior medial, and pulvinar thalamic nuclei).
Results:
Relative to controls, patients with a history of brain injury showed reductions in fractional anisotropy in both the anterior and posterior corona radiata, forceps major, the body of the corpus callosum, and fibers identified from seed voxels in the anterior and ventral anterior thalamic nuclei. Fractional anisotropy from cortico-cortico and corpus callosum regions of interest did not account for significant variance in neuropsychological function. However, fractional anisotropy from the thalamic seed voxels did account for variance in executive function, attention, and memory.
Conclusions:
The data provide preliminary evidence that traumatic brain injury and resulting diffuse axonal injury results in damage to the thalamic projection fibers and is of clinical relevance to cognition.
GLOSSARY
= anterior corona radiata;
= anterior thalamic nucleus;
= body of the corpus callosum;
= cortical-spinal tract;
= diffuse axonal injury;
= dorsomedial nucleus;
= diffusion tensor imaging;
= fractional anisotropy;
= forceps major;
= forceps minor;
= field of view;
= fast spin echo;
= genu of the corpus callosum;
= internal capsule;
= inferior frontal occipital fasciculus;
= loss of consciousness;
= mild TBI;
= moderate to severe TBI;
= number of excitations;
= posterior corona radiata;
= posttraumatic amnesia;
= pulvinar;
= region of interest;
= splenium of the corpus callosum;
= superior longitudinal fasciculus;
= sagittal stratum;
= traumatic brain injury;
= echo time;
= repetition time;
= ventral anterior thalamic nucleus;
= ventral lateral thalamic nucleus;
= ventral posterior lateral nucleus;
= ventral posterior medial nucleus.
doi:10.1212/WNL.0b013e3181cff5d5
PMCID: PMC2830915  PMID: 20089945
12.  White Matter Alterations in Cognitively Normal apoE ε2 Carriers: Insight into Alzheimer Resistance? 
BACKGROUND AND PURPOSE
The basis for decreased vulnerability to AD among apoE ε2 carriers is unknown. The purpose of this study was to use diffusion tensor imaging to detect possible differences in white matter integrity between cognitively normal elderly apoE ε2 carriers and apoE ε3/ε3 controls.
MATERIALS AND METHODS
Thirty-nine cognitively normal elderly individuals (19 heterozygous carriers of the apoE ε2 allele, 20 apoE ε3/ε3 subjects as controls) underwent diffusion tensor MR imaging on a 4T scanner. Fractional anisotropy, MD, and axial and radial diffusivity were compared using a ROI approach. In addition, an exploratory whole-brain analysis of fractional anisotropy between the 2 groups was undertaken using TBSS.
RESULTS
apoE ε2 carriers had higher FA in the posterior cingulate white matter (P = .01) and anterior corpus callosum (P = .005) than apoE ε3/ε3 controls, secondary to lower radial diffusivity. No significant differences in the FA of the posterior corpus callosum, anterior cingulate white matter, or parahippocampal white matter were seen. Whole-brain TBSS analysis detected regions of higher FA in the apoE ε2 group in the superior longitudinal fasciculus, right thalamus, and the bilateral anterior limbs of the internal capsule, in addition to the posterior cingulum and corpus callosum (P < .005). There were no regions in which the apoE ε3/ε3 group had higher FA.
CONCLUSIONS
apoE ε2 carriers harbor more robust white matter integrity that may be associated with decreased vulnerability to developing AD. This provides further evidence that regional DTI metrics may serve as early imaging biomarkers of AD risk.
doi:10.3174/ajnr.A2984
PMCID: PMC3951461  PMID: 22383234
13.  Multi-modal MRI of mild traumatic brain injury 
NeuroImage : Clinical  2014;7:87-97.
Multi-modal magnetic resonance imaging (MRI) that included high resolution structural imaging, diffusion tensor imaging (DTI), magnetization transfer ratio (MTR) imaging, and magnetic resonance spectroscopic imaging (MRSI) were performed in mild traumatic brain injury (mTBI) patients with negative computed tomographic scans and in an orthopedic-injured (OI) group without concomitant injury to the brain. The OI group served as a comparison group for mTBI. MRI scans were performed both in the acute phase of injury (~24 h) and at follow-up (~90 days). DTI data was analyzed using tract based spatial statistics (TBSS). Global and regional atrophies were calculated using tensor-based morphometry (TBM). MTR values were calculated using the standard method. MRSI was analyzed using LC Model. At the initial scan, the mean diffusivity (MD) was significantly higher in the mTBI cohort relative to the comparison group in several white matter (WM) regions that included internal capsule, external capsule, superior corona radiata, anterior corona radiata, posterior corona radiata, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major and forceps minor of the corpus callosum, superior longitudinal fasciculus, and corticospinal tract in the right hemisphere. TBSS analysis failed to detect significant differences in any DTI measures between the initial and follow-up scans either in the mTBI or OI group. No significant differences were found in MRSI, MTR or morphometry between the mTBI and OI cohorts either at the initial or follow-up scans with or without family wise error (FWE) correction. Our study suggests that a number of WM tracts are affected in mTBI in the acute phase of injury and that these changes disappear by 90 days. This study also suggests that none of the MRI-modalities used in this study, with the exception of DTI, is sensitive in detecting changes in the acute phase of mTBI.
doi:10.1016/j.nicl.2014.07.010
PMCID: PMC4299969  PMID: 25610770
Mild traumatic brain injury; Orthopedic injury; Magnetic resonance imaging; Diffusion tensor imaging; Magnetic resonance spectroscopic imaging; Magnetization transfer ratio; Tensor based morphometry; acr, anterior region of corona radiata; alic, anterior limb of internal capsule; cc, corpus callosum; cs, centrum semiovale; cst, corticospinal tract; ec, external capsule; ic, internal capsule; ifo, inferior fronto-occipital fasciculus; ilf, inferior longitudinal fasciculus; pcr, posterior region of corona radiata; plic, posterior limb of internal capsule; scr, superior region of corona radiata; sfo, superior fronto-occipital fasciculus; slf, superior longitudinal fasciculus; sfg, superior frontal gyrus; mfg, superior frontal gyrus; jlc, juxtapositional lobule cortex; cg, cingulate gyrus; pcg, paracingulate gyrus
14.  Posterior Cingulum White Matter Disruption and Its Associations with Verbal Memory and Stroke Risk in Mild Cognitive Impairment 
Journal of Alzheimer's Disease  2012;29(3):589-603.
Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer’s disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk.
doi:10.3233/JAD-2012-102103
PMCID: PMC3341099  PMID: 22466061
Aging; diffusion tensor imaging; memory; mild cognitive impairment; posterior cingulum; white matter
15.  A prospective diffusion tensor imaging study in mild traumatic brain injury 
Neurology  2010;74(8):643-650.
Objectives:
Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls.
Methods:
Twenty-two patients with semi-acute mTBI (mean = 12 days postinjury), 21 matched healthy controls, and a larger sample (n = 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3–5 months after their initial visit.
Results:
mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts.
Conclusions:
Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.
GLOSSARY
= apparent diffusion coefficient;
= corpus callosum;
= cortical impact injury model;
= corona radiata;
= diffusion tensor imaging;
= external capsule;
= fractional anisotropy;
= fluid percussion injury model;
= healthy controls;
= internal capsule;
= Johns Hopkins University;
= multivariate analysis of covariance;
= mild traumatic brain injury;
= radial diffusivity;
= region of interest;
= superior corona radiata;
= superior longitudinal fasciculus;
= uncinate fasciculus.
doi:10.1212/WNL.0b013e3181d0ccdd
PMCID: PMC2830922  PMID: 20089939
16.  Diffusion Tensor MRI of the Corpus Callosum in Amyotrophic Lateral Sclerosis 
Purpose
To determine if decline in corpus callosum (CC) white matter integrity in patients with amyotrophic lateral sclerosis (ALS) is localized to motor-related areas.
Materials and Methods
Twenty-one ALS patients and 21 controls participated. Diffusion tensor images (DTI) were acquired using 3 Tesla (T) MRI. Tract-based spatial statistics were used to examine whole-brain white matter damage. A segmentation schema was used to define CC volumes-of-interest (VOI). Fractional anisotropy (FA) and radial- and axial-diffusivity (RD, AD) were extracted from VOIs and compared between groups. DTI measurements in motor-related Area III were tested for correlation with symptoms and disease duration.
Results
Extracted FA values from CC VOIs were reduced in ALS patients (P≤0.0001), particularly in Areas II and III (P≤0.01). Reduced FA in Area III correlated with disease symptomology (P≤0.05) and duration (P≤0.02). Between-group whole-brain comparisons (P≤0.05, corrected) showed reduced FA and increased RD throughout white matter regions including the CC, corona radiata, and internal capsule. AD was increased in the left corona radiata and internal and external capsules.
Conclusion
FA in motor-related regions of the CC is more affected than other CC areas in ALS patients. Microstructural pathology of transcallosal fiber tracts may represent a future component of an imaging biomarker for ALS.
doi:10.1002/jmri.24218
PMCID: PMC3888481  PMID: 23843179
DTI; corpus callosum; amyotrophic lateral sclerosis
17.  Structural Modifications of the Brain in Acclimatization to High-Altitude 
PLoS ONE  2010;5(7):e11449.
Adaptive changes in respiratory and cardiovascular responses at high altitude (HA) have been well clarified. However, the central mechanisms underlying HA acclimatization remain unclear. Using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) with fractional anisotropy (FA) calculation, we investigated 28 Han immigrant residents (17–22 yr) born and raised at HA of 2616–4200 m in Qinghai-Tibetan Plateau for at least 17 years and who currently attended college at sea-level (SL). Their family migrated from SL to HA 2–3 generations ago and has resided at HA ever since. Control subjects were matched SL residents. HA residents (vs. SL) showed decreased grey matter volume in the bilateral anterior insula, right anterior cingulate cortex, bilateral prefrontal cortex, left precentral cortex, and right lingual cortex. HA residents (vs. SL) had significantly higher FA mainly in the bilateral anterior limb of internal capsule, bilateral superior and inferior longitudinal fasciculus, corpus callosum, bilateral superior corona radiata, bilateral anterior external capsule, right posterior cingulum, and right corticospinal tract. Higher FA values in those regions were associated with decreased or unchanged radial diffusivity coinciding with no change of longitudinal diffusivity in HA vs. SL group. Conversely, HA residents had lower FA in the left optic radiation and left superior longitudinal fasciculus. Our data demonstrates that HA acclimatization is associated with brain structural modifications, including the loss of regional cortical grey matter accompanied by changes in the white matter, which may underlie the physiological adaptation of residents at HA.
doi:10.1371/journal.pone.0011449
PMCID: PMC2897842  PMID: 20625426
18.  Aging White Matter and Cognition: Differential Effects of Regional Variations in Diffusion Properties on Memory, Executive Functions, and Speed 
Neuropsychologia  2009;47(3):916-927.
Disruption of cerebral white matter has been proposed as an explanation for age-related cognitive declines. However, the role of specific regions in specific cognitive declines remains unclear. We used diffusion tensor imaging to examine the associations between regional microstructural integrity of the white matter and performance on age-sensitive cognitive tasks in a sample of healthy adults (N = 52, age 19–81 years). White matter integrity was assessed by fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in multiple regions of interest (genu and splenium of corpus callosum, internal capsule limbs, prefrontal, temporal, superior/posterior parietal, occipital white matter) and related to processing speed, working memory, inhibition, task switching, and episodic memory. We found that age and regional white matter integrity differentially influenced cognitive performance. Age-related degradation in anterior brain areas was associated with decreased processing speed and poorer working memory, whereas reduced inhibition and greater task switching costs were linked to decline in posterior areas. Poorer episodic memory was associated with age-related differences in central white matter regions. The observed multiple dissociations among specific age-sensitive cognitive skills and their putative neuroanatomical substrates support the view that age-related cognitive declines are unlikely to stem from a single cause.
doi:10.1016/j.neuropsychologia.2009.01.001
PMCID: PMC2643310  PMID: 19166865
aging; brain; MRI; diffusion tensor imaging; cognition; white matter; disconnection
19.  Diffusion Tensor Anisotropy in Adolescents and Adults 
Neuropsychobiology  2007;55(2):96-111.
We acquired diffusion tensor images on 33 normal adults aged 22–64 and 15 adolescents aged 14–21. We assessed relative anisotropy in stereotaxically located regions of interest in the internal capsule, corpus callosum, anterior thalamic radiations, frontal anterior fasciculus, fronto-occipital fasciculus, temporal lobe white matter, cingulum bundle, frontal inferior longitudinal fasciculus, frontal superior longitudinal fasciculus, and optic radiations. All of these structures except the optic radiations, corpus callosum, and frontal inferior longitudinal fasciculus exhibited differences in anisotropy between adolescents and adults. Areas with anisotropy increasing with age included the anterior limb of the internal capsule, superior levels of the frontal superior longitudinal fasciculus and the inferior portion of the temporal white matter. Areas with anisotropy decreasing with age included the posterior limb of the internal capsule, anterior thalamic radiations, fronto-occipital fasciculus, anterior portion of the frontal anterior fasciculus, inferior portion of the frontal superior longitudinal fasciculus, cingulum bundle and superior portion of the temporal axis. Sex differences were found in the majority of areas but were most marked in the cingulum bundle and internal capsule. These results suggest continuing white matter development between adolescence and adulthood.
doi:10.1159/000104277
PMCID: PMC2806688  PMID: 17587876
Age; White matter; Magnetic resonance imaging
20.  White matter integrity is associated with alcohol cue reactivity in heavy drinkers 
Brain and Behavior  2013;4(2):158-170.
Neuroimaging studies have shown that white matter damage accompanies excessive alcohol use, but the functional correlates of alcohol-related white matter disruption remain unknown. This study applied tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) data from 332 heavy drinkers (mean age = 31.2 ± 9.4; 31% female) to obtain averaged fractional anisotropy (FA) values of 18 white matter tracts. Statistical analyses examined correlations of FA values with blood-oxygenation-level-dependent (BOLD) response to an alcohol taste cue, measured with functional magnetic resonance imaging (fMRI). FA values of nine white matter tracts (anterior corona radiata, body of corpus callosum, cingulate gyrus, external capsule, fornix, inferior frontooccipital fasciculus, posterior corona radiata, retrolenticular limb of internal capsule, and superior longitudinal fasciculus) were significantly, negatively correlated with BOLD activation in medial frontal gyrus, parahippocampal gyrus, fusiform gyrus, cingulum, thalamus, caudate, putamen, insula, and cerebellum. The inverse relation between white matter integrity and functional activation during the alcohol taste cue provides support for the hypothesis that lower white matter integrity in frontoparietal and corticolimbic networks is a factor in loss of control over alcohol consumption.
doi:10.1002/brb3.204
PMCID: PMC3967532  PMID: 24683509
Alcohol use disorders; diffusion tensor imaging; functional magnetic resonance imaging; tract-based spatial statistics; white matter
21.  Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia 
Neurology  2010;74(16):1279-1287.
Objective:
To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA).
Methods:
This was a case-control study where 16 subjects with bvFTD, 7 with PNFA, and 4 with SMD were identified and matched by age and gender to 19 controls. All subjects had 3-T head MRI with a DTI sequence with diffusion encoding in 21 directions. Gray matter mean diffusivity (MD) was assessed using a region-of-interest (ROI) and voxel-level approach, and voxel-based morphometry was used to assess patterns of gray matter loss. White matter tract diffusivity (fractional anisotropy and radial diffusivity) was assessed by placing ROIs on tracts of interest.
Results:
In bvFTD, increased gray matter MD and gray matter loss were identified bilaterally throughout frontal and temporal lobes, with abnormal diffusivity observed in white matter tracts that connect to these regions. In SMD, gray matter loss and increased MD were identified predominantly in the left temporal lobe, with tract abnormalities observed in the inferior longitudinal fasciculus and uncinate fasciculus. In PNFA, gray matter loss and increased MD were observed in left inferior frontal lobe, insula, and supplemental motor area, with tract abnormalities observed in the superior longitudinal fasciculus.
Conclusions:
The diffusivity of gray matter is increased in regions that are atrophic in frontotemporal dementia, suggesting disruption of the cytoarchitecture of remaining tissue. Furthermore, damage was identified in white matter tracts that interconnect these regions, supporting the hypothesis that these diseases involve different and specific brain networks.
GLOSSARY
= automated anatomic labeling;
= anterior cingulate;
= Alzheimer's Disease Research Center;
= Alzheimer's Disease Patient Registry;
= apraxia of speech;
= behavioral variant frontotemporal dementia;
= coefficient of variation;
= axial diffusivity;
= radial diffusivity;
= diffusion tensor imaging;
= fractional anisotropy;
= false discovery rate;
= field of view;
= frontotemporal dementia;
= full-width at half-maximum;
= genu of the corpus callosum;
= high-dimensional warping;
= inferior longitudinal fasciculus;
= mean diffusivity;
= magnetization prepared rapid acquisition gradient echo;
= posterior cingulate;
= progressive nonfluent aphasia;
= partial volume correction;
= region of interest;
= superior longitudinal fasciculus;
= semantic dementia;
= uncinate fasciculus.
doi:10.1212/WNL.0b013e3181d9edde
PMCID: PMC2860485  PMID: 20404309
22.  Abnormal White Matter Integrity in Adolescents with Internet Addiction Disorder: A Tract-Based Spatial Statistics Study 
PLoS ONE  2012;7(1):e30253.
Background
Internet addiction disorder (IAD) is currently becoming a serious mental health issue around the globe. Previous studies regarding IAD were mainly focused on associated psychological examinations. However, there are few studies on brain structure and function about IAD. In this study, we used diffusion tensor imaging (DTI) to investigate white matter integrity in adolescents with IAD.
Methodology/Principal Findings
Seventeen IAD subjects and sixteen healthy controls without IAD participated in this study. Whole brain voxel-wise analysis of fractional anisotropy (FA) was performed by tract-based spatial statistics (TBSS) to localize abnormal white matter regions between groups. TBSS demonstrated that IAD had significantly lower FA than controls throughout the brain, including the orbito-frontal white matter, corpus callosum, cingulum, inferior fronto-occipital fasciculus, and corona radiation, internal and external capsules, while exhibiting no areas of higher FA. Volume-of-interest (VOI) analysis was used to detect changes of diffusivity indices in the regions showing FA abnormalities. In most VOIs, FA reductions were caused by an increase in radial diffusivity while no changes in axial diffusivity. Correlation analysis was performed to assess the relationship between FA and behavioral measures within the IAD group. Significantly negative correlations were found between FA values in the left genu of the corpus callosum and the Screen for Child Anxiety Related Emotional Disorders, and between FA values in the left external capsule and the Young's Internet addiction scale.
Conclusions
Our findings suggest that IAD demonstrated widespread reductions of FA in major white matter pathways and such abnormal white matter structure may be linked to some behavioral impairments. In addition, white matter integrity may serve as a potential new treatment target and FA may be as a qualified biomarker to understand the underlying neural mechanisms of injury or to assess the effectiveness of specific early interventions in IAD.
doi:10.1371/journal.pone.0030253
PMCID: PMC3256221  PMID: 22253926
23.  DTI and MTR abnormalities in schizophrenia: Analysis of white matter integrity 
NeuroImage  2005;26(4):1109-1118.
Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multi-directional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.
doi:10.1016/j.neuroimage.2005.03.026
PMCID: PMC2768051  PMID: 15878290
Diffusion tensor imaging; Magnetization transfer ratio; Schizophrenia; White matter integrity
24.  White Matter Integrity is Reduced in Bulimia Nervosa 
Objective
To investigate brain white matter (WM) functionality in bulimia nervosa (BN) in relation to anxiety.
Method
Twenty-one control (CW, mean age 27±7 years) and 20 BN women (mean age 25±5 years) underwent brain diffusion tensor imaging (DTI) to measure fractional anisotropy (FA; an indication of WM axon integrity) and the apparent diffusion coefficient (ADC; reflecting WM cell damage).
Results
FA was decreased in BN in the bilateral corona radiata extending into the posterior limb of the internal capsule, the corpus callosum, the right sub-insular white matter and right fornix. In CW but not BN trait anxiety correlated negatively with fornix, corpus callosum and left corona radiata FA. ADC was increased in BN compared to CW in the bilateral corona radiata, corpus callosum, inferior fronto-occipital and uncinate fasciculus. Alterations in BN WM functionality were not due to structural brain alterations.
Discussion
WM integrity is disturbed in BN, especially in the corona radiate, which has been associated with taste and brain reward processing. Whether this is a premorbid condition or an effect from the illness is yet uncertain. The relationships between WM FA and trait anxiety in CW but not BN may suggest that altered WM functionality contributes to high anxious traits in BN.
doi:10.1002/eat.22083
PMCID: PMC3722416  PMID: 23354827
25.  Children with New Onset Epilepsy Exhibit Diffusion Abnormalities in Cerebral White Matter in the Absence of Volumetric Differences 
Epilepsy research  2009;88(2-3):208-214.
SUMMARY
The purpose of this investigation was to examine the diffusion properties of cerebral white matter in children with recent onset epilepsy (n=19) compared to healthy controls (n=11). Subjects underwent DTI with quantification of mean diffusion (MD), fractional anisotropy (FA), axial diffusivity (Dax) and radial diffusivity (Drad) for regions of interest including anterior and posterior corpus callosum, fornix, cingulum, and internal and external capsules. Quantitative volumetrics were also performed for the corpus callosum and its subregions (anterior, midbody and posterior) and total lobar white and gray matter for the frontal, parietal, temporal and occipital lobes. The results demonstrated no group differences in total lobar gray or white matter volumes or volume of the corpus callosum and its subregions, but did show reduced FA and increased Drad in the posterior corpus callosum and cingulum. These results provide the earliest indication of microstructural abnormality in cerebral white matter among children with idiopathic epilepsies. This abnormality occurs in the context of normal volumetrics and suggests disruption in myelination processes.
doi:10.1016/j.eplepsyres.2009.11.011
PMCID: PMC2826144  PMID: 20044239
DTI; volumetrics; MRI; epilepsy

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