Edited by: Qing Yun Wang, Beihang University, China
Reviewed by: Lianchun Yu, Lanzhou University, China; Federico Giove, Centro Fermi, Italy
*Correspondence: Liang Yu
Cheng Luo
†These authors have contributed equally to this work.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The purpose of this study was to evaluate the spatiotemporal Consistency of spontaneous activities in local brain regions in patients with generalized tonic-clonic seizures (GTCS). The resting-state fMRI data were acquired from nineteen patients with GTCS and twenty-two matched healthy subjects. FOur-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) metric was used to analyze the spontaneous activity in whole brain. The FOCA difference between two groups were detected using a two sample
Epilepsy is recognized as a neuropsychic disease with hyper-synchronous neuronal activity (Schevon et al.,
Although substantial efforts have been made in the past decade, the pathophysiological mechanisms of GTCS remain largely unclear. Recent advances in neuroimaging techniques have provided efficient and noninvasive ways for better understanding of GTCS. Blood oxygenation level-dependent (BOLD) fMRI has been recognized as an effective noninvasive technique to investigate epilepsy (Luo et al.,
In this study, we attempt to investigate the intrinsic resting-state brain activity of GTCS patients. Four-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) is a new method proved to be effective in the investigation of temporal and spatial information of the local region (Dong et al.,
Nineteen patients (mean age: 22.9 ± 8.8 years; mean years of illness duration: 6.2± 6.2, 9 females) with GTCS were recruited in the Center for Information in Medicine, University of Electronic Science and Technology of China. All patients recruited were diagnosed as GTCS only relied on the clinical and seizure semiology information in line with the International League Against Epilepsy (ILAE) guidelines (Engel,
All subjects underwent MRI scanning in a 3T GE scanner with an eight-channel-phased array head coil (MR750; GE Discovery, Milwaukee, WI) in the MRI research center of University of Electronic Science and Technology of China. An echo-planar imaging sequence was utilized to collect resting-state functional data, with the following parameters: echo time (
The SPM8 software package (statistical parametric mapping available at:
The FOCA calculation was performed using a neuroscience information toolbox (NIT, v1.1, RRID:SCR_014501
No excessive head motion was observed in our subjects.
The results of the one-sample
The group results of high FOCA values in patients with GTCS and healthy controls. Significant regions with a threshold
The significant differences of FOCA between two groups (
Statistic Z-map showing the FOCA difference between the GTCS group and the healthy control (
Brain regions showing significantly different FOCA in patients with GTCS.
Supp_Motor_Area_B | 9 | −20 | 64 | 4 | 5.06 | 1103 |
Precental_B | 40 | −25 | 62 | 4 | 5.1 | |
Postcentral_B | 45 | −20 | 38 | 3 | 4.23 | |
Paracentral_lobule_B | 3 | −22 | 68 | 4 | 5.32 | |
Putamen_L | −28 | −5 | −4 | - | 4.38 | 63 |
Occipital_Mid_L | −33 | −76 | 0 | 19 | 4.54 | 275 |
Occipital_Inf_L | −41 | −82 | −10 | 19 | 4.95 | |
Lingual_R | 15 | −97 | −10 | 18 | 4.88 | 146 |
Vermis_6 | 2 | −74 | −10 | - | 5.11 | |
Lingual_L | −22 | 100 | −13 | 18 | 4.94 | |
Cerebellum_Crus2_R | 7 | −79 | −40 | - | 3.51 | |
Cerebellum_6_L | −32 | −41 | −37 | - | 3.68 | 53 |
Frontal_Mid_R | 43 | 38 | 32 | 46 | 4.59 | 630 |
Frontal_Sup_R | 23 | 42 | 44 | 9 | 3.72 | |
Frontal_Sup_Medial_R | 8 | 59 | 18 | 10 | 3.92 | |
Frontal_Inf_Tri_R | 53 | 36 | 14 | 45 | 3.97 | |
Angular_L | −50 | −65 | 27 | 39 | 4.78 | 203 |
Parietal_Inf_L | −35 | −78 | 42 | 7 | 4.25 | |
Occipital_Mid_L | −42 | −75 | 32 | 39 | 4.35 | |
Precuneus_B | 11 | −62 | 32 | - | 7.03 | 481 |
Angular_R | 47 | −65 | 32 | 39 | 5.32 | |
Cinglum_Post_B | 3 | −53 | 32 | 23 | 6.27 | |
Parietal_Inf_R | 49 | −50 | 40 | 40 | 4.76 | |
Frontal_Mid_L | 28 | 30 | 44 | 9 | 4.16 | 153 |
Frontal_Sup_L | 23 | 32 | 45 | 9 | 4.25 | |
Cerebelum_9_R | 10 | −53 | −48 | - | 3.44 |
Significant positive correlations were demonstrated between age of onset and FOCA value in bilateral SMA and bilateral paracentral lobule (Figure
The correlation between age at onset and FOCA values in the brain regions which showed significant group difference. *The coordinate value implicates the residuals after controlling for the influence of the gender (linear regression with covariates including gender).
The correlation between duration of epilepsy and FOCA values in the brain regions which showed significant group difference. *The coordinate value implicates the residuals after controlling for the influence of the gender (linear regression with covariates including gender).
To our knowledge, this is the first study to investigate the alterations of spatiotemporally spontaneous activity in GTCS patients, using the FOCA feature in resting-state fMRI. The patients with GTCS demonstrated increased FOCA in motor related regions (SMA and pre-motor), basal ganglia and cerebellum, and decreased FOCA in DMN when compared with controls. In addition, several brain regions in DMN demonstrated a greater reduction with a longer duration of epilepsy and a later onset age, and the motor-related regions showed enhanced FOCA value with a later onset age.
The brain activity has been widely studied using various metrics, in which the ReHo is a known measurement to investigate the synchronization of spontaneous BOLD oscillations within local brain regions (Zang et al.,
In the present work, compared with healthy controls, GTCS patients demonstrated decreased FOCA values in DMN. It has been suggested that the activity of DMN represent the intrinsic function of human brain (Shulman et al.,
It has been demonstrated that epileptic activity may interrupt the resting state and result in the deactivation of the DMN (Luo et al.,
Connectivity within the DMN of the GTCS patients (Ralchle and Snyder,
In the present study, the increased FOCA values are mainly located in the SMA and pre-motor system. A notion has been proposed in previous study that the myoclonic jerks in IGE may be caused by the motor circuitry hyper-excitability (Vollmar et al.,
Compared with controls, patients with GTCS showed significantly increased FOCA values in the left basal ganglia (BG). The BG forms a very complex system of nuclei and pathways and may act as an integrated system. As other studies have shown, subcortical areas including putamen were connected with a wide range of brain regions, including the frontal lobe, parietal lobe, temporal lobe and cerebellum. The disruption of functional connectivity in basal ganglia networks was identified using independent component analysis (Luo et al.,
Stimulation targets for controlling seizures. For example, it has been proposed that the basal ganglia nuclei are structures controlling cortical seizure activity (Rektor et al.,
Furthermore, patients with GTCS showed the enhanced FOCA in cerebellum. It has been widely acknowledged that the cerebellum is crucial for motor control, and contributes to coordination instead of motion initiation. At the same time, the cerebellum integrates the information from many brain regions including sensory systems and spinal cord into fine motor activity (Fine et al.,
In this research, we used FOCA to study the pattern of local spontaneous activity in the epilepsy with GTCS only patients. Compared with healthy controls, patients with GTCS demonstrated higher spatiotemporal consistency in the motor-related cortex, and decreased FOCA in regions of DMN. Furthermore, the altered FOCA in several regions demonstrated significant correlation with the onset age and duration of epilepsy. These findings might reflect the disturbed baseline status of the brain and hyper-exciting spontaneous activity in motor-related regions in patients with GTCS. These results also provide evidence to support that the FOCA methods might be a potential tool to study intrinsic epileptic activity, which could help to understand the underlying pathophysiological mechanisms of GTCS.
This study was carried out in accordance with the recommendations of “Declaration of Helsinki” with written informed consent from all subjects. The protocol was approved by the ethical committee of the University of Electronic Science and Technology of China.
SM, SJ, and CL wrote the paper. SJ, LY, and CL conceived the data analysis procedure. SM, HS, QZ, and LY collected the clinical data. RP, XJ, and JL recorded MRI data sets. SJ and RP performed the data analysis. IG provided some useful suggestions in paper writing.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This study was supported by the National Nature Science Foundation of China (No. 81330032, 81771822, 81371636), Special-Funded Program on National Key Scientific Instruments and Equipment Development of China (No. 2013YQ490859), the 111 project (B12027), Sichuan province science and technology supported project (No. 2017SZ0004) and the Sixth Science and Technology Project from the Chengdu Science and Technology Bureau (No. 2013-11).