Introduction
There is mounting evidence for brain pathology extending beyond the temporal lobe in patients with temporal lobe epilepsy (TLE)—one of the most common forms of focal epilepsy. Theoretical work and animal models suggest that TLE-related brain remodeling follows a specific temporal trajectory, with both focal and distributed cortico-subcortical changes that are further modulated in the course of disease (Bernhardt et al.
2013a; Sutula
2004). Most recent reports support the notion of dynamic bidirectional brain anatomy changes related to disease progression, where the initial seizure-induced boost in neurogenesis is followed by gliosis due to depletion of hippocampal stem cells and shift towards astrocytes production (Sierra et al.
2015a,
b). Cross-sectional (Bonilha et al.
2004) and longitudinal computational anatomy studies (Bernhardt et al.
2013b) in TLE patients provide indirect evidence for this process, showing hippocampal volume loss in the chronic stages of disease. Given the gap of knowledge about the neurobiology underlying TLE-associated gray matter volume and cortical thickness changes, new magnetic resonance imaging (MRI) techniques provide a window of opportunity to assess pathology related to brain’s iron and myelin homeostasis.
Animal models confirmed the notion that seizures induce axonal and myelin loss in the hippocampus paralleled by dysfunctional axonal sprouting and re-myelination (Savaskan and Nitsch
2001). Under the supposition of seizure-induced neurogenesis rate increase, evidence from animal models shows that newly generated neuronal granule cells migrate into the hilus as far as the hippocampal CA3, where due to abnormal integration into hippocampal networks they start contributing to recurrent excitatory circuits (Scharfman et al.
2000). This seizure-related aberrant network development is followed by hippocampal myelin loss and fiber degeneration in TLE, especially for small diameter axons, demonstrated by animal models and post mortem investigations (Ozdogmus et al.
2009). Correspondingly, human studies demonstrate increased oligodendroglia density and subsequent gliosis in white matter areas adjacent to the seizure onset zone (Kasper and Paulus
2004; Stefanits et al.
2012). Supported by findings showing epilepsy-associated changes of hilar ectopic granule cells (Scharfman et al.
2000) paralleled by changes in myelinated fibers (Luo et al.
2015; Ye et al.
2013), myelin-sensitive neuroimaging techniques would allow to probe microstructural tissue differences in TLE patients.
In the context of TLE, there is strong evidence from animal models about the epileptogenic role of abnormal iron homeostasis in combination with blood–brain-barrier leakage, local inflammation and cellular oxidative stress in the hippocampus (Duffy et al.
2012; van Vliet et al.
2007). Recent studies demonstrate an association between seizure activity, histological and neuroimaging signatures corresponding to pathological iron deposits (Aggarwal et al.
2018). Ferroptosis—the regulated cell death dependent on iron, occurs in the hippocampus following pharmacological-induced TLE in rodents (Ye et al.
2019). Confirmatory for this notion, there is compelling evidence that inhibitors targeting iron homeostasis can prevent hippocampal ferroptosis and ameliorate cognitive impairment associated to TLE (Ye et al.
2019). Human studies find a similar relationship between epilepsy and seizure-dependent inflammation in association to altered iron transfer and iron saturation rates (Tombini et al.
2013; Zhang et al.
2014).
The majority of computational anatomy studies in epilepsy rely on T1- and T2-weighted brain imaging data that are governed by unknown MR contrast contributions, which are a function of the underlying tissue properties. Morphometric features—cortical thickness, surface area or grey matter volume, extracted from this type of MRI data, are heavily dependent on local MR contrast properties that remain unaccounted for across all surface- and voxel-based methods at hand. The missing link between brain tissue properties and resulting morphometry results hinder the straightforward neurobiological interpretation of “spurious” findings (Lorio et al.
2016b). Recent advances in qMRI provide the opportunity to assess in vivo quantitatively specific tissue properties in the healthy and diseased brain with particular focus on myelin, iron and tissue free water content (Draganski et al.
2011; Weiskopf et al.
2013).
Up to date, detection of tissue microstructure pathology in TLE was restricted to histology studies of post-surgery ex-vivo tissue samples that showed altered intracortical myelination and fiber arrangement, particularly in superficial cortical layers (Thom et al.
2000). The combination of state-of-the-art histology and ex-vivo MRI-based morphometry confirmed the spatial correspondence between axonal degeneration of temporopolar white matter and blurring of grey-white matter boundaries (Garbelli et al.
2012). Recent qMRI study in TLE patients demonstrated an ipsilateral cortical and hippocampal increase of the longitudinal relaxation time—a measure sensitive to intracortical myelin, however, with unaccounted contribution of the effects of iron (Bernhardt et al.
2018). This was interpreted as a sign of disrupted fiber architecture that finds correlates in histology specimens of TLE patients.
Our in-vivo study investigated the differences in brain tissue properties associated with TLE clinical phenotype characteristics—disease duration and frequency, beyond the established brain morphometry assessment in TLE patients. To this aim, we acquired qMRI data according to our established relaxometry-based protocol followed by state-of-the-art whole-brain statistical analysis using voxel-based quantification (VBQ) in SPM12s computational anatomy framework (Draganski et al.
2011). We hypothesized that individuals’ seizure frequency and overall duration will correlate with tissue property patterns in hippocampus and associated nodes of limbic circuits.
Conclusion
Our combined VBM/VBQ study offers additional neurobiological interpretation linking disease duration, seizure frequency, brain volume and tissue properties in pharmaco-responsive and -resistant TLE patients. We interpret our results as evidence for a seizure-induced boost of neurogenesis and axonal sprouting associated with myelination, which is followed by a continuous, but reversible accumulation of iron in the mesial temporal lobe. Non-invasive assessment of brain tissue properties could become relevant for the clinical evaluation and outcome prediction in TLE.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.