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.
Highlights
Idiopathic generalised epilepsies (IGEs) constitute nearly a third of all epilepsies and can manifest with typical absences, myoclonic jerks, and generalised tonic-clonic (GTC) seizures, alone or in varying combinations (Panayiotopoulos, 2005; Berg et al, 2009)
McGill et al, 2012 demonstrated that with the seed placed in the posterior cingulate cortex (PCC), its functional connectivity to the ventral part of the medial prefrontal cortex (MPFC) is reduced in IGE patients. These regions are located within the PCC and MPFC, two of the prominent nodes of the default mode network
We found that the fibre integrity of superior longitudinal fasciculus was compromised in patients with IGE for a wide range of thresholds
Summary
Idiopathic generalised epilepsies (IGEs) constitute nearly a third of all epilepsies and can manifest with typical absences, myoclonic jerks, and generalised tonic-clonic (GTC) seizures, alone or in varying combinations (Panayiotopoulos, 2005; Berg et al, 2009). Several clinical IGE syndromes are traditionally distinguished (e.g., juvenile myoclonic epilepsy (JME); juvenile absence epilepsy; epilepsy with generalised tonic-clonic seizures on awakening (GTC-A)), observational data suggests considerable overlap between these syndromes (Reutens and Berkovic, 1995). The “idiopathic” modifier implies an unknown cause in contrast to, for example, epilepsies where an underlying structural cause is evident. There is strong empirical evidence for heritability (Berg et al, 2009), reflected in the recently proposed change in terminology to genetic generalised epilepsies (Berg et al, 2010). The IGE term is still widespread in non-clinical literature and will be used here
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