Introduction
Epilepsy with centrotemporal spikes (ECTS) is the most common focal epilepsy syndrome in children, accounting for 15–20% of pediatric epilepsy [
1]. Although ECTS was originally treated as “benign” due to its relatively low seizure frequency [
2], current consensus has reached that ECTS is not benign and can lead to delayed cognitive and behavioral maturation [
3,
4]. Language and working memory impairments have been widely investigated in ECTS patients [
3,
5]; however, little is known about processing speed dysfunction. Processing speed is a key cognitive ability that measures the capacity of decision-making and visual and auditory information processing [
6]. Specially, processing speed dysfunction may weaken the learning efficiency of ECTS patients, who are usually school-age children [
7]. In order to provide rational bases to improve processing speed, it is necessary to investigate processing speed dysfunction and its associated brain functional abnormality in ECTS patients.
The cortical–striatal circuit provides a physiologic basis for processing speed, as described in previous studies of dementia, trauma, and schizophrenia [
8‐
10]. In this circuit, information is transferred from the cerebral cortex to basal ganglia through the striatum, which can be anatomically divided into caudate, putamen, and nucleus accumbens (NAc), primarily associated with cognitive, motor, and motivational processes, respectively [
11]. Particularly, the large amount of interictal epileptic discharges in ECTS patients may disrupt local neuronal activity and functional connectivity of the circuit [
12]. Local neuronal activity changes within the circuit can be assessed by glucose metabolic rate using
18F-fluorodeoxyglucose (
18F-FDG) positron emission tomography (PET) molecular imaging [
13]. On the other hand, the functional connectivity alternations can be measured by synchronous fluctuations of blood oxygen level–dependent (BOLD) using resting-state functional magnetic resonance imaging (rs-fMRI) [
14]. Furthermore, the combination of PET and rs-fMRI can provide a rich description of functional abnormality for the in-depth investigation of processing speed dysfunction in ECTS patients.
Therefore, in this study, we hypothesize that epileptic discharges of ECTS patients disrupt corticostriatal connections, which is associated with impairments in processing speed. Thus, this study aimed to investigate the glucose metabolism and functional connectivity of cortical–striatal circuit and the relationship with processing speed dysfunction in ECTS patients.
Discussion
In this study, we investigated the processing speed dysfunction in ECTS patients using 18F-FDG PET and rs-fMRI. Our study showed that the reduced PSI was associated with the decreased SUVR and FC of cortical–striatal circuit in ECTS patients. Particularly, the caudate played an important role in processing speed dysfunction. To the best of our knowledge, this is the first study to investigate functional neuroimaging biomarkers of processing speed dysfunction in ECTS patients.
Most neuroimaging studies concentrated on cognitive impairments of language, attention, and working memory in ECTS patients [
1,
3]; however, only one study investigated processing speed [
21]. Our study, together with the previous study, showed that processing speed could be impaired in patients with ECTS [
28]. The functional abnormality of processing speed could be associated with the large amount of epileptic charges during interictal period, despite relatively infrequent seizures in patients with ECTS [
12]. In our study, the main PSI-related NBS subnetwork involved FCs between bilateral rolandic areas. Moreover, the decreased absolute FC between bilateral rolandic areas was significantly correlated with reduced PSI in ECTS patients. It could suggest that epileptic discharges originated from rolandic areas result in processing speed dysfunction of ECTS patients.
Our findings indicated that functional abnormality of cortical–striatal circuit was associated with processing speed impairment in ECTS patients. The cortical–striatal circuit is the neural pathway connecting cortical regions and basal ganglia to mediate motor, cognitive, and behavioral functions [
11]. In this pathway, the bilateral caudate, putamen, pallidum, left NAc, right rostral middle frontal gyrus, and frontal pole showed significantly decreased glucose metabolism in ECTS patients, indicating reduced neuronal activity in these regions [
13]. In addition, SUVR in the caudate was positively correlated with PSI. Moreover, the PSI-related NBS main subnetwork involved FCs between the bilateral rolandic areas and FCs from the rolandic areas to the caudate, the thalamus, and then the frontal and temporal lobes. It may indicate how the epileptic discharges influence the cortical–striatal circuit. The caudate could be directly influenced by the epileptic discharges originated from the rolandic areas. This finding is consistent with a previous finding that caudate is particularly vulnerable to pathological factors due to its topological centrality [
29]. The decreased SUVR and FC of caudate could therefore suggest that the caudate is a primary structure of processing speed dysfunction in ECTS patients, in consistence with a previous study of processing speed in traumatic brain injury [
30].
The cortical–striatal circuit from NBS analysis also involved cortical regions including the frontal pole (FP) and the superior temporal (ST) and middle temporal (MT) gyri. The FP played an import role in decision processing [
31], and ST and MT gyri were considered to be associated with speech processing [
32]. The main NBS subnetwork also involved precuneus and isthmus cingulate, impairments of which were related to slowed processing speed [
31,
33]. Moreover, there were significantly decreased connections between NBS main and additional subnetworks, which were not correlated with PSI and thus removed from NBS analysis. Therefore, the two NBS additional subnetworks may be branches of the cortical–striatal circuit in the main subnetwork. The cortical regions in the two branches, including the fusiform, pericalcarine, lateral orbitofrontal, rostral anterior cingulate, and superior parietal, were also considered to be associated with processing speed [
33‐
37].
In this study, ECTS patients were treated with the second-generation AEDs, including OXC, LEV, VPA, and LTG. These new AEDs had very little side effects on cognition, and most of them could even protect processing speed ability [
38‐
43]. The group comparison showed no significant differences in PSI among AED-naïve patients and patients who underwent monotherapy and polytherapy. Therefore, the processing speed impairment could be resulted from epileptic discharges rather than AED treatment. The processing speed depends on various functional abilities, such as attention, planning, and visuospatial and auditory skills [
6]. These functions are supported by complex brain network that provides the physiological basis for information processing [
44]. In this study, the decreased FCs were connecting to regions related to processing speed and formed a subnetwork associated with decreased PSI. It indicated that network deficit may be the pathological basis of processing speed dysfunction in ECTS, similar to other neuropsychological disorders [
30,
45]. As pediatric brains are highly plastic, processing speed can be improved like other cognitive abilities. Our findings could provide rational bases to improve processing speed of ECTS patients, such as physical exercise [
46], brain training game [
47], and transcranial stimulation [
48].
On the other hand, AED could still influence glucose metabolism and functional connectivities. VPA could reduce whole-brain glucose metabolism; however, this reduction is very slight at a negligible level [
40]. Patients taking LEV showed increased glucose metabolism in the bilateral caudate, frontal lobes, and left parietal lobe [
40], and those taking LTG showed reduced glucose metabolism in the thalamus and basal ganglia [
49]. In a previous fMRI study, ECTS patients who underwent AED treatment showed decreased FC in default network, while those who did not take AEDs showed increased FC in default network and motion-related networks [
16]. Similarly, a combined EEG-fMRI study showed increased whole-brain FC after withdrawal of AEDs in focal epilepsy [
50]. Although group comparison showed no significant difference in regional SUVR and FC among AED-naïve patients and patients who underwent monotherapy and polytherapy, the potential influences cannot be totally avoided and formed a major limitation of our study. Similar to previous studies, the AED treatment was specialized by an experienced physician according to patient seizure condition in this study [
17,
51]. Future works may consider to recruit more AED-naïve patients to validate our findings.
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