Dr. Ji Hyun Kim is an associate professor in Neurology at Korea University Guro Hospital, Seoul, Republic of Korea.
Idiopathic generalized epilepsy (IGE) constitutes a heterogeneous group of epilepsy syndromes with a nonfocal mechanism of seizure onset and no identifiable cause other than a genetic predisposition. Childhood absence epilepsy (CAE), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), and IGE with generalized tonic–clonic seizures only (GTCS) are the well-recognized subsyndromes of IGE, according to predominant seizure semiology and age of seizure onset. Based on genetic traits, similar seizure semiology, and typical electroencephalography (EEG) features of 3- to 5-Hz generalized spike-wave discharges (GSWDs), these IGE subsyndromes are considered to share a common pathogenetic mechanism.
The fundamental pathogenesis that underlies IGE is not fully elucidated; however, converging evidence has suggested a critical role of abnormal thalamocortical circuit in the generation of GSWDs. Recent advances in computational analysis of multimodal neuroimaging, such as voxel-based morphometry (VBM), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and functional magnetic resonance imaging (fMRI) have contributed greatly to the understanding of structural and functional changes of the thalamus and frontal cortex in IGE.[1, 2] In particular, contribution of the thalamocortical network to the generation of GSWDs has been highlighted in simultaneous EEG-fMRI studies that showed both thalamic activation and widespread cortical deactivation in IGE.[3, 4] Recently, resting-state functional connectivity MRI (fcMRI) has been used increasingly to investigate large-scale functional networks at a whole-brain level, based on the temporal correlation of spontaneous fluctuations of blood oxygen level–dependent (BOLD) signals in a very low frequency range (0.01–0.1 Hz).[5, 6] Because fcMRI reliably identifies a variety of intrinsic corticocortical and corticosubcortical networks, it is widely used to noninvasively evaluate changes in functional brain networks in diverse neurologic and psychiatric disorders as well as in the normal aging process.
Previous fcMRI studies have consistently shown decreased functional connectivity (FC) within the default mode network (DMN) in IGE, suggesting a disruption of functional integration of DMN in association with impaired consciousness and cognitive dysfunctions.[7-11] Given the hypothesis of thalamocortical network abnormality in the fundamental pathomechanism underlying IGE, investigation of the thalamocortical FC seems more likely to provide valuable information regarding functional changes of this network.
The purpose of the current study was to investigate FC alterations within the thalamocortical network in IGE, by using the thalamic seed derived from the VBM of group difference between patients with IGE and controls. We predicted that FC between thalamus and frontal cortex may be altered in patients relative to controls. Correlation analyses were additionally performed between thalamocortical FC and neuropsychological measures and clinical variables to explore the possible influence of the clinical and cognitive factors on FC changes.
- Top of page
- Supporting Information
This study attempted to investigate functional alterations of thalamocortical network in IGE, and to explore their relationships with clinical variables and frontal cognitive functions. We found a reduction of GM in the anteromedial thalamus and decreased FC of the anteromedial thalamic seed with bilateral MPFC and precuneus/PCC in IGE patients compared to controls. Thalamocortical FC strength of bilateral MPFC correlated negatively with disease duration in IGE patients.
The regional thalamic structural change found in our study accords well with previous VBM studies,[18-20] suggesting a preferential involvement of anteromedial thalamus in IGE. Recent EEG-fMRI studies identified anteromedial thalamic activation in the generation or maintenance of GSWDs in patients with IGE.[3, 21, 22] In addition, structural and functional abnormalities of the thalamus and frontal lobe, especially the prefrontal cortex, have been repetitively demonstrated in previous studies using FDG-PET,[23, 24] morphometric MRI,[25-27] MRS,[28-30] and DTI.[12, 31, 32] It is of note that the anteromedial thalamus has intense structural and functional connectivity with cingulate, premotor, and prefrontal cortices, as consistently replicated in both DTI and fcMRI studies.[33, 34] Our findings of anteromedial thalamic GM reduction and decreased FC between this thalamic region and MPFC in patients with IGE are in line with the above-mentioned studies, further implicating alterations of structural and functional connectivity between anteromedial thalamus and MPFC in the pathophysiologic hypothesis of thalamoprefrontal network abnormality in IGE.
Our findings are in good agreement with previous fcMRI studies that showed FC decreases in the MPFC and precuneus/PCC, the main components of DMN, in patients with absence epilepsy, GTCS,[8, 10, 20] and heterogeneous IGE. A number of neuropsychological studies have pointed to frontal executive dysfunctions and frontal cortical abnormalities in IGE,[2, 14, 15, 35] consistent with our results. The precuneus/PCC is proposed to play a crucial role in the neuronal network that sustains a sense of self-consciousness that is engaged in self-referential mental thoughts during rest. An EEG-fMRI study found deactivation of PCC in relation to spontaneously occurring GSWDs, suggesting that reduced activity in PCC may be involved in the initiation and facilitation of GSWDs. Another EEG-fMRI study showed FC decreases in the PCC during the interictal state without epileptic discharges in absence epilepsy. Taken together, it seems plausible that decreased FC of precuneus/PCC may not only be associated with GSWD generation, but may also reflect specific characteristics inherent to IGE. Given our finding of FC decreases between anteromedial thalamus and bilateral MPFC in relation to increasing disease duration, we speculate that aberrant DMN could be the consequences of long-standing burden of the disease, and that aberrant DMN has a potential role as a biomarker for disease progression in IGE.
Most of previous fcMRI studies on IGE employed data-driven independent component analysis (ICA) algorithms that are used extensively to evaluate FC in the resting-state networks without a priori anatomic hypothesis. Given the thalamocortical alteration as a fundamental pathogenesis of IGE, thalamic seed-based FC analysis may provide additional information with regard to FC within the thalamocortical network. An fcMRI study using thalamic seed found decreased FC between the thalamic mediodorsal nucleus and bilateral orbital frontal cortex, caudate nucleus, putamen, and amygdala. The inconsistent findings between our study and theirs could not be properly explained but might, in part, be ascribed to genetic heterogeneity and different IGE subsyndromes included (mixed IGE in ours vs. only GTCS in theirs). Albeit with a common pathophysiologic mechanism shared by IGE subsyndromes, different anatomic substrates between JME and GTCS have recently been proposed.[30, 38] In our subgroup analyses, a similar finding of thalamocortical FC decreases in the MPFC was shown in JME and GTCS patients compared to controls, whereas no difference was found between JME and GTCS patients. Relatively small numbers of patients and probably heterogeneous genetic causes in each group may not be sufficient to draw a conclusion that there is no difference in thalamocortical FC changes between JME and GTCS. With increasing advances in molecular diagnostic research studies, IGE syndromes are now referred to as genetic generalized epilepsy syndromes that are known to have varied and complex molecular bases. Future prospective studies using a more genetically homogenous cohort of IGE should address the issue of whether there are differences in both structural and functional connectivity between the IGE subsyndromes.
Several limitations of our study should be addressed. First, a limitation is the possibility of selection bias affecting the patient recruitment. Our patients were recruited prospectively from an epilepsy clinic of a university-affiliated hospital rather than from the community-based patient population. It is therefore possible that they were not representative of the general IGE population. Second, our study is cross-sectional, and thus interpretation of our findings with regard to causal relationship is limited. Given our finding of FC decreases in relation to increasing disease duration, we speculate that decreased thalamocortical FC may be the consequence of long-standing burden of the disease. Alternatively, based on a large number of neuroimaging studies that consistently identified structural and functional abnormalities of the thalamus and frontal lobe, the observed FC alterations could be a reflection of an intrinsic pathology as the cause of GSW and seizures in IGE. Future prospective studies incorporating a longitudinal design would provide a hint to disentangle causal relations between FC alterations and disease progression. Third, because fcMRI data of our study were acquired without simultaneous EEG recording, possible effects of interictal epileptic discharges on the thalamocortical FC cannot be totally excluded. Finally, we should consider the effects of AEDs on cognitive functions. Most (96%) of our patients remained on valproate, lamotrigine, or levetiracetam at the time of study, all of which are known to have little negative effects on cognitive functions. Only two of our patients were taking topiramate, a drug that is well known to have detrimental effects on multiple cognitive domains including frontal functions, which makes it unlikely that the use of topiramate affected our results.
In summary, our results indicate that IGE is associated with frontal cognitive dysfunction and decreased thalamocortical FC between anteromedial thalamus and MPFC and precuneus/PCC. Our finding of greater reduction of medial prefrontal FC in relation to increasing disease duration suggests that thalamoprefrontal network abnormality, the proposed pathophysiologic mechanism underlying IGE, may be the consequence of the long-standing burden of the disease.