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Computer modelling of connectivity change suggests epileptogenesis mechanisms in idiopathic generalised epilepsy.

ABSTRACT: Patients with idiopathic generalised epilepsy (IGE) typically have normal conventional magnetic resonance imaging (MRI), hence diagnosis based on MRI is challenging. Anatomical abnormalities underlying brain dysfunctions in IGE are unclear and their relation to the pathomechanisms of epileptogenesis is poorly understood. In this study, we applied connectometry, an advanced quantitative neuroimaging technique for investigating localised changes in white-matter tissues in vivo. Analysing white matter structures of 32 subjects we incorporated our in vivo findings in a computational model of seizure dynamics to suggest a plausible mechanism of epileptogenesis. Patients with IGE have significant bilateral alterations in major white-matter fascicles. In the cingulum, fornix, and superior longitudinal fasciculus, tract integrity is compromised, whereas in specific parts of tracts between thalamus and the precentral gyrus, tract integrity is enhanced in patients. Combining these alterations in a logistic regression model, we computed the decision boundary that discriminated patients and controls. The computational model, informed with the findings on the tract abnormalities, specifically highlighted the importance of enhanced cortico-reticular connections along with impaired cortico-cortical connections in inducing pathological seizure-like dynamics. We emphasise taking directionality of brain connectivity into consideration towards understanding the pathological mechanisms; this is possible by combining neuroimaging and computational modelling. Our imaging evidence of structural alterations suggest the loss of cortico-cortical and enhancement of cortico-thalamic fibre integrity in IGE. We further suggest that impaired connectivity from cortical regions to the thalamic reticular nucleus offers a therapeutic target for selectively modifying the brain circuit for reversing the mechanisms leading to epileptogenesis.

SUBMITTER: Sinha N

PROVIDER: S-EPMC6356007 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Computer modelling of connectivity change suggests epileptogenesis mechanisms in idiopathic generalised epilepsy.

Sinha Nishant N Wang Yujiang Y Dauwels Justin J Kaiser Marcus M Thesen Thomas T Forsyth Rob R Taylor Peter Neal PN

NeuroImage. Clinical 20190111

Patients with idiopathic generalised epilepsy (IGE) typically have normal conventional magnetic resonance imaging (MRI), hence diagnosis based on MRI is challenging. Anatomical abnormalities underlying brain dysfunctions in IGE are unclear and their relation to the pathomechanisms of epileptogenesis is poorly understood. In this study, we applied connectometry, an advanced quantitative neuroimaging technique for investigating localised changes in white-matter tissues in vivo. Analysing white mat ...[more]

PMID: 30685702

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Project description:ObjectiveTissue remodeling has been described in brain circuits that are involved in the generation and propagation of epileptic seizures. Human and animal studies suggest that the anterior piriform cortex (aPC) is crucial for seizure expression in focal epilepsies. Here, we investigate the effect of kainic-acid (KA)-induced seizures on the effective connectivity of the aPC with bilateral hippocampal CA3 regions using cerebro-cerebral evoked potentials (CCEPs).MethodsAdult male Sprague-Dawley rats were implanted with a tripolar electrode in the left aPC for stimulation and recording, and with unipolar recording electrodes in bilateral CA3 regions. Single pulse stimulations were given to the aPC and CCEPs were averaged before KA injections and after the emergence of spontaneous recurrent seizures (SRS). Similar recordings at equivalent time intervals were obtained from animals that received saline injections instead of KA (controls).ResultsIn the experimental group, the percentage change of increased amplitude of the contralateral (but not ipsilateral) CA3 CCEPs between pre-KA injection and after the emergence of SRS was significantly greater than in controls. No significant single-pulse-induced spectral change responses were observed in either epileptic or control rats when comparing pre- and post-stimulus time intervals. Also, we found no correlation between seizure frequency and the extent of amplitude changes in the CCEPs.ConclusionsIn the KA model, epileptogenesis results in plastic changes that manifest as an amplification of evoked potential amplitudes recorded in the contralateral hippocampus in response to single-pulse stimulation of the aPC. These results suggest epileptogenesis-induced facilitation of interhemispheric connectivity between the aPC and the hippocampus. Since the amplitude increase of the contralateral CCEP is a possible in vivo biomarker of epilepsy, any intervention (e.g. neuromodulatory) that can reverse this phenomenon may hold a potential antiepileptic efficacy.

Project description:Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared messenger RNA (mRNA) expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE was distinct from that found in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. We also found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

Dataset Information

Computer modelling of connectivity change suggests epileptogenesis mechanisms in idiopathic generalised epilepsy.

Publications

Computer modelling of connectivity change suggests epileptogenesis mechanisms in idiopathic generalised epilepsy.

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