Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy

Abstract

This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.

Keywords: MRI; PET; SPECT; biomarkers; epilepsy; epileptogenesis; imaging; seizures.

Figure 1

The process of epilepsy development and MRI biomarkers. (A) Epileptogenesis can be described in three progressive stages: (1) the initial injury (epileptogenic trigger); (2) the latent period (silent period with no seizures); and (3) chronic period with spontaneous recurrent seizures. The initial precipitating factor, such as brain injury, infections, stroke, and status epileptics, activates diverse signaling events, such as inflammation, oxidation, apoptosis, neurogenesis and synaptic plasticity, which eventually lead to structural and functional changes in neurons. These changes are eventually manifested as abnormal synchronized hyperexcitability and spontaneous seizures. (B) Representative MR images of brain before and after exposure to the organophosphate DFP in rats. T2-weighted coronal images showing the progressive changes in brain edema and damage at 3, 7 and 28 days post-DFP exposure. White arrows signify areas of pathological abnormalities. Overall, the hippocampus, limbic structures, and cortical regions show striking atrophy and lesions, while fluid expansion is evident in the lateral ventricles. C-1, C-2, C-3 and C-4 represents various coronal sections from rat brain. Animal use protocol was approved by the Institutional IACUC (#2017-0261) on 10/27/2017.

Figure 2

The cellular and molecular abnormalities that are observed during the latent period as predictive biomarkers of epileptogenesis. Various modalities as putative biomarkers of epileptogenesis include biochemical, neuroimaging, electrophysiological markers. Neuroimaging biomarkers can be developed based on cellular and mechanistic changes, such as neurodegeneration, astrocyte activation, microglial activation, vascular remodeling, axonal sprouting, oxidative stress and calcium deposition.