Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy

Jonathan O'Muircheartaigh, Christian Vollmar, Gareth J Barker, Veena Kumari, Mark R Symms, Pam Thompson, John S Duncan, Matthias J Koepp, Mark P Richardson, Jonathan O'Muircheartaigh, Christian Vollmar, Gareth J Barker, Veena Kumari, Mark R Symms, Pam Thompson, John S Duncan, Matthias J Koepp, Mark P Richardson

Abstract

Juvenile myoclonic epilepsy is the most common idiopathic generalized epilepsy, characterized by frequent myoclonic jerks, generalized tonic-clonic seizures and, less commonly, absences. Neuropsychological and, less consistently, anatomical studies have indicated frontal lobe dysfunction in the disease. Given its presumed thalamo-cortical basis, we investigated thalamo-cortical structural connectivity, as measured by diffusion tensor imaging, in a cohort of 28 participants with juvenile myoclonic epilepsy and detected changes in an anterior thalamo-cortical bundle compared with healthy control subjects. We then investigated task-modulated functional connectivity from the anterior thalamic region identified using functional magnetic resonance imaging in a task consistently shown to be impaired in this group, phonemic verbal fluency. We demonstrate an alteration in task-modulated connectivity in a region of frontal cortex directly connected to the thalamus via the same anatomical bundle, and overlapping with the supplementary motor area. Further, we show that the degree of abnormal connectivity is related to disease severity in those with active seizures. By integrating methods examining structural and effective interregional connectivity, these results provide convincing evidence for abnormalities in a specific thalamo-cortical circuit, with reduced structural and task-induced functional connectivity, which may underlie the functional abnormalities in this idiopathic epilepsy.

Figures

Figure 1
Figure 1
Thalamo–cortical bundles showing reduced tractography-defined connectivity between normal subjects and patients with juvenile myoclonic epilepsy (blue, P < 0.05, corrected for multiple comparisons; red, P < 0.05, uncorrected) relative to healthy controls. Images on the right show the regions in the thalamus from which the bundles originate.
Figure 2
Figure 2
Group average results for each group for the word generation task (A), positive (B) and negative (C) correlation with the thalamic seed region, and psychophysiological interaction between the thalamic seed time series and the task (D). This interaction is negative, i.e. functional connectivity decreases as a function of task performance. All results are presented P < 0.05, corrected for multiple comparisons. The thalamic bundle defined by the DTI analysis is overlaid in purple.
Figure 3
Figure 3
(A) Differential psychophysiological interaction between healthy controls and patients with juvenile myoclonic epilepsy. Patients with juvenile myoclonic epilepsy show increased psychophysiological interaction with the thalamic seed region. Psychophysiological interaction in patients with active juvenile myoclonic epilepsy correlated significantly with the number of generalized tonic clonic seizures in the previous year. (B and C) The relationship between performance on the verbal fluency test and psychophysiological interaction in the mesial pre-SMA region. There is an interaction in this relationship dependent on disease status in the juvenile myoclonic epilepsy group. GTCS = general tonic-clonic seizures.
Figure 4
Figure 4
(A) Decreasing thalamo–cortical structural connectivity with the SMA is associated with increased thalamic functional connectivity to subcortical structures including hippocampus, amydala, putamen and globus pallidus. Reduced structural thalamo–cortical connectivity is associated with reduced co-activity within the thalamus and anterior cingulate (B) and bilateral basal ganglia regions (C).

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