Evaluation of subcortical grey matter abnormalities in patients with MRI-negative cortical epilepsy determined through structural and tensor magnetic resonance imaging
© Peng et al.; licensee BioMed Central Ltd. 2014
Received: 31 December 2013
Accepted: 15 April 2014
Published: 14 May 2014
Although many studies have found abnormalities in subcortical grey matter (GM) in patients with temporal lobe epilepsy or generalised epilepsies, few studies have examined subcortical GM in focal neocortical seizures. Using structural and tensor magnetic resonance imaging (MRI), we evaluated subcortical GM from patients with extratemporal lobe epilepsy without visible lesion on MRI. Our aims were to determine whether there are structural abnormalities in these patients and to correlate the extent of any observed structural changes with clinical characteristics of disease in these patients.
Twenty-four people with epilepsy and 29 age-matched normal subjects were imaged with high-resolution structural and diffusion tensor MR scans. The patients were characterised clinically by normal brain MRI scans and seizures that originated in the neocortex and evolved to secondarily generalised convulsions. We first used whole brain voxel-based morphometry (VBM) to detect density changes in subcortical GM. Volumetric data, values of mean diffusivity (MD) and fractional anisotropy (FA) for seven subcortical GM structures (hippocampus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, thalamus and amygdala) were obtained using a model-based segmentation and registration tool. Differences in the volumes and diffusion parameters between patients and controls and correlations with the early onset and progression of epilepsy were estimated.
Reduced volumes and altered diffusion parameters of subcortical GM were universally observed in patients in the subcortical regions studied. In the patient-control group comparison of VBM, the right putamen, bilateral nucleus accumbens and right caudate nucleus of epileptic patients exhibited a significantly decreased density Segregated volumetry and diffusion assessment of subcortical GM showed apparent atrophy of the left caudate nucleus, left amygdala and right putamen; reduced FA values for the bilateral nucleus accumbens; and elevated MD values for the left thalamus, right hippocampus and right globus pallidus A decreased volume of the nucleus accumbens consistently related to an early onset of disease. The duration of disease contributed to the shrinkage of the left thalamus.
Patients with neocortical seizures and secondary generalisation had smaller volumes and microstructural anomalies in subcortical GM regions. Subcortical GM atrophy is relevant to the early onset and progression of epilepsy.
KeywordsSubcortical grey matter Neocortical epilepsy Volumetry Diffusion tensor imaging
Recent studies have demonstrated the importance of cortical-subcortical network interactions in seizure generation and propagation [1, 2]. Through several magnetic resonance imaging (MRI) acquisition and processing techniques, investigators explore not only the cortex but also subcortical grey matter (GM) abnormalities in epileptic patients. It has been reported that patients with temporal lobe epilepsy (TLE) and idiopathic generalised epilepsy (IGE) have structural alterations in the subcortical nuclei and, more generally, in the thalamus [3–16]. Furthermore, the changes in subcortical GM correlate with the age at seizure onset and the duration of epilepsy [3, 4, 10, 15, 16]. A small number of longitudinal studies have shown that recurrent seizures may lead to progressive microstructural alterations [17, 18]. However, few neuroimaging studies have addressed the abnormalities in the subcortical GM of patients with neocortical epilepsy. Here, we investigated the subcortical GM of patients with neocortical epilepsy and without any identifiable MRI lesion, compared with age-matched controls. Our patients shared a seizure semiology indicating secondary generalisation. First, we demonstrated density changes in subcortical GM using voxel-based morphometry (VBM). We then correlated the volume changes and diffusion parameters of seven subcortical regions (the hippocampus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, thalamus and amygdala) with age at seizure onset and disease duration. Our aim was to determine the associations between changes in subcortical GM and disease progression, especially in patients whose seizures arise from neocortical structures.
Clinical data on 24 patients with focal neocortical epilepsy
Age at onset
R F, T
R F, T, O
R and L F
R F, T
All subjects were scanned in a 3T MRI scanner (General Electric, Waukesha, WI, USA). Anatomic T1-weighted images were acquired using a high-resolution, axial, three-dimensional, T1-weighted, fast spoiled gradient recalled echo (3D T1-FSPGR) sequence. Congruent slices with a thickness of 1 mm were generated with a repetition time (TR) of 11.812 ms, an echo time (TE) of 5.036 ms, a field of view (FOV) of 22 × 22 cm, a flip angle of 15 degrees and a 512 × 512 matrix. The DTI protocol consisted of a single-shot-spin-echo planar-imaging sequence. Thirty-four contiguous slices were acquired with a matrix size of 256 × 256, a voxel size of 1 mm × 1 mm, a slice thickness of 3 mm, a TR of 8,000 ms, a TE of 82.4 ms, a number of excitation of 2 and a FOV of 25 × 25 cm. Diffusion-weighted images were acquired in 25 directions (b = 1000 s/mm2), as was a null image (b = 0 s/mm2).
VBM analysis of whole brain GM
VBM was carried out using the FSL-VBM v1.1 software tool included in the FSL (FMRIB Software Library; the University of Oxford). The VBM analysis procedure comprised the following steps . First, 3D T1-FSPGR images were brain-extracted and GM -segmented before being registered to the Montreal Neurological Institute (MNI) 152 standard space using non-linear registration. The resulting images were averaged and flipped along the x-axis to create a left-right symmetric, study-specific GM template. Second, all native GM images were non-linearly registered to this study-specific GM template and “modulated” to correct for local expansion (or contraction) due to the non-linear component of the spatial transformation. The modulated GM images were then smoothed with an isotropic Gaussian kernel with a sigma of 3 mm for the TFCE-based analysis . Finally, differences in cerebral GM density between the patient and control groups were evaluated using the voxelwise generalised linear model applied using permutation-based non-parametric testing (5000 permutations) . We identified the regions with significant differences in GM density between the patient and control groups using these postprocessing methods and a cluster-size threshold of p < 0.05.
Measurement of volumes and diffusion parameters of subcortical GM structures
All diffusion-weighted images were corrected for eddy current distortion and head motion using the FDT v2.0 software package (FMRIB's Diffusion Toolbox). The preprocessed DTI data were fit to a diffusion tensor model to generate the mean diffusivity (MD) and fractional anisotropy (FA) maps. To obtain transformation parameters, the individual T1-FSPGR image was registered to the null image to fit the DTI resolution using a 12-parameter rigid body transformation. We applied these parameters to transform the segmentation mask to the DTI space using a rigid registration and a nearest neighbour interpolation based on the normalised mutual information method. For each subject, the corresponding values of the MD and FA were calculated for each automatically segmented region.
Using the independent-samples t-test, the normalised volume, FA and MD values in the patient group were compared with those in the control group for the seven subcortical structures studied. To investigate the underlying relation between the significantly altered diffusion parameters or volume of subcortical structures and duration of epilepsy or age at epilepsy onset, linear regression analysis was performed. A significant difference was accepted if the p value was less than 0.05.
We enrolled 24 patients with neocortical epilepsy and without gross cerebral abnormalities. In this study group, more patients had seizures originating in anterior regions of the brain. The proportion of patients with frontal lobe seizures was equal between the right hemispheric epilepsy and left hemispheric epilepsy subgroups.
Local maximums of significant clusters showing decreased cerebral GM density in neocortical epilepsy patients, compared to controls ( p < 0.05)
Z-MAX MNI (mm)
33% Left Cerebral White Matter
23% Left Nucleus accumbens
13% Left Cerebral Cortex
87% Right Putamen
12% Right Cerebral White Matter
58% Right Nucleus accumbens
19% Right Cerebral White Matter
9% Right Caudate nucleus
8% Right Cerebral Cortex
4% Right Lateral Ventricle
Normalised subcortical structure volumes and FA and MD values in focal neocortical epilepsy patients
Diffusion parameter difference
In general, the MD values for the subcortical structures studied were higher in our patients. The MD value was increased in the left thalamus (0.894 ± 0.050 vs. 0.863 ± 0.059, t = -2.188, p = 0.045), right globus pallidus (0.979 ± 0.046 vs. 0.771 ± 0.041, t = -0.777, p = 0.035) and right hippocampus (1.101 ± 0.102 vs. 1.042 ± 0.053, t = -1.801, p = 0.009). The differences in the FA values were minimal and inconsistent. The FA values were reduced in the bilateral nucleus accumbens in the patients, compared with the controls (left nucleus accumbens, 0.265 ± 0.055 vs. 0.295 ± 0.049, t = -1.991, p = 0.038; right nucleus accumbens, 0.240 ± 0.047 vs. 0.285 ± 0.053, t = -1.555, p = 0.002).
Correlations with age at seizure onset and disease duration
Generalised tonic-clonic seizures occur in primary generalised epilepsy and can arise as a secondary generalisation of partial seizures. Over 70% of patients with focal seizures experience secondary generalisation .
Many studies emphasise the importance of the thalamus in generalised seizures. It has also been demonstrated that the basal ganglia contribute to seizure regulation and ictal dystonia [25, 26]. In this study, we have observed that focal cortical seizures with secondarily generalised tonic-clonic convulsions are associated with variable changes in the subcortical GM of individual patients. Subcortical GM atrophy was related to the early onset and progression of epilepsy. Involvement of the nucleus accumbens in secondary seizure generalisation has not been reported previously in humans.
DeCarli first discussed volume asymmetry in the extratemporal structures of patients with complex partial seizures of left temporal origin. In addition to changes in the hippocampus, they also observed the significantly reduced volumes of the left thalamus, left caudate nucleus and bilateral lenticular nuclei . Consequently, the amygdala , putamen [10, 12–14, 16], caudate nucleus [11, 14–16], globus pallidus  and hippocampus [11, 13–15] were also found to show atrophy in patients with temporal lobe epilepsy with or without MRI-visible hippocampal lesions. Thereafter, patients with IGEs, including absence epilepsy, juvenile myoclonic epilepsy (JME) and primary generalised tonic-clonic seizures, were also found to have subcortical abnormalities [3–10]. Here, we further demonstrated that the reduction in volume of subcortical GM in patients with frontal, lateral temporal or occipital lobe seizures is universal. Recently, several studies have addressed differences in the shapes of subcortical structures between patients with generalised epilepsies and normal controls using FSL-FIRST, a vertex-based shape analysis method. Du et al. found significant regional atrophy in the left thalamus, left putamen and bilateral globus pallidus in patients with GTCs . Kim identified regional bilateral atrophy on the anterior-medial and posterior-dorsal aspects of the thalamus in 50 adult patients with IGE . In patients with JME, Saini observed focal surface area reductions in the medial and lateral aspects of the bilateral thalami .
For tensor imaging supporting the evaluation of white matter rather than GM, we calculated diffusion parameters for original subcortical GM structures individually instead of by whole brain voxel-based analysis to guard against the possibility of causing partial volume averaging effects via smoothing. Although we did not anticipate a demonstration of the delicate microstructural changes of subcortical GM by DTI, we nonetheless observed a general alteration of diffusion parameters. Furthermore, the decrease in FA values in the bilateral nucleus accumbens has not yet been reported. Groppa reported increases in the regional FA in the thalamus in patients with IGE . Luo and Yang found increased MD values in the bilateral thalami, putamen and left caudate nucleus and increased FA values in the bilateral caudate nuclei in patients with absence epilepsy [4, 8]. Keller reported the first evidence of combined microstructural and macrostructural putamen abnormalities in patients with JME and identified an early age at onset and a longer duration of epilepsy as predictors for greater architectural alterations . In patients with TLE and abnormal hippocampal MRI scans, Kimiwada showed an increasing trend in the MD values for the thalami ipsilateral to the epileptic focus, and Keller showed changes in the mean FA values of the bilateral thalamus and putamen [12, 29]. In Keller’s study, the duration of epilepsy was significantly negatively correlated with the mean FA of both the ipsilateral thalamus and the contralateral thalamus .
Saini found a correlation between age at onset and the volume of the right hippocampus in 40 patients with JME . While the ipsilateral-to-contralateral volume ratios of subcortical structures were estimated using data from 40 patients with TLE, thalamic volume loss was found to correlate with epilepsy onset . In two early studies by Dreifuss and Gärtner, the relations between age at onset or epilepsy duration and volume changes in the thalamus or striatum in patients with temporal lobe epilepsy and extratemporal lobe epilepsy were not significant. However, these two studies included patients with neoplasms or cortical dysplasia, which reflect different temporal lobe epileptogenic processes [16, 30]. Luo found significant correlations between diffusion parameters for the caudate nucleus and age at onset in patients with absence seizures . In our patients, the age at seizure onset positively correlated with the volume of the right nucleus accumbens, and the reduction in volume observed with disease progression was consistent across the subcortical structures studied, especially the left thalamus.
In 2010, Hermann et al. characterised neurodevelopmental changes in brain structure in children with negative MRI scans and new-onset generalised and localisation-related epilepsies (including extratemporal lobe epilepsy). In their prospective study, they observed reductions in the volume of cerebral GM and a delayed age-appropriate increase in white matter volume over 2 years . In 2011, they further concluded that the baseline grey and white matter volumes differed in the controls, suggesting that anomalies in brain development were antecedent to the onset of seizures and that the neurodevelopmental changes that they observed involved several subcortical structures . The results of our cross-sectional study, demonstrating a correlation between structural abnormalities and age at seizure onset or disease duration, are consistent with the results of their prospective study.
With regard to the postictal state, functional brain imaging has been used in a limited number of studies. Fong et al. conducted a single-photon emission computed tomography (SPECT) study of 2 patients with right TLE in whom postictal psychosis developed; these authors reported a marked hyperperfusion of the left basal ganglia . Blumenfeld and his colleague also used SPECT to observe the involvement of the caudate nucleus during seizure generalisation and in the postictal period . The nucleus accumbens, a region of the brain in the basal forebrain, plays a central role in the reward circuit and the in pathogenesis of psychiatric disorders [33, 34]. Studying the involvement of the nucleus accumbens in epilepsy models focuses on postictal behaviors [35, 36]. Ma et al. found that the μ opioid receptors of nucleus accumbens mediate immediate postictal decrease in locomotion after an amygdaloid kindled seizure in rats . Using the pilocarpine model, Scholl et al. observed neuronal degeneration in the outside hippocampal regions including the nucleus accombens and the accumbens shell. These findings support our findings indirectly and encourage future research the association of nucleus accumbens with epilepsy.
Subcortical GM involvement in the pathogenesis of chronic neocortical epilepsy is supported by our DTI-derived and T1-weighted MRI-derived evidence. However, a longitudinal study is needed to determine whether neurodegeneration observed in subcortical regions in neocortical epilepsy patients is accelerated beyond the effects of normal aging. Comorbid interictal and postictal psychomotor symptoms also require further investigation in light of coexisting subcortical structural changes.
Diffusion tensor imaging
FMRIBs diffusion toolbox
FMRIB’s integrated registration and segmentation tool
Field of view
FMRIB software library
Idiopathic generalised epilepsies
Juvenile myoclonic epilepsy
Montreal neurological institute
Magnetic resonance imaging
Single-photon emission computed tomography
Temporal lobe epilepsy
- 3D T1-FSPGR:
Three-dimensional, T1-weighted, fast spoiled gradient recalled echo.
This work was supported in part by National Science Council (NSC), R.O.C., under project 102-2220-E-009-001 and in part by “Aim for the Top University Plan” of the National Chiao Tung University and Ministry of Education, Taiwan, R.O.C. and by National Science Council (NSC), R.O.C., under project 100-2220-E-303-001 and by Buddhist Tzu Chi Research Grant (TCRD100-53-1).
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