ReviewImaging biomarkers of epileptogenecity after traumatic brain injury – Preclinical frontiers
Section snippets
Initial injury to the brain, final outcome epilepsy and the chaos in between –neuroimaging unveiling patterns and order from the chaos
Traumatic brain injury is caused by external mechanical forces to the brain. The initial impact causes both focal injury (contusion) and diffuse injuries (axonal injury, vascular injury), and launches secondary injury cascades that may progress for months and years (neurodegeneration, axonal plasticity, hemodynamic deficits, inflammation). The chronic outcome can be different types of cognitive disorders, or epilepsy. The exact mechanisms of how traumatic brain injury (TBI) leads to the
Atrophy and structural diaschisis after TBI
A hallmark of moderate to severe traumatic brain injury is a progressive cortical lesion at the primary contusion site after experimental TBI. The location of the atrophic lesion is dictated by location of the primary impact site and the direction of the impact forces, and thus varies across different animal models of PTE. The primary contusion and subsequent atrophic lesion are robustly detectable by structural MRI acutely after impact. In particular, the T2-weighted (T2-wt) images highlight
Diffuse axonal injury
Shear stress of the impact force results in diffuse axonal injury (DAI) across the brain - predominantly along the thickest white matter bundles such as corpus callosum, external capsule, internal capsule, fimbria and fornix. Information extracted from diffusion-weighted imaging (DWI) data using a range of methodologies can report on axon and myelin integrity as well as general tissue microstructure including cell size and packing densities. Accumulating evidence has shown that axonal pathology
Imaging of BBB disruption and findings in TBI or epilepsy models other than posttraumatic epilepsy
The significance of blood-brain barrier (BBB) permeability in PTE is discussed and reviewed in greater detail in another contribution of this special issue (‘Breakdown of blood brain barrier as a mechanism of posttraumatic epilepsy’ by Dadas and Janigro (Dadas & Janigro, 2018). Here we briefly summarize the related imaging findings in animal models:
Van Vliet utilized a slow infusion paradigm of gadolinium to image the sporadic BBB during epileptogenesis in status model of TLE (van Vliet et al.,
Imaging of chronic inflammation by PET tracers
Inflammatory signaling cascades in epileptogenesis after TBI were recently reviewed by Webster et al. (Webster et al., 2017) and role of glia in epilepsy more broadly by Devinsky et al. (Devinsky et al., 2013). MR imaging biomarkers of neuroinflammation relating to TBI were covered by Koepp et al. highlighting several techniques that either directly or indirectly serve as a probe for inflammatory components (Koepp et al., 2017). Animal studies have provided a priori information about the
Blood flow deficits
Hemodynamic regulation (autoregulation) fails after injury and long-lasting blood flow deficits are found in trauma patients and in animal models of TBI (Hayward et al., 2011; Kenney et al., 2016; Toth et al., 2016). Vascular dilatation and hyper/hypotension present post trauma are also contributing factors to cascades leading to chronic hemodynamic imbalance. Hypertension leads to compromised integrity of the BBB, and the resulting hypoperfusion in turn compromises the blood supply and can
Plasticity, axonal sprouting and astrocyte mediated circuit shaping
Beneficial plasticity and epileptogenic plasticity are the ‘ying and yang’ of brain in the post-injury period. Spontaneous plasticity recovers a portion of brain function after TBI. Plasticity can also be aberrant and detrimental to function since it results in adverse outcomes, for example, the occurrence of spontaneous seizures. Local structural network alterations due to axonal sprouting in hippocampus and in perilesional cortex are putative causes for seizure activity. Some forms of
Functional MRI of whole brain: functional connectivity and seizure onset and spread
Correlations of fluctuations in resting state fMRI (rs-fMRI) signal can be used to indicate functional connectivity between brain regions. The major benefit of the approach is that it allows large-scale network level assessment of post-traumatic alterations, in whole brain (Fig. 4). As epilepsy is increasingly recognized to be a network-level disorder, it is highly intriguing concept to try to evaluate how local lesion and modification of white matter pathology modulates the connectivity
Inhibitory / excitatory imbalance by proton spectroscopy
Magnetic resonance spectroscopic imaging (MRSI) and magnetic resonance spectroscopy (MRS) measurements of GABA, glutamate or glutamate+glutamine concentrations or their ratios as indicators of brain excitatory-inhibitory balance have not succeeded in providing a link to epileptogenecity in experimental PTE models. Although decreases in GABA have been found in ipsilateral hippocampus 5 months after LFPI (Immonen et al., 2009), this drop did not correlate with seizure susceptibility 6 months
Hypometabolism associated with seizure focus lateralization
[18F]-Fluorodeoxyglucose PET ([18F]-FDG PET) is used to lateralize the seizure foci in temporal lobe epilepsy patients and metabolic dysregulation is one major factor in epileptogenesis (Bazzigaluppi et al., 2017). Seizure focus shows inter-ictal hypometabolism and ictal hypermetabolism (Sarikaya, 2015). Also, chronic inhibition of brain glycolysis by daily injections of non-metabolizable glucose analog 2-deoxy-D-glucose initiates epileptogenesis (Samokhina et al., 2017). In TBI models the
Conclusions
The numerous pathophysiological features described in this review (local or diffuse inflammation, vascular injury, diffuse axonal injury and network plasticity) are among the consequences of the head injury and considered as mechanisms contributing to the development of posttraumatic epilepsy. The lesion at the contusion site per se is not the direct cause for tissue hyperexcitability but instead the secondary cascades and the interplay of the many brain alterations and extra stressors are.
Disclosure
The authors declare no conflict of interest.
Acknowledgements
This research was supported by the National Institute of Neurological Disorders and Stroke (NINDS) Center without Walls of the National Institutes of Health (NIH) under Award Number U54NS100064 (EpiBioS4Rx).
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