Quantitative Research Of Multimodal Brain Network Connection Mode In IGE Based On FMRI

BackgroundIdiopathic generalized epilepsy (IGE) is a group of genetically determined epilepsies. These types of epilepsies constitute nearly 15-25% of all epilepsies but show no abnormities in routine MRI examinations, although they exhibit some generalized spike and wave (GSW) or polyspike discharges against a normal background in EEG monitoring. At present antiepileptic drugs are mainly used to control such seizures as symptomatic treatment. So can we the fundamentally solve the treatment problem in idiopathic generalized epilepsy, and this depends on the in-depth study of its pathogenesis. However, there are many different pathogenesis theories about idiopathic generalized epilepsy, such as the Centrencephalic theory, Cortical theory, Corticoreticular theroy, etc., but most of these hypotheses based on different experimental animal models of epilepsy. Therefore, it is necessary to systematic analysis of the IGE brain research in vivo, so more conducive to our in-depth understanding of idiopathic generalized epilepsy.In addition, although cerebellar stimulation or vagus nerve stimulation and other surgical treatments have certain anti-epileptic effect, but the mechanism of the therapeutic effect is not clear. Some scholars speculate that the loop between cerebellar and cerebral cortex can inhabite seizure discharge. The experiments in this area are very rarely reported in the literature. Previous idiopathic generalized epilepsy research has mainly focused on animal models or molecular biology research.Materials and MethodsA total of 42 right-handed people were included in this study. Fourteen patients with IGE (all male, mean age±SD = 26±6 years; range = 19-36 years) were recruited from our epilepsy clinic. They showed no abnormities in routine MRI examinations. However, all the patients had generalized spike and wave (GSW) or polyspike discharges with normal backgrounds in Video-EEG monitoring. They had no history of drug intoxication, encephalopathy, or brain trauma. Based on their seizure history, seizure semiology and results from video-EEG recording, all the patients were diagnosed as having IGE with only generalized tonic-clonic seizures (GTCS) according to the International League Against Epilepsy (ILAE) classification.The patients were compared to twenty-eight age- and sex-matched normal controls (all male, mean age±SD = 27±4 years; range = 21-36 years), who were recruited from surrounding regions by advertisement. The controls underwent a comprehensive brain examination to ensure that they had a normal brain structure and no neurological lesions. Subjects with brain trauma, brain tumor(s), psychiatric disorders, systemic disease or other MRI contraindications such as phobia claustrophobia were excluded from this study. All subjects gave written informed consent, and this study was approved by the Ethics Committee of our Hospital.The MRI brain scanning was performed using a SIEMENS Trio 3.0 Tesla scanner with a head matrix coil at the Department of Radiology. During the examination, each subject laid supine in the scanner with his eyes closed. Scanner noise was attenuated with earplugs and head motion was restricted with foam padding (provided by the manufacturer) around the head, and the necessity of head immobility was emphasized to each subject. Resting state images were acquired with an EPI sequence with the following parameters: slice number=36 (interleaved), matrix=64×64, slice thickness=3mm, inter-slice gap=1mm, TR=2000ms, TE=30ms, flip angle (FA) =90°. Anatomical image datasets were acquired with a standard T1-weighted high-resolution anatomical scan using a magnetization- prepared rapid gradient echo (MPRAGE) sequence: TR=2530ms, TE=2.34ms, TI=1100ms, flip angle=7°, FOV=256mm×256mm, NEX=1, matrix=256×192, sagittial slices with slice thickness of 1 mm and slices=160. Using the MPRAGE acquisition for each study ensured the same slice orientation (parallel to the anterior commissure (AC) and commissural posterior (PC) line). The obtained images were used for subcortical structure analysis. A single shot echo planar imaging sequence (TR = 6100ms, TE = 93ms) was employed. The diffusion sensitizing gradients were applied along 64 non-collinear directions (b = 1000 s/mm2), together with a non-diffusion-weighted acquisition (b = 0 s/mm2). An integrated parallel acquisition technique (iPAT) was used with an acceleration factor of 2. The acquisition time can be reduced by the iPAT method with less image distortion from susceptibility artifacts. From each subject, 45 axial slices were collected. The field of view was 256 mm×256 mm; the acquisition matrix was 128×128 and zero filled into 256×256; the number of average was 1; and the slice thickness was 3 mm with no gap, which resulted in a voxel-dimension of 1 mm×1 mm×3 mm.Additionally, T2-weighted axial/oblique coronal images and FLAIR oblique coronal images were acquired for the epilepsy patients only. All images were submitted for visual analysis by experienced neuroradiologists at the Department of Radiology and were reported as being normal.Results1. In the functional connectivity analysis, we found that all functional connectivities within the default network were significantly greater than 0 in the normal control group (P<0.05, corrected). Comparing the strength of the functional connectivity within the default mode network (DMN) between the two groups, we found significantly deceased functional connectivity in the GTCS epilepsy patients group (P<0.05, corrected). We did not find any increased functional connectivity for the GTCS epilepsy patients in comparison to the normal controls. Specially, most of the significantly deceased functional connectivities were associated with the brain regions in the prefrontal cortex, such as the anterior medial prefrontal cortex (aMPFC) and bilateral superior frontal cortex. And the degree of many brain areas within DMN was significantly reduced (P<0.05, corrected), including the aMPFC, bilateral superior frontal cortex, posterior cingulate cortex, bilateral parietal cortex and bilateral inferior temporal cortex. Additionally, we found that the strength of the functional connectivity between the aMPFC and ventral anterior cingulate cortex (vACC) was significantly correlated to the NHS3 score of the GTCS epilepsy patients (r=-0.64, P<0.05).2. A two-sample t-test was used in a voxel-wise manner to determine the brain regions that showed significant differences between the epilepsy patients and normal subjects in the functional connectivity of the bilateral thalamus with other brain regions. Compared with the normal subjects, the IGE patients showed some increased functional connectivity. The brain regions that show increased functional connectivity with the right thalamus were in the left inferior frontal gyrus, left precentral gyrus, left inferior parietal gyrus and left middle frontal gyrus. The brain regions that showed increased functional connectivity with the left thalamus were in the left inferior parietal gyrus, right middle frontal gyrus, and right middle temporal gyrus and left middle frontal gyrus.3. Compared with healthy controls, there were 34 significantly decreased correlations (p<0.01, FDR corrected) in IGE patients . The results show decreased correlations between the anterior and posterior regions. These decreased correlations were mainly between prefrontal lobe and parietal lobe, within cerebellum and within occipital lobe. In addition, 13 functional interactions showed a significantly increased correlation (p<0.01, FDR corrected) in IGE patients. These increased correlations were mainly in intralobes including temporal lobe and frontal lobe. There were also some increased positive correlations between prefrontal and temporal lobe and between occipital and precuneus.4. Significantly reduced FA values were detected in three clusters of the IGE patients located in right cerebellum, left cerebellum and left parahippocampal gyrus.5. The IGE patients showed significant lower FA values in AAL regions Cerebelum_6R and Cerebelum_45R (P < 0.05, FDR corrected). No significant result was found in AAL regions Cerebelum_Crus1_L and ParaHippocampal_L as well as in the brainstem ROI. Also, no significant correlation was found between the average FA values of all selected ROIs and the clinical measurements we investigated including the NHS3 scores as well as the duration of years.6. Significant decreased connectivity values were found in IGE patients initiated from Cerebelum_45R to AAL regions ParaHippocampal_L (left hemisphere) and Temporal_Pole_Mid_R (right hemisphere) with P < 0.01 (uncorrected). On the other hand, no significant difference of the connectivity values between Cerebelum_6R and all the other 115 AAL regions was found between the IGE patients and the healthy controls.7. Comparisons of the vertex locations between the patient and control groups showed significant regional atrophy in the left thalamus (p<0.0286, corrected), the left putamen (p<0.00234, corrected) and the bilateral globus pallidus (left, p<0.0262; right, p<0.0369, corrected).ConclusionOur results indicate that the brain, subcortical structures, cerebellum of idiopathic generalized epilepsy have anatomical and functional alterations, which may be an important cause of seizure discharge. We explore the mechanism of epileptic seizures in non-invasive way by using fMRI technology, which may have some applications in the clinical diagnosis and treatment of this disease in the future.