Connectomics and epilepsy

Abstract

Purpose of review: Tremendous advances have occurred in recent years in elucidating basic mechanisms of epilepsy at the level of ion channels and neurotransmitters. Epilepsy, however, is ultimately a disease of functionally and/or structurally aberrant connections between neurons and groups of neurons at the systems level. Recent advances in neuroimaging and electrophysiology now make it possible to investigate structural and functional connectivity of the entire brain, and these techniques are currently being used to investigate diseases that manifest as global disturbances of brain function. Epilepsy is such a disease, and our understanding of the mechanisms underlying the development of epilepsy and the generation of epileptic seizures will undoubtedly benefit from research utilizing these connectomic approaches.

Recent findings: MRI using diffusion tensor imaging provides structural information, whereas functional MRI and electroencephalography provide functional information about connectivity at the whole brain level. Optogenetics, tracers, electrophysiological approaches, and calcium imaging provide connectivity information at the level of local circuits. These approaches are revealing important neuronal network disturbances underlying epileptic abnormalities.

Summary: An understanding of the fundamental mechanisms underlying the development of epilepsy and the generation of epileptic seizures will require delineation of the aberrant functional and structural connections of the whole brain. The field of connectomics now provides approaches to accomplish this.

FIGURE 1

Mapping brain connectivity with diffusion MRI. Diffusion-weighted MRI can reveal the profile of water diffusion in brain tissue (colored shapes, top left). Neural pathways can be tracked by following the dominant directions of diffusion in the scan (top right). Whole-brain tractography extracts fibers throughout the brain (row 2), and these may be grouped into bundles that intersect specific regions of interest (such as the cortical regions shown in color in ‘Parcellation’, row 3). By measuring the density or integrity of fibers that run between all pairs of cortical regions, a connectivity matrix may be built. The major connections may be shown as a graph or network (row 4).

FIGURE 2

Functional connectivity of 16 controls based on functional MRI, with a 4-mm seed in left hippocampus. Statistic images are thresholded at Z more than 2.3, with a cluster significance threshold of P <0.05.

FIGURE 3

Comparison of the resolutions possible with genetically encoded Ca²⁺-indicators and opto-fMRI. (a) Sagittal brain section and (b) layer V of the motor cortex showing the high resolution fluorescent staining for the GECI CerTn-L15 expressed in Thy-1 transgenic mice (scale bar 0.5 mm in a, and 20 μm in b; adapted with permission from Supplementary Fig. 2 of Heim et al. [42]. (c) Opto-fMRI blood oxygenation level dependent signal (boxcar correlation coloring) in a Thy1-ChR2 expressing mouse under 0.5% isoflurane anesthesia at 100 μm × 100 μm × 500 μm resolution during a 10 mW laser power illumination. (Scale bar: 1 mm; blue triangle indicates the site of illumination); adapted with permission from Supplementary Fig. 2 of Desai et al. [40]. fMRI, functional MRI; GECI, genetically encoded Ca²⁺-indicators.