Altered regional homogeneity in epileptic patients with infantile spasm: A resting-state fMRI study

Abstract

Infantile spasm (IS) syndrome is an age-related epileptic encephalopathy that occurs in children. The purpose of this study was to investigate regional homogeneity (ReHo) changes in IS patients. Resting-state fMRI was performed on 11 patients with IS, along with 35 age- and sex-matched healthy subjects. Group comparisons between the two groups demonstrate that the pattern of regional synchronization synchronization in IS patients is changed. Decreased ReHo values were found in default mode network, bilateral motor-related areas and left occipital gyrus of the patient group. Increased ReHo was found in regions of cingulum, cerebellum, supplementary motor area and brain deep nucleus, such as hippocampus, caudate, thalamus and insula. The significant differences might indicate that epileptic action have some injurious effects on the motor, executive and cognitive related regions. In addition, ReHo values of left precuneus and right superior frontal gyrus were associated with the epilepsy duration in the IS group. The correlation results indicate that the involvement of these regions may be related to the seizure generation. Our results suggest that IS may have an injurious effect on the brain activation. The findings may shed new light on the understanding the neural mechanism of IS epilepsy.

Keywords

Epilepsy resting-state fMRI regional homogeneity infantile spasm thalamus DMN

1 Introduction

Infantile spasm (IS) syndrome, or West syndrome is an age-related epileptic encephalopathy that occurs in children, usually between the ages of 3 months and 18 months [7, 20]. The overall incidence of IS is one in 3000 live births [6]. This kind of intractable seizure is always diagnosed with one or many of the following: Nodding spasm clusters, mental retardation, development delay and a pathognomonic electroencephalography (EEG) pattern of hypsarrhythmia. Because epileptic activity itself contributes to behavioral and developmental consequences, cognitive outcome of IS is always poor [1, 8].

For this kind of patients, underlying etiology is complex and the apparent causes of IS in individual children are extremely variable. An EEG evaluation is recommended to conduct as soon as possible following the identification of spasms. A previous study has shown that EEG signal in children with IS had marked abnormalities in coherence and spectral power compared with the normal group [4]. There is reduced functional connectivity and integration of the frontal lobe. Magnetic resonance imaging (MRI) of brain remains the highest yield initial study in determining the etiology in IS. Previous study has found that the functional brain network and brain structural development are impaired following IS [6]. Voxel-based morphometry grey matter volume was increased at the left temporal lobe. The total gray matter volume in temporal lobe correlated with the duration of IS. The predominant pattern of brain injury in children with IS shown an important role in the brain developing. MRI findings have shown that the development of IS after hypoxic-ischemic encephalopathy is associated with the injury to the basal ganglia and the thalami on neonatal MRI [9]. Although the clinical data have shown that the brain function and structure in children with IS would be affected, the pathophysiological substrate related to this kind of epilepsy is not fully elucidated. The synchronization pattern of haemodynamic activity remains unclear.

To address these issues, resting state functional MRI (rs-fMRI) would provide a possible to study the neural mechanism in children with IS. Resting state functional MRI is increasingly recognized as a useful tool to measure temporal correlation of neural activity-induced signal variations of anatomically different brain regions [24, 26]. Based on this, one of the rs-fMRI methods, regional homogeneity (ReHo), were developed to measure the functional coherence or synchronization of a given voxel with its nearest voxels [31]. ReHo value might reflect the local synchronization of the spontaneous blood-oxygen-level-dependent fluctuations and use to investigate the intact and/or abnormal brain function [38]. This method has been widely used to investigate the functional modulations in the resting state in the patients with neurological diseases [5 , 35]. In addition, this method has also been used in adult and pediatric epilepsy patients [16 , 36] and found abnormal ReHo in the regional brain, such as thalamus, insula, cerebellum, brain stem, parahippocampus and default mode network (DMN) [30, 36]. However, until now, no study has observed the alteration of synchrony in epilepsy patients with IS using the ReHo method.

In the present study, we applied this method to a cohort of epilepsy patients with IS and healthy controls. We applied the ReHo method to rs-fMRI data to characterize differences between the IS group and the control group. We also investigated the correlation between the local synchronization of brain and the duration of epilepsy. Based on the research on other type of epilepsy [23 , 36], we hypothesized that abnormal regional synchronization would be found in IS patients in the resting state.

2 Materials and methods

2.1 Subjects

A total of eleven patients (4 females; mean 2.8 years) with IS were recruited from the Shenzhen Children’s Hospital, Guangdong, China. These IS patients all met the following inclusion criteria: (1) clinical and EEG findings evident of IS; (2) clinical history of at least one seizure that was consistent with the diagnosis of IS; (3) without history of addictions or neurologic diseases other than epilepsy; (4) no other accompanying neurological disorders such as brain tumor or cerebral palsy. The control group consisted of 35 healthy volunteers (13 females; mean 2.5 years) with no history of neurological or psychiatric disorders. Participants in the control group had no significant difference from the patient group with respect to age and gender. The participants in both groups were all right dominant hand. All participants were scanned using rs-fMRI at the time of recruitment. Information on both groups can be found in Table 1. The study protocol was approved by the Ethics Committee of Shenzhen Children’s Hospital, and the method was carried out in accordance with the approved guidelines. Written informed consent was obtained from all parents.

2.2 Image acquisition

Imaging data was collected using an eight-channel head coil with a 3T Siemens scanner (MAGNETOM Trio Tim, Siemens, Germany) at the Shenzhen Children’s Hospital, Guangdong, China. Foam cushions were used in the scan process to reduce head translation movement and rotation. Resting-state fMRI was collected using an echo-planar imaging sequence with the following scan parameters: TR/TE = 2000/30 ms, FOV = 220×220 mm², matrix = 94×94, flip angle = 90°, slice thickness = 3 mm, 36 interleaved axial slices, and 130 volumes. All participants were instructed to keep their eyes closed and to remain motionless.

2.3 Imaging processing and statistical analysis

The resting-state fMRI data was processed using DPARSF based on the Statistical Parametric Mapping (SPM8, http://www.fil.ion.ucl.ac.uk/spm) and REST (http://www.restfmri.net) package. The preprocessing steps referenced a previous study which included slice timing, spatial realignment, normalization into the Montreal Neurological Institute template and smoothing [13]. A temporal filter (0.01–0.08 Hz) was then applied to reduce the effect of very low frequency and high frequency physiological noise. Individual ReHo maps were generated by calculating the Kendall’s coefficient concordance of the time series of a given voxel with those of its nearest neighbors (26 voxels), on a voxel-wise basis [32]. For standardization, the individual ReHo map was divided by its whole brain mean ReHo value. Finally, the standardized ReHo maps were smoothed with a Gaussian filter of 6mm full width at half-maximum to reduce noise and residual differences in the brain.

To observe the spatial patterns of brain ReHo distribution in each group, one-sample t-tests were performed to generate the T maps (p < 0.05, AlphaSim corrected implementation based on the Monte Carlo simulation in REST). To explore the differences in local synchronization between two groups, two-sample t-tests were performed on the individual standardized ReHo maps. Age and gender were controlled as covariates in all the above statistical analyses. Significant threshold was set at p < 0.05, corrected for comparisons using the AlphaSim program in the REST software (combined height threshold p < 0.001 and a minimum cluster size of 13 voxels). Furthermore, the relationship between local synchronization and clinical behavior in children with IS was explored. A correlation analysis of ReHo versus the epilepsy duration was performed in the patient group at each voxel of the whole brain. The statistical threshold was set at p < 0.05.

3 Results

3.1 Between-group ReHo analyses

ReHo results for the healthy control group and IS patient group were shown respectively in A and B of Fig. 1. Significantly increased ReHo was found mainly in the post part of the brain in the both groups. In the control group, significantly increased ReHo was found mainly in bilateral middle occipital gyrus (MOG), precuneus, right middle temporal gyrus and left motor-related areas. In the IS group, significantly increased ReHo was found mainly in left parietal lobe and right precuneus and MOG.

Compared with the healthy controls, the results obtained from the two-sample t-test showed significant ReHo difference between the two groups (shown in Fig. 2). We found that ReHo was decreased in bilateral precuneus, MOG, right middle temporal gyrus, inferior parietal lobe, calcarine, postcentral gyrus and left precentral, angular. The increased ReHo was found in anterior cingulum, brainstem, bilateral hippocampus, thalamus, caudate, cerebellum and opercular part of inferior frontal gyrus, right insula, supplementary motor area (SMA) and olfactory, left inferior temporal lobe. Table 2 show the detail information of clusters with significantly different ReHo values between two groups.

3.2 Correlation between ReHo and epilepsy duration

Then correlation analysis determined which regions showed significant relationships between the ReHo and the epilepsy duration. Analysis by regressing ReHo at each voxel in the whole brain with the epilepsy duration in the IS group revealed that the most significant correlation occurs in right precuneus and left superior parietal lobule (shown in Fig. 3).

4 Discussion

This is the first study to explore the alterations of regional synchronization in IS patients during resting state through ReHo analysis. Between-group results showed that ReHo changes were observed widely in cortical and subcortical regions. Compared with the healthy children, children with IS showed decreased ReHo at DMN, bilateral motor-related areas and left occipital gyrus. Increased ReHo was found in regions of brain deep nucleus, such as hippocampus, caudate, thalamus and insula. Cingulum, cerebellum and SMA also showed an increased regional synchronization in the patient group. In addition, ReHo value of right precuneus and left superior parietal lobule was associated with the epilepsy duration in the IS group. These results indicate that these involved regions might be related to the neurological deficits observed in IS patients.

ReHo measures the regional synchronization of functional MRI signals in the regional brain. Increased ReHo is indicative of abnormal enhancement of local neuronal activity [31]. In our study, significantly increased ReHo was found in the bilateral thalamus. This result was consistent with previous finding that the thalamus plays an important role of the subcortical structure in the generalization of epileptic seizures [18 , 36]. Abnormal cortical-subcortical electrical discharges were transferred through the thalamus to generate epileptic spasms motor activity and cognitive impaired. A previous study in benign epilepsy with centrotemporal spokes have observed increased intrinsic activity in thalamus during the transient active state characterized by interictal epileptiform discharges [37]. This phenomenon was explained that transient epileptic events should result in temporal changes in BOLD signal. Study for intractable lateralized epilepsy have also found an enhanced thalamocortical connectivity following functional hemispherectomy [12]. In our study, the regional synchronization was enhanced in the thalamus and right SMA, which was supported by the above previous studies. These regions are involved in the planning of movement and executive control. Transient epileptic events might result in the pattern of cortical and subcortical structure hyperexcitability via thalamocortical circuitry.

We also found significantly increased ReHo in insula, hippocampus and cerebellum in the patient group. All of these regions were located in the subcortical of the brain, which have been shown in processing of sensory-motor processing, memory, executive control and general cognition [2 , 22].In the domain of epileptic, previous studies have found increased spontaneous activity of insula in childhood absence epilepsy patients [30, 36]. A EEG-fMRI study of patients with generalized epilepsy have found a clear activation in the cerebellum [10]. A increased ReHo were also found in the cerebellum and parahippocampus of epileptic patients with generalized tonic-clonic seizures [36]. Complex motor manifestations have seen in the epileptic seizures so that these sensory-motor regions showed an enhanced activation in the epilepsy patients. For the epilepsy patients with IS, no previous study were performed on the neuroimage to research the brain activation. Our study firstly gave the brain regional synchronization in IS during resting-state. The results of regions with ReHo increased were in agreement with previous epilepsy studies, such as the studies of childhood absence epilepsy and idiopathic generalized epilepsy [18, 30]. The explanation for the enhanced ReHo in these regions might be that patients’ motor control ability would be broken. In behavioral, these kind of patients shown with nodding spasm clusters, mental retardation. Cerebellum, hippocampu, insula and SMA have strong functional and structural connections with thalamus. So the regions crucial for the motor manifestations in IS would show a significant increased regional synchronization. These results showed that these subcortical structures and motor-related regions might consist of a local network. The increased ReHo value in these regions might indicate abnormal enhanced coherence patterns which might serve to interrupt normal motor and sensory network and function in the IS patients.

The group analysis revealed decreased regional synchronization, bilateral precuneus, MOG, right middle temporal gyrus, inferior parietal lobe, calcarine and postcentral gyrus, left precentral, angular. Some of these affected brain regions (precuneus, right middle temporal and inferior parietal lobe, left angular) overlap with the components of DMN [11]. A study have systematically reviewed the role of DMN and shown that the regions within the default network transiently interact with sensory, motor, and emotional systems to represent the content of the imagined event [3]. Previous imaging studies on epileptic have shown that decreased ReHo were mainly in the DMN that is involved in the integration of cognitive and emotional processing [30, 36]. For the epileptic patients with generalized tonic-clonic seizures, impaired integrations of the DMN were found during the interictal period and the period absence seizures [21 , 36]. Graph theoretical analysis in idiopathic generalized epilepsy have found a decrease of nodal topological characteristics in areas of the DMN [34]. So it can say that the epileptic action have a long-term injurious effects in the default-mode regions of these patients. For the IS patients in the present study, the decreased ReHo in the precuneus and inferior parietal lobe indicates DMN abnormalities in this kind of epilepsy patients during the resting state. In accordance with previous studies, a thalamic activation along with deactivation in the default mode areas was found in the present study [18 , 36]. The regional dysfunction in these regions may be due to the chronicity of the disorder. The changes mode of occipital during the resting-state period is various in the child epilepsy patients for the previous studies [30, 33]. Increased ReHo value were found in left occipital cortex of childhood absence epilepsy [30], however, decreased ReHo value were detected in bilateral occipital lobes in benign epilepsy children with centrotemporal spikes [33]. In the present study, decreased ReHo values were also found in bilateral occipital regions during the resting-state period. Decreased regional synchronization in bilateral occipital lobes might be due to long-term injurious effects.

Furthermore, positive correlations between the ReHo values in the right precuneus and left superior parietal lobule and the disease duration were found. The positive correlation regions in precuneus was largely in agreement with the previous report in the childhood absence epilepsy [30]. The precuneus is considered as a “core hub” in the default mode network [3]. The correlation result in this region may reflect that precuneus have an important role in the chronicity of IS. The patient’s cognitive function was disrupted with the disease duration increased, a compensatory spontaneous activity was increased in the precuneus. The correlation results can also be explained on the point of brain connectivity broken. Previous brain functional connectivity study and graph theory analysis on epilepsy patients supported with this view. With the epilepsy duration increase, the decreased integration within DMN showed more seriously during resting-state in the absence epilepsy patients [15]. Structural network connection strength, local efficiency, and nodal features in sub-cortical structures were significantly negatively correlated with the duration of epilepsy [29]. With the duration of epilepsy enhanced, the disrupted topological organization of white matter network in absence epilepsy patients was increased. So our correlation results can be explained by the long-term disrupted effect of the brain function in IS patients. Positive correlation between the disease duration and the ReHo values was found in the left superior parietal lobule. The ReHo values in this parietal region were enhanced significantly in the one-sample t-test result of both groups. But the between group comparison of ReHo value did not found significant difference in the left superior parietal lobule. Previous study of epilepsy in child or adult have also not found the correlation between the brain imaging indices and the disease duration in this region. So the explain of this result in the present study is not easy. Future study with larger sample sizes would give more inspiration on the understanding the neural mechanismof IS.

5 Limitations

The present study has several limitations. Firstly, the sample sizes were not large enough, and future investigations with larger sample sizes are required to make the correlation with behavioral data. Additionally, the antiepileptic medications were taken by the patients, which might confound the present results. Thirdly, simultaneous EEG during the MRI scanning was not collected. So the ReHo results could not be completely rule out the confounding epilepsy discharges during the imaging scanning.

6 Conclusion

In conclusion, the current study demonstrate that the pattern of regional synchronization synchronization in IS patients is changed. Using ReHo analyses, decreased ReHo values were found in DMN, bilateral motor-related regions and left occipital gyrus of the patient group. Increased ReHo was found in regions of cingulum, cerebellum, SMA and brain deep nucleus, such as hippocampus, caudate, thalamus and insula. These findings were consistent with the location of previous studies of children with epilepsy. The significant differences indicate that epileptic action might have some injurious effects on the motor, executive and cognitive related regions. In addition, ReHo value of right precuneus and left superior parietal lobule was associated with the epilepsy duration in the IS group. The correlation results indicate that the involvement of these regions may be related to the seizure generation. Our results suggest that IS may have a long-term injurious effects on the brain activation. Precuneus and thalamus regions play an important role in IS epilepsy.

Sources of funding

This work has been supported by National Key Technology R&D Program of China (2012BAI03B02), National Natural Science Foundation of China(81171228). This work also supported by the research startup foundation of Southern Medical University (PY2015N001).

Conflict of interest

Authors have nothing to disclose, and there are no conflicts of interest.

Footnotes

Acknowledgments

We would like to think all doctors and participants who collocated in this study for their cooperation.

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