Changes In Normal-appearing White Matter Research Articles

Distinct white matter microstructural abnormalities and extracellular water increases relate to cognitive impairment in Alzheimer\u2019s disease with and without cerebrovascular disease

BackgroundMixed vascular and neurodegenerative dementia, such as Alzheimer’s disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method.MethodsWe compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects.ResultsThe cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance.ConclusionsOur findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

Diffusion tensor imaging of normal-appearing white matter in patients with neuromyelitis optica spectrum disorder and multiple sclerosis.

The occult changes in normal-appearing white matter (NAWM) were investigated and compared amongst patients with neuromyelitis optica spectrum disorder (NMOSD), patients with multiple sclerosis (MS) and healthy controls (HCs) by applying tract-based spatial statistics to diffusion tensor imaging (DTI) data. Diffusion tensor imaging was performed with a 3-T scanner in 93 patients with NMOSD, 53 patients with MS and 43 HCs. Voxel-wise statistical analyses of the DTI data were performed using tract-based spatial statistics. Compared to HCs, patients with NMOSD had significantly lower mean global fractional anisotropy, higher mean diffusivity and radial diffusivity, and no significant differences in axial diffusivity in their NAWM. Patients with MS demonstrated significantly lower mean global fractional anisotropy and higher mean diffusivity, axial diffusivity and radial diffusivity in the NAWM than did patients with NMOSD and HCs. Compared to patients with NMOSD, patients with MS had NAWM damage that was more extensive, particularly in the inferior cerebellar peduncle, external capsule, cingulum, superior fronto-occipital fasciculus and uncinate fasciculus. Using DTI, widespread occult damage was demonstrated in the NAWM of patients with NMOSD. However, the NAWM was less affected in patients with NMOSD than it was in patients with MS; specifically, the axonal injuries and diffusion abnormalities in the association fibers were more severe in patients with MS than they were in patients with NMOSD.

Susceptibility-sensitive MRI of multiple sclerosis lesions and the impact of normal-appearing white matter changes.

Susceptibility-sensitive magnetic resonance imaging (MRI) has gained importance in multiple sclerosis (MS) research because of its versatility, high resolution and excellent sensitivity to changes in tissue structure and composition. In particular, mapping of the resonance frequency of the MR signal and quantitative susceptibility mapping (QSM) have been explored for the description of MS lesions. Many current studies utilizing these techniques attribute increases in the MR frequency or QSM to elevated tissue iron content, in addition to myelin loss. However, this common interpretation is inconsistent with recent histopathological studies. Here, we investigate the nature of MR frequency shifts related to MS lesions by comparing post-mortem MRI data with histology, and contrast them with numerical simulations of the MR signal. We demonstrate that iron accumulation is not the driving source of the MR frequency or QSM image contrast in our sample; rather, most chronic MS lesions are characterized by advanced loss of both myelin and iron. Moreover, our results suggest that the appearance of MS lesions on MR frequency maps and QSM depends on changes in the non-lesional white matter surrounding the lesions. Understanding and accounting for these changes is essential for the quantitative interpretation of MR frequency or QSM data in white matter.

Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging.

DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years. Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis. A significant increase was observed for axial diffusivity (P < .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions (P < .001) and chronic T2 lesions (P = .02) compared with normal-appearing white matter. An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.

Influence of cigarette smoking on white matter in patients with clinically isolated syndrome as detected by diffusion tensor imaging.

Cigarette smoking has been associated with increased occurrence of multiple sclerosis (MS), as well as clinical disability and disease progression in MS. We aimed to assess the effects of smoking on the white matter (WM) in patients with clinically isolated syndrome (CIS) using diffusion tensor imaging. Smoker patients with CIS (n=16), smoker healthy controls (n=13), nonsmoker patients with CIS (n=17) and nonsmoker healthy controls (n=14) were included. Thirteen regions-of-interest including nonenhancing T1 hypointense lesion and perilesional WM, and 11 normal-appearing white matter (NAWM) regions were drawn on color-coded fractional anisotropy (FA) maps. Lesion load was determined in terms of number and volume of WM hyperintensities. A tendency towards greater lesion load was found in smoker patients. T1 hypointense lesions and perilesional WM had reduced FA and increased mean diffusivity to a similar degree in smoker and nonsmoker CIS patients. Compared with healthy smokers, smoker CIS patients had more extensive NAWM changes shown by increased mean diffusivity. There was no relationship between diffusion metrics and clinical disability scores, duration of the disease and degree of smoking exposure. Smoker patients showed a tendency towards having greater number of WM lesions and displayed significantly more extensive NAWM abnormalities.

Diffusion tensor imaging in children with tuberous sclerosis complex: tract-based spatial statistics assessment of brain microstructural changes.

There is evidence of microstructural changes in normal-appearing white matter of patients with tuberous sclerosis complex. To evaluate major white matter tracts in children with tuberous sclerosis complex using tract-based spatial statistics diffusion tensor imaging (DTI) analysis. Eight children (mean age ± standard deviation: 8.5 ± 5.5 years) with an established diagnosis of tuberous sclerosis complex and 8 age-matched controls were studied. The imaging protocol consisted of T1-weighted high-resolution 3-D spoiled gradient-echo sequence and a spin-echo, echo-planar diffusion-weighted sequence. Differences in the diffusion indices were evaluated using tract-based spatial statistics. Tract-based spatial statistics showed increased axial diffusivity in the children with tuberous sclerosis complex in the superior and anterior corona radiata, the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the uncinate fascicle and the anterior thalamic radiation. No significant differences were observed in fractional anisotropy, mean diffusivity and radial diffusivity between patients and control subjects. No difference was found in the diffusion indices between the baseline and follow-up examination in the patient group. Patients with tuberous sclerosis complex have increased axial diffusivity in major white matter tracts, probably related to reduced axonal integrity.

Serial diffusion tensor imaging for early detection of radiation‐induced injuries to normal‐appearing white matter in high‐grade glioma patients

To study the potential of diffusion tensor imaging (DTI) to serve as a biomarker for radiation-induced brain injury during chemo-radiotherapy (RT) treatment. Serial DTI data were collected from 18 high-grade glioma (HGG) patients undergoing RT and 7 healthy controls. Changes across time in mean, standard deviation (SD), skewness, and kurtosis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λa ), and transversal diffusivity (λt ) within the normal-appearing white matter (NAWM) were modeled using a linear mixed-effects model to assess dose dependent changes of five dose bins (0-60 Gy), and global changes compared with a control group. Mean MD, λa and λt were all significantly increasing in >41 Gy dose regions (0.14%, 0.10%, and 0.18% per week) compared with <12 Gy regions. SD λt had significant dose dependent time evolution of 0.019*dose per week. Mean and SD MD, λa and λt in the global NAWM of the patient group significantly increased (mean; 0.06%, 0.03%, 0.09%, and SD; 0.57%, 0.34%, 0.51 per week) compared with the control group. The changes were significant at week 6 of, or immediately after RT. DTI is not sensitive to acute global NAWM changes during the treatment of HGG, but sensitive to early posttreatment changes.

Decreased T1 Contrast between Gray Matter and Normal-Appearing White Matter in CADASIL

CADASIL is the most frequent hereditary small-vessel disease of the brain. The clinical impact of various MR imaging markers has been repeatedly studied in this disorder, but alterations of contrast between gray matter and normal-appearing white matter remain unknown. The aim of this study was to evaluate the contrast alterations between gray matter and normal-appearing white matter on T1-weighted images in patients with CADASIL compared with healthy subjects. Contrast between gray matter and normal-appearing white matter was assessed by using histogram analyses of 3D T1 high-resolution MR imaging in 23 patients with CADASIL at the initial stage of the disease (Mini-Mental State Examination score > 24 and modified Rankin scale score ≤ 1; mean age, 53.5 ± 11.1 years) and 30 age- and sex-matched controls. T1 contrast between gray matter and normal-appearing white matter was significantly reduced in patients compared with age- and sex-matched controls (patients: 1.35 ± 0.08 versus controls: 1.43 ± 0.04, P < 10(-5)). This reduction was mainly driven by a signal decrease in normal-appearing white matter. Contrast loss was strongly related to the volume of white matter hyperintensities. Conventional 3D T1 imaging shows significant loss of contrast between gray matter and normal-appearing white matter in CADASIL. This probably reflects tissue changes in normal-appearing white matter outside signal abnormalities on T2 or FLAIR sequences. These contrast alterations should be taken into account for image interpretation and postprocessing.

Development of white matter lesions is preceded by changes in normal-appearing white matter

Development of white matter lesions is preceded by changes in normal-appearing white matter

Development of white matter lesions is preceded by changes in normal-appearing white matter

Development of white matter lesions is preceded by changes in normal-appearing white matter

Diffusion tensor imaging of normal‐appearing white matter in unilateral cerebral arterial occlusive disease

To use MR with diffusion tensor imaging (DTI) and conventional and high b value to assess diffusion changes in normal-appearing white matter (NAWM) in patients with unilateral, severe stenosis, or occlusion of the middle cerebral artery (MCA). In total, 28 patients with NAWM and unilateral, severe stenosis, or occlusion of the MCA underwent DTI with b values 1000 and 2200 s/mm(2) at 3.0T MR. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity (eigenvalues λ1 , λ2 ), and axial diffusivity (eigenvalue λ3 ) were measured for the ipsilateral and contralateral corona radiata. Mean FA was significantly lower for the ipsilateral than contralateral corona radiata with high b value, 2200 s/mm(2) , and ipsilateral corona radiata with conventional low b value, 1000 s/mm(2) (all P < 0.01). Mean ADC, λ1 , λ2 , and λ3 were significantly higher for the ipsilateral than contralateral corona radiata with high b value (all P < 0.05) but not for ipsilateral than contralateral corona radiata with low b value (P > 0.05). DTI with a high b value detects diffusion changes in NAWM in patients with unilateral, severe stenosis, or occlusion of the MCA not seen with conventional b value or conventional MRI contrasts.

Changes in Normal-Appearing White Matter Precede Development of White Matter Lesions

It is unknown whether white matter lesions (WML) develop abruptly in previously normal brain areas, or whether tissue changes are already present before WML become apparent on MRI. We therefore investigated whether development of WML is preceded by quantifiable changes in normal-appearing white matter (NAWM). In 689 participants from the general population (mean age 67 years), we performed 2 MRI scans (including diffusion tensor imaging and Fluid Attenuation Inversion Recovery [FLAIR] sequences) 3.5 years apart using the same 1.5-T scanner. Using automated tissue segmentation, we identified NAWM at baseline. We assessed which NAWM regions converted into WML during follow-up and differentiated new WML into regions of WML growth and de novo WML. Fractional anisotropy, mean diffusivity, and FLAIR intensity of regions converting to WML and regions of persistent NAWM were compared using 3 approaches: a whole-brain analysis, a regionally matched approach, and a voxel-wise approach. All 3 approaches showed that low fractional anisotropy, high mean diffusivity, and relatively high FLAIR intensity at baseline were associated with WML development during follow-up. Compared with persistent NAWM regions, NAWM regions converting to WML had significantly lower fractional anisotropy (0.337 vs 0.387; P<0.001), higher mean diffusivity (0.910 × 10(-3) mm(2)/s vs 0.729 × 10(-3) mm(2)/s; P<0.001), and relatively higher normalized FLAIR intensity (1.233 vs -0.340; P<0.001). This applied to both NAWM developing into growing and de novo WML. White matter changes in NAWM are present and can be quantified on diffusion tensor imaging and FLAIR before WML develop. This suggests that WML develop gradually, and that visually appreciable WML are only the tip of the iceberg of white matter pathology.

Diffusion Tensor Imaging in NAWM and NADGM in MS and CIS: Association with Candidate Biomarkers in Sera

The aim of this study was to evaluate diffusion tensor imaging (DTI) indices in the corpus callosum and pyramidal tract in normal-appearing white matter (NAWM) and the caudate nucleus and thalamus in deep grey matter (NADGM) in all MS subtypes and clinically isolated syndrome (CIS). Furthermore, it was determined whether these metrics are associated with clinical measures and the serum levels of candidate immune biomarkers. Apparent diffusion coefficients (ADC) values were significantly higher than in controls in all six studied NAWM regions in SPMS, 4/6 regions in RRMS and PPMS and 2/6 regions in CIS. In contrast, decreased fractional anisotropy (FA) values in comparison to controls were detected in 2/6 NAWM regions in SPMS and 1/6 in RRMS and PPMS. In RRMS, the level of neurological disability correlated with thalamic FA values (r = 0.479, P = 0.004). In chronic progressive subtypes and CIS, ADC values of NAWM and NADGM were associated with the levels of MIF, sFas, and sTNF-α. Our data indicate that DTI may be useful in detecting pathological changes in NAWM and NADGM in MS patients and that these changes are related to neurological disability.

Diffusional kurtosis imaging of normal-appearing white matter in multiple sclerosis: preliminary clinical experience

We evaluated diffusional changes in normal-appearing white matter (NAWM) regions remote from multiple sclerosis (MS) plaques by using diffusional kurtosis imaging (DKI) to investigate the non-Gaussian behavior of water diffusion. Participants were 11 MS patients and 6 age-matched healthy volunteers. DKI was performed on a 3-T MR imager. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), and diffusional kurtosis (DK) maps were computed. Regions of interest (ROIs) were compared in 24 cerebral regions, including the frontal, parietal, and temporal lobe white matter (WM) in controls and NAWM in MS patients. The mean FA of all ROIs was 0.468 ± 0.014 (SD) (controls) or 0.431 ± 0.029 (MS group) (P = 0.016). Mean ADC was 0.785 ± 0.034 × 10(-3) mm(2)/s (controls) or 0.805 ± 0.041 × 10(-3) mm(2)/s (MS group). The mean DK of all ROIs was 0.878 ± 0.020 (controls) or 0.823 ± 0.032 (MS group) (P = 0.002). Analysis of individual ROIs revealed significant differences in DK in 3 ROIs between normal WM and NAWM, but significant differences in ADC and FA in only one ROI each. DKI may be a new sensitive indicator for detecting tissue damage in MS patients in addition to conventional diffusional evaluations, for example diffusion tensor imaging.

Multiple Sclerosis: Effects of Cognitive Rehabilitation on Structural and Functional MR Imaging Measures—An Explorative Study

To evaluate brain changes after cognitive rehabilitation in patients with clinically stable relapsing-remitting (RR) multiple sclerosis (MS) by using neuropsychologic assessment and structural and functional magnetic resonance (MR) imaging techniques. The study was conducted with approval of the involved institutional review boards. Written informed consent was obtained from each participant. Twenty patients with RR MS and cognitive deficits at baseline were randomly assigned to undergo treatment (n = 10), which entailed computer-assisted cognitive rehabilitation of attention and information processing and executive functions, or to serve as a control subjects (n = 10) without cognitive rehabilitation. All patients underwent a standardized neuropsychologic assessment and MR imaging at baseline and after 12 weeks. Changes in gray matter (GM) volumes on three-dimensional T1-weighted images and changes in normal-appearing white matter (NAWM) architecture on diffusion-weighted images were assessed. Changes in functional activity at functional MR imaging during the Stroop task and at rest were also investigated by using linear models. As compared with their performance at baseline, the patients in the treatment group improved at tests of attention and information processing and executive functions. Neither structural modifications to GM volume nor modifications to NAWM architecture were detected at follow-up in both groups. Functional MR imaging demonstrated modifications of the activity of the posterior cingulate cortex (PCC)/precuneus and dorsolateral prefrontal cortex (PFC) during the Stroop task, as well as modifications of the activity of the anterior cingulum, PCC and/or precuneus, left dorsolateral PFC, and right inferior parietal lobule at rest in the treatment group compared with the control group. In the treatment group, functional MR imaging changes were correlated with cognitive improvement (P < .0001 to .01). Rehabilitation of attention and information processing and executive functions in RR MS may be effected through enhanced recruitment of brain networks subserving the trained functions.

Everolimus alters white matter diffusion in tuberous sclerosis complex

Diffusion tensor imaging (DTI) analysis was performed on patients with tuberous sclerosis complex (TSC) to investigate potential changes in normal-appearing white matter after treatment with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Recently, a phase I/II trial of everolimus demonstrated significant reductions in subependymal giant cell astrocytoma (SEGA) volume and decreased seizure frequency. Subgroup analysis was performed on DTI data available from this study. TSC patients with SEGA received everolimus, titrated to tolerability to achieve target trough concentrations of 5-15 ng/mL. DTI (1.5 T, 15 directions) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivity within regions of interest (ROIs). Baseline scans were compared to 12-18 months post-treatment and compared to a TSC age- and gender-matched nontreatment control cohort. Of 28 enrolled patients, 20 had sufficient DTI data. Comparing baseline values with those acquired 12-18 months after treatment, a significant change in FA was observed in the corpus callosum, internal capsule, and geniculo-calcarine region (p < 0.05). Mean change in FA was 0.04 (p < 0.01), driven primarily by a significant decrease in radial diffusivity. Mean diffusivity of the combined ROIs decreased slightly (p < 0.05), axial diffusivity remained stable. The control group showed no change over time. Significant changes in FA and radial diffusivity were observed after treatment with everolimus in patients with TSC, suggesting that the genetic defect of TSC in the brain may be modified pharmacologically, even in normal-appearing white matter.

Short-term stability of T 1 and T 2 relaxation measures in multiple sclerosis normal appearing white matter

The presence of diffuse and widespread abnormalities within the 'normal appearing' white matter (NAWM) of multiple sclerosis (MS) brain has been established. T(1) histogram analysis has revealed increased T(1) (related to water content) in segmented NAWM, while quantitative assessment of T(2) relaxation measures has demonstrated decreased myelin water fraction (MWF, related to myelin content) and increased geometric mean T(2) (GMT(2)) of the intra/extracellular water pool. Previous studies with follow-up periods of 1-5 years have demonstrated longitudinal changes in T(1) histogram metrics over time; however, longitudinal changes in MWF and GMT(2) of segmented NAWM have not been examined. We examined the short-term evolution of MWF, GMT(2) and T(1) in MS NAWM based on monthly scanning over 6 months in 18 relapsing remitting (RR) MS subjects. Histogram metrics demonstrated short-term stability of T(1), MWF and remitting (RR) MS subjects. We observed no change in MWF, GMT(2) or T(1) histogram metrics in NAWM in RRMS over the course of 6 months. Longer follow-up periods may be required to establish demonstrable changes in NAWM based on of MWF, GMT(2) and T(1) metrics.

White Matter Integrity and Core Cognitive Function in Children Diagnosed With Sickle Cell Disease

Children diagnosed with sickle cell disease (SCD) have an increased risk of stroke, often associated with white matter damage and neurocognitive morbidity. Growing evidence suggests that subtle changes in white matter integrity, which do not pass the threshold to be visible on a clinical magnetic resonance image and classified as stroke, may contribute to decreased cognitive performance. We used archived diffusion-weighted imaging and neurocognitive assessment data to identify associations between microstructural changes in normal-appearing white matter and cognitive performance in children with SCD. Study participants included 10 healthy children and 15 pediatric SCD patients (5 with identified lesions and 10 without lesion). After excluding lesioned tissue from analyses, we detected significant increases in apparent diffusion coefficient across the brains of patients in comparison with control children, suggesting compromise to the structure of normal-appearing white matter. Deficits in working memory and processing speed were also apparent in patients. Increased apparent diffusion coefficient and deficiencies in processing speed were again detected in a subanalysis including only the patients without lesion. Correlation analyses evidenced associations between the microstructure of the right frontal lobe and cerebellum, and processing speed. This outcome suggests a relationship between tissue integrity and cognitive morbidity in SCD patients.

Impaired Cerebrovascular Reactivity With Steal Phenomenon Is Associated With Increased Diffusion in White Matter of Patients With Moyamoya Disease

Reduced cerebrovascular reactivity (CVR) with steal phenomenon is an independent predictor for stroke and may indicate tissue exposed to episodic low-grade ischemia. The apparent diffusion coefficient (ADC) calculated using diffusion-weighted MRI is effective in characterizing focal brain ischemia and subtle structural changes in normal-appearing white matter (WM). We hypothesized that regions of steal phenomenon are associated with increased ADC in normal-appearing WM of patients with Moyamoya disease. Twenty-two patients with unilateral CVR impairment secondary to Moyamoya disease and 12 healthy control subjects underwent diffusion-weighted MRI and functional MRI mapping of the cerebrovascular response to hypercapnia. Parametric maps of ADC and CVR were calculated, coregistered, and segmented using automated image processing methods. ADC of normal-appearing WM was compared between hemispheres, and between WM with negative CVR (ie, steal phenomenon) and WM with positive CVR. In patients, ADC of normal-appearing WM was elevated in the hemisphere ipsilateral to the CVR impairment compared with the contralateral hemisphere (P<0.005) and in WM with negative CVR compared with WM with positive CVR (P<0.001). WM in regions of steal phenomenon within the affected hemisphere had higher ADC than homologous contralateral WM (P<0.005). In control subjects, negative CVR in WM was not associated with elevated ADC. Regions of steal phenomenon are spatially correlated with elevated ADC in normal-appearing WM of patients with Moyamoya disease. This structural abnormality may reflect low-grade ischemic injury after exhaustion of the cerebrovascular reserve capacity.

Diffusion tensor imaging identifies changes in normal-appearing white matter within the epileptogenic zone in tuberous sclerosis complex

To evaluate diffusion tensor imaging (DTI) indices of (i) cortical tubers and (ii) normal-appearing subcortical white matter adjacent to cortical tubers within the epileptogenic zone and non-epileptogenic zone. Twelve children with tuberous sclerosis complex underwent MRI, DTI and magnetoencephalography (MEG). Regions of interest (ROIs) were placed within cortical tubers and normal-appearing subcortical white matter adjacent to cortical tubers within MEG identified epileptogenic zone and non-epileptogenic zone. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(parallel)) and radial diffusivity (lambda(perpendicular)) were calculated. 26 out of 104 cortical tubers were in the epileptogenic zone. FA of cortical tubers in the epileptogenic zone was significantly lower than non-epileptogenic zone (p=0.015). There were no significant differences between MD (p=0.896), lambda(parallel) (p=0.672) and lambda(perpendicular) (p=0.651) of cortical tubers in the epileptogenic and non-epileptogenic zone. In normal-appearing subcortical white matter within the epileptogenic zone, FA was lower (p=0.001) and lambda(perpendicular) (p=0.011) was higher than non-epileptogenic zone. There were no significant differences between MD (p=0.110) and lambda(parallel) (p=0.735) of normal-appearing subcortical white matter within the epileptogenic and non-epileptogenic zone. DTI changes in normal-appearing white matter within the epileptogenic zone could represent abnormal white matter related to MRI-occult dysplastic cortex or ictal/interictal activity.