Manganese enhanced MRI (MEMRI): neurophysiological applications

Manganese ion (Mn(2+)) is a calcium (Ca(2+)) analog that can enter neurons and other excitable cells through voltage gated Ca(2+) channels. Mn(2+) is also a paramagnetic that shortens the spin-lattice relaxation time constant (T(1)) of tissues where it has accumulated, resulting in positive contrast enhancement. Mn(2+) was first investigated as a magnetic resonance imaging (MRI) contrast agent approximately 20 years ago to assess the toxicity of the metal in rats. In the late 1990s, Alan Koretsky and colleagues pioneered the use of manganese enhanced MRI (MEMRI) towards studying brain activity, tract tracing and enhancing anatomical detail. This review will describe the methodologies and applications of MEMRI in the following areas: monitoring brain activity in animal models, in vivo neuronal tract tracing and using MEMRI to assess in vivo axonal transport rates.     

Magnetic source imaging and reactivity to rhythmical stimulation in tuberous sclerosis

The present study combined functional magnetoencephalography (MEG) and anatomical magnetic resonance imaging (MRI) information in three patients affected by tuberous sclerosis and partial epilepsy. MEG recordings were performed during both spontaneous and visual evoked activity. The former showed a large variety of complexes whose spatial and temporal distribution suggested different neuronal populations acting simultaneously in the same focal district. When these data were integrated with MRI images (magnetic source imaging, MSI) there was agreement in the definition of tubers and extension of the epileptogenic area. Furthermore, cortical reactivity to rhythmical stimulation was studied with trains of visual stimuli according to a recently proposed frequency responsiveness procedure (FRP). As compared to normal controls, a large 6 Hz activity was observed during the pause after a non-resonant stimulation. This altered resonance property may indicate a disturbed primary sensory processing notwithstanding a preserved associated processing. These results show that neuronal malfunctioning in tuberous sclerosis complex patients may not be restricted to the area of cortical tubers, but can also affect functionally correlated regions.     

The effects of a neuregulin 1 variant on white matter density and integrity

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.     

Multimodal magnetic resonance imaging: The coordinated use of multiple,mutually informative probes to understand brain structure and function

Differing imaging modalities provide unique channels of information to probe differing aspects of the brain's structural or functional organization. In combination, differing modalities provide complementary and mutually informative data about tissue organization that is more than their sum. We acquired and spatially coregistered data in four MRI modalities—anatomical MRI, functional MRI, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS)—from 20 healthy adults to understand how interindividual variability in measures from one modality account for variability in measures from other modalities at each voxel of the brain. We detected significant correlations of local volumes with the magnitude of functional activation, suggesting that underlying variation in local volumes contributes to individual variability in functional activation. We also detected significant inverse correlations of NAA (a putative measure of neuronal density and viability) with volumes of white matter in the frontal cortex, with DTI‐based measures of tissue organization within the superior longitudinal fasciculus, and with the magnitude of functional activation and default‐mode activity during simple visual and motor tasks, indicating that substantial variance in local volumes, white matter organization, and functional activation derives from an underlying variability in the number or density of neurons in those regions. Many of these imaging measures correlated with measures of intellectual ability within differing brain tissues and differing neural systems, demonstrating that the neural determinants of intellectual capacity involve numerous and disparate features of brain tissue organization, a conclusion that could be made with confidence only when imaging the same individuals with multiple MRI modalities. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Short- and long-term limbic abnormalities after experimental febrile seizures

Experimental febrile seizures (FS) are known to promote hyperexcitability of the limbic system and increase the risk for eventual temporal lobe epilepsy (TLE). Early markers of accompanying microstructural and metabolic changes may be provided by in vivo serial MRI. FS were induced in 9-day old rats by hyperthermia. Quantitative multimodal MRI was applied 24 h and 8 weeks later, in rats with FS and age-matched controls, and comprised hippocampal volumetry and proton spectroscopy, and cerebral T2 relaxometry and diffusion tensor imaging (DTI). At 9 weeks histology was performed. Hippocampal T2 relaxation time elevations appeared to be transient. DTI abnormalities detected in the amygdala persisted up to 8 weeks. Hippocampal volumes were not affected. Histology showed increased fiber density and anisotropy in the hippocampus, and reduced neuronal surface area in the amygdala. Quantitative serial MRI is able to detect transient, and most importantly, long-term FS-induced changes that reflect microstructural alterations.     

Neuroimaging of Focal Cortical Dysplasia

Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy that is amenable to surgical resective treatment. The identification of structural FCD by magnetic resonance imaging (MRI) can contribute to the detection of the epileptogenic zone and improve the outcome of epilepsy surgery. MR epilepsy protocols that include specific T1 and T2 weighted, and fluid-attenuated inversion recovery (FLAIR) sequences give complementary information about the characteristic imaging features of FCD; focal cortical thickening, blurring of the gray-white junction, high FLAIR signal, and gyral anatomical abnormalities. Novel imaging techniques such as magnetic resonance spectroscopy (MRS), magnetization transfer imaging (MTI), and diffusion tensor imaging (DTI) can improve the sensitivity of MR to localize the anatomical lesion. Functional/metabolic techniques such as positron emission tomography (PET), ictal subtraction single photon emission computed tomography (SPECT), functional MRI (fMRI), and magnetic source imaging (MSI) have the potential to visualize the metabolic, vascular, and epileptogenic properties of the FCD lesion, respectively. Identification of eloquent areas of cortex, to assist in the surgical resection plan, can be obtained non-invasively through the use of fMRI and MSI. Although a significant number of FCD lesions remain unidentified using current neuroimaging techniques, future advances should result in the identification of an increasing number of these cortical malformations.     

White matter abnormalities and brain activation in schizophrenia: a combined DTI and fMRI study

Diffusion tensor imaging (DTI) studies of schizophrenia have revealed white matter abnormalities in several areas of the brain. The functional impact on either psychopathology or cognition remains, however, poorly understood. Here we analysed both functional MRI (during a working memory task) and DTI data sets in 18 patients with schizophrenia and 18 controls. Firstly, DTI analyses revealed reductions of fractional anisotropy (FA) in the right medial temporal lobe adjacent to the right parahippocampal gyrus, likely to contain fibres of the inferior cingulum bundle, and in the right frontal lobe. Secondly, functional MRI revealed prefrontal, superior parietal and occipital relative hypoactivation in patients with the main effect of task. This was accounted for by reduced prefrontal activation during the encoding phase of the task, but not during maintenance or retrieval phases. Thirdly, we found a direct correlation in patients between the frontal FA reduction (but not medial temporal reductions) and fMRI activation in regions in the prefrontal and occipital cortex. Our study combining fMRI and DTI thus demonstrates altered structure-function relationships in schizophrenia. It highlights a potential relationship between anatomical changes in a frontal-temporal anatomical circuit and functional alterations in the prefrontal cortex.     

Quantitative white matter analysis by diffusion tensor imaging and potential functional correlation

Diffusion tensor imaging (DTI) is an MRI modality used to measure the thermal motion of water molecules by combining the measured water diffusion with a simple tensor model of a 3 × 3 symmetric matrix. Since there are many structures that restrict the free motion of water molecules in the brain, we can use the diffusion property of water to study the brain anatomy. Because DTI can provide directional information about axonal fiber bundles, this technique may be one of the most effective MR tools for the investigation of the human white matter anatomy in vivo. Along with the qualitative analysis of fiber pathways using tractography, the quantitative analysis using DTI enables researchers to investigate relationships between white matter anatomy and brain functions as well as to identify tract-specific developmental patterns or disease-specific alterations of the fiber tracts. Several methods have been proposed for whole-brain DTI analysis without an a priori hypothesis. Voxel-based analysis (VBA) is one of the most widely used approaches, although it has concerning limitations, especially when isotropic spatial smoothing is applied. Alternative methods such as tract-based spatial statistics and atlas-based analysis have been introduced to overcome the limitations of VBA. Future studies combining the anatomical connectivity illustrated by using DTI and the functional connectivity illustrated by using resting-state fMRI will provide an emerging landscape of human brain connectivity.     

Preferential networks of the mediodorsal nucleus and centromedian-parafascicular complex of the thalamus-A DTI tractography study

Distinct thalamic nuclei, like the mediodorsal (MD) nucleus and the centromedian/parafascicular complex (CM/Pf), are embedded in different basal ganglia—thalamocortical loops, which were shown to integrate cognitive and emotional aspects of human behavior. Despite well described connections on a microscopic scale, derived from tracing studies in animals, little is known about the intrinsic anatomical connections of these nuclei in humans. This lack of knowledge limits not only interpretation of functional imaging studies but also estimation of direct effects of deep brain stimulation which treats diseases as different as epilepsy or major depression. Therefore, non‐invasive diffusion tensor imaging (DTI) studies are key to analyzing connectivity patterns and elaborate approaches to close this gap. For our study, we explored the structural connectivity of the MD thalamic nuclei and the CM/Pf complex towards five cortical and six subcortical regions by using a preferential fiber calculation. We found both thalamic nuclei to be preferentially associated to distinct networks: whereas the MD is preferentially connected to prefrontal and limbic cortical regions, the CM is linked to subcortical regions. The anterior insula was the only cortical region associated with the subcortical network of the CM and the cortical network of the MD comprised one subcortical hub, the caudate nucleus, suggesting an integrative role of these two regions. Adding to predescribed anatomical tract tracing connectivities in animal studies, our finding lends support to the existence of similar basal ganglia‐thalamocortical circuits in humans and we could show a robust distinction of preferential connectivity for both thalamic nuclei. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Multimodal MR Imaging: Functional, Diffusion Tensor, and Chemical Shift Imaging in a Patient with Localization-Related Epilepsy

PURPOSE: To demonstrate the integration of complementary functional and structural data acquired with magnetic resonance imaging (MRI) in a patient with localization-related epilepsy. METHODS: We studied a patient with partial and secondarily generalized seizures and a hemiparesis due to a malformation of cortical development (MCD) in the right hemisphere by using EEG-triggered functional MRI (fMRI), diffusion tensor imaging (DTI), and chemical shift imaging (CSI). RESULTS: fMRI revealed significant changes in regional blood oxygenation associated with interictal epileptiform discharges within the MCD. DTI showed a heterogeneous microstructure of the MCD with reduced fractional anisotropy, a high mean diffusivity, and displacement of myelinated tracts. CSI demonstrated low N-acetyl aspartate (NAA) concentrations in parts of the MCD. CONCLUSIONS: The applied MR methods described functional, microstructural, and biochemical characteristics of the epileptogenic tissue that cannot be obtained with other noninvasive means and thus improve the understanding of the pathophysiology of epilepsy.     

Fiber ball white matter modeling in focal epilepsy

Multicompartment diffusion magnetic resonance imaging (MRI) approaches are increasingly being applied to estimate intra‐axonal and extra‐axonal diffusion characteristics in the human brain. Fiber ball imaging (FBI) and its extension fiber ball white matter modeling (FBWM) are such recently described multicompartment approaches. However, these particular approaches have yet to be applied in clinical cohorts. The modeling of several diffusion parameters with interpretable biological meaning may offer the development of new, noninvasive biomarkers of pharmacoresistance in epilepsy. In the present study, we used FBI and FBWM to evaluate intra‐axonal and extra‐axonal diffusion properties of white matter tracts in patients with longstanding focal epilepsy. FBI/FBWM diffusion parameters were calculated along the length of 50 white matter tract bundles and statistically compared between patients with refractory epilepsy, nonrefractory epilepsy and controls. We report that patients with chronic epilepsy had a widespread distribution of extra‐axonal diffusivity relative to controls, particularly in circumscribed regions along white matter tracts projecting to cerebral cortex from thalamic, striatal, brainstem, and peduncular regions. Patients with refractory epilepsy had significantly greater markers of extra‐axonal diffusivity compared to those with nonrefractory epilepsy. The extra‐axonal diffusivity alterations in patients with epilepsy observed in the present study could be markers of neuroinflammatory processes or a reflection of reduced axonal density, both of which have been histologically demonstrated in focal epilepsy. FBI is a clinically feasible MRI approach that provides the basis for more interpretive conclusions about the microstructural environment of the brain and may represent a unique biomarker of pharmacoresistance in epilepsy.     

Imaging the Brain's Highways—Diffusion Tensor Imaging in Epilepsy

Diffusion tensor imaging evaluates the motion of water at the voxel level and can provide data on the structural integrity of brain tissue, with quantitative measures of diffusion and fractional anisotropy. Imaging of the orientation of preferential diffusion of water in the brain can visualize major white matter pathways and infer the structural basis of cerebral networks. Thus, how these pathways and networks may be altered in specific epilepsy syndromes and in consequence to therapies can be assessed with the aid of these images.     

Diffusion tensor imaging abnormalities in focal cortical dysplasia

PURPOSE: Focal cortical dysplasia (FCD) is one of the most common underlying pathologic substrates in patients with medically intractable epilepsy. While magnetic resonance imaging (MRI) evidence of FCD is an important predictor of good surgical outcome, conventional MRI is not sensitive enough to detect all lesions. Previous reports of diffusion tensor imaging (DTI) abnormalities in FCD suggest the potential of DTI in the detection of FCD. The purpose of this study was to study subcortical white matter underlying small lesions of FCD using DTI. METHODS: Five patients with medically intractable epilepsy and FCD were investigated. Diffusion tensor imaging images were acquired (20 contiguous 3 mm thick axial slices) with maps of fractional anisotropy (FA), trace apparent diffusion coefficient (trace/3 ADC), and principal eigenvalues (ADC parallel and ADC perpendicular to white matter tracts) being calculated for each slice. Region of interest analysis was used to compare subcortical white matter ipsilateral and contralateral to the lesion. RESULTS: Three subjects with FCD associated with underlying white matter hyperintensities on T2 weighted MRI were observed to have increased trace/3 ADC, reduced fractional anisotropy and increased perpendicular water diffusivity which was greater than the relative increase in the parallel diffusivity. No DTI abnormalities were identified in two patients with FCD without white matter hyperintensities on conventional T2-weighted MRI. CONCLUSIONS: While DTI abnormalities in FCD with obvious white matter involvement are consistent with micro-structural degradation of the underlying subcortical white matter, DTI changes were not identified in FCD lesions with normal appearing white matter.     

FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report

PURPOSE: Patients with tuberous sclerosis complex (TSC) are potential surgical candidates if the epileptogenic region(s) can be accurately identified. This retrospective study determined whether FDG-PET/MRI coregistration and diffusion-tensor imaging (DTI) showed better accuracy in the localization of epileptogenic cortex than structural MRI in TSC patients. METHODS: FDG-PET/MRI coregistration and/or DTI for apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were utilized in 15 TSC patients. Presurgery scalp EEG and postsurgery seizure control identified epileptogenic tubers (n = 27) and these were compared with nonepileptogenic tubers (n = 204) for MRI tuber volume, volume of FDG-PET hypometabolism on MRI coregistration, DTI, ADC, and FA values. RESULTS: Compared with nonepileptogenic tubers, epileptogenic regions had increased volume of FDG-PET hypometabolism (p < 0.0001), and increased ADC values in subtuber white matter (p < 0.0001). In contrast, the largest MRI identified tuber (p = 0.046) and decreased FA values (p = 0.58) were less accurate in identifying epileptogenic regions. Larger volumes of FDG-PET hypometabolism correlated positively with increased ADC values (p = 0.029), and localized to areas of cortical dysplasia adjacent to the tuber in four cases. CONCLUSIONS: Larger volumes of FDG-PET hypometabolism relative to MRI tuber size and higher ADC values identified epileptogenic tubers and adjoining cortex containing cortical dysplasia in TSC patients with improved accuracy compared with largest tuber by MRI or lowest FA values. Used in conjunction with ictal scalp EEG and interictal magnetoencephalography, these newer neuroimaging techniques should improve the noninvasive evaluation of TSC patients with intractable epilepsy in distinguishing epileptogenic sites for surgical resection.     

室管膜下型灰质异位脑纤维结构连接的MR弥散张量成像研究

目的观察室管膜下型灰质异位（PNH）所发出白质纤维束的空间分布形式以及与正常脑组织的空间位置关系。方法8例以癫痫症状就诊的PNH患者经3．0T磁共振仪T1及T：加权成像诊断,并采集弥散张量成像数据。采用白质纤维束追踪技术,以异位灰质团块作为种子点,对异位灰质相连的白质纤维束进行描绘,并观察总结其空间分布模式及与其他大脑结构之间的关系。结果异位灰质白质纤维束有以下分布特点：①异位灰质均能发出自身的白质纤维,其中有4例表现为仅与位于同侧大脑半球的长联络纤维连接;3例除联络纤维外,还可见到其白质纤维参与对侧的胼胝体连接;6例可见到连接至皮层的弓状纤维;②结构连接空间模式与灰质异位所处位置有关,位于侧脑室前角旁的异位灰质发出的联络纤维主要分布于前方,位于侧脑室后角旁的异位灰质发出的联络纤维主要分布于后方,靠近胼胝体的异位灰质其自质纤维较易连接到对侧,靠近皮层的异位灰质较易发出弓状纤维与皮层相连。结论异位灰质不是孤立的结构,其可发出或长或短的白质纤维,并较广泛地与正常脑结构保持连接;其纤维连接分布的空间模式与异位灰质所处的位置有关。     

Diffusion tensor imaging in radiosurgical callosotomy

Callosotomy by radioneurosurgery induces slow and progressive axonal degeneration of white matter fibers, a key consequence of neuronal or axonal injury (radionecrosis). However, the acute effects are not apparent when using conventional MRI techniques. Diffusion tensor imaging (DTI) during the first week following radioneurosurgical callosotomy allowed evaluation of these microstructural changes. The present report details that the use of sequential DTI to evaluate axonal degeneration following radioneurosurgical callosotomy in a patient normalized with the data of six healthy subjects. We describe a 25-year old woman with symptomatic generalized epilepsy who underwent a radioneurosurgical callosotomy using LINAC (Novalis^® BrainLAB). DTI was acquired at the baseline, 3 and 9 months and showed a progressive decrease of the fractional anisotropy values in the irradiated areas compared to the controls that could be interpreted as a progressive disconnection of callosal fibers related to the outcome.     

Neuroaxonal ion dyshomeostasis of the normal-appearing corpus callosum in experimental autoimmune encephalomyelitis

Atrophy of the corpus callosum (CC) is a well-documented observation in clinically definite multiple sclerosis (MS) patients. One recent hypothesis for the neurodegeneration that occurs in MS is that ion dyshomeostasis leads to neuroaxonal damage. To examine whether ion dyshomeostasis occurs in the CC during MS onset, experimental autoimmune encephalomyelitis (EAE) was utilized as an animal MS model to induce autoimmunity-mediated responses. To date, in vivo investigations of neuronal ion homeostasis has not been feasible using traditional neuroscience techniques. Therefore, the current study employed an emerging MRI method, called Mn2+-enhanced MRI (MEMRI). Mn2+ dynamics is closely associated with important neuronal activity events, and is also considered to be a Ca2+ surrogate. Furthermore, when injected intracranially, Mn2+ can be used as a multisynaptic tracer. These features enable MEMRI to detect neuronal ion homeostasis within a multisynaptic circuit that is connected to the injection site. Mn2+ was injected into the visual cortex to trace the CC, and T1-weighted imaging was utilized to observe temporal changes in Mn2+-induced signals in the traced pathways. The results showed that neuroaxonal functional changes associated with ion dyshomeostasis occurred in the CC during an acute EAE attack. In addition, the pathway appeared normal, although EAE-induced immune-cell infiltration was visible around the CC. The findings suggest that ion dyshomeostasis is a major neuronal aberration underlying the deterioration of normal-appearing brain tissues in MS, supporting its involvement in neuroaxonal functioning in MS.     

Quantitative evaluation of brain development using anatomical MRI and diffusion tensor imaging

The development of the brain is structure-specific, and the growth rate of each structure differs depending on the age of the subject. Magnetic resonance imaging (MRI) is often used to evaluate brain development because of the high spatial resolution and contrast that enable the observation of structure-specific developmental status. Currently, most clinical MRIs are evaluated qualitatively to assist in the clinical decision-making and diagnosis. The clinical MRI report usually does not provide quantitative values that can be used to monitor developmental status. Recently, the importance of image quantification to detect and evaluate mild-to-moderate anatomical abnormalities has been emphasized because these alterations are possibly related to several psychiatric disorders and learning disabilities. In the research arena, structural MRI and diffusion tensor imaging (DTI) have been widely applied to quantify brain development of the pediatric population. To interpret the values from these MR modalities, a “growth percentile chart,” which describes the mean and standard deviation of the normal developmental curve for each anatomical structure, is required. Although efforts have been made to create such a growth percentile chart based on MRI and DTI, one of the greatest challenges is to standardize the anatomical boundaries of the measured anatomical structures. To avoid inter- and intra-reader variability about the anatomical boundary definition, and hence, to increase the precision of quantitative measurements, an automated structure parcellation method, customized for the neonatal and pediatric population, has been developed. This method enables quantification of multiple MR modalities using a common analytic framework. In this paper, the attempt to create an MRI- and a DTI-based growth percentile chart, followed by an application to investigate developmental abnormalities related to cerebral palsy, Williams syndrome, and Rett syndrome, have been introduced. Future directions include multimodal image analysis and personalization for clinical application.     

Correlating 3T MRI and histopathology in patients undergoing epilepsy surgery

Purpose

To investigate whether specific semi-quantitative 3T MRI parameters are associated with particular histological features in temporal lobe specimens in epilepsy surgery patients whose conventional MRI scan appeared normal. These MRI techniques have the potential to visualise subtle structural abnormalities currently undetected on conventional MRI; but correlation between pre-operative in vivo MRI and histopathology is needed to understand the basis of these MRI abnormalities. Predicting subtle histopathology with semi-quantitative MRI techniques could contribute to pre-surgical evaluation of epilepsy patients.

Materials and methods

MRI techniques: normalised FLAIR signal intensity (nFSI), grey matter probability and diffusion tensor imaging (DTI) were correlated with quantitative histopathological measures: NeuN (neuronal nuclear antigen); GFAP (glial fibrillary acidic protein) and MBP (myelin basic protein) field fractions and stereological neuronal densities obtained in grey and white matter regions in twenty-four patients who underwent anterior temporal lobe resections.

Results

There were no significant correlations between the histopathological measurements and MRI values in grey or white matter in macroscopically normal appearing tissue.

Conclusion

Findings suggest that in macroscopically normal appearing tissue, the studied semiquantitative MRI measurements are not significantly related to the measures of gliosis, neuronal loss/gain and myelin used in the current study. Studies of macroscopically abnormal tissue as well as improvements to the MRI techniques may increase the sensitivity of future correlative studies to improve our understanding of the histopathological basis of MRI signal characteristics.     

MRI-negative refractory partial epilepsy: role for diffusion tensor imaging in high field MRI

OBJECTIVE: Our aim is to use the high field MR scanner (3T) to verify whether diffusion tensor imaging (DTI) could help in locating the epileptogenic zone in patients with MRI-negative refractory partial epilepsy. METHOD: Fifteen patients with refractory partial epilepsy who had normal conventional MRI, and 40 healthy volunteers were recruited for the study. DTI was performed on a 3T MR scanner, individual maps of mean diffusivity (MD) and fractional anisotropy (FA) were calculated, and Voxel-Based Analysis (VBA) was performed for individual comparison between patients and controls. RESULT: Voxel-based analysis revealed significant MD increase in variant regions in 13 patients. The electroclinical seizure localization was concurred to seven patients. No patient exhibited regions of significant decreased MD. Regions of significant reduced FA were observed in five patients, with two of these concurring with electroclinical seizure localization. Two patients had regions of significant increase in FA, which were distinct from electroclinical seizure localization. CONCLUSION: Our study's results revealed that DTI is a responsive neuroradiologic technique that provides information about the epileptogenic areas in patients with MRI-negative refractory partial epilepsy. This technique may also helpful in pre-surgical evaluation.