Quantitative magnetic resonance techniques in epilepsy

Epilepsy is a chronic brain disorder characterized by unprovoked recurrent seizures that give rise to episodes of abnormal neuronal activity in the central nervous system. The most common application of magnetic resonance imaging (MRI) techniques in the epileptic brain is the identification of the underlying cause for a person’s epilepsy, and possibly the localization of the epileptic focus. In addition, quantitative magnetic resonance (MR) techniques enable examining certain relatively subtle aspects of epilepsy within the brain that go beyond the identification of seizure focus within the brain. In this thesis a number of studies are presented that investigate the application of quantitative MR techniques to epilepsy-related abnormalities of metabolism, microstructures and brain function. The research project was aimed at developing and validating quantitative MR techniques (spectroscopy, diffusion, T2 relaxometry, and functional magnetic resonance imaging) with clinical diagnostic potential. The main focus was on data acquisition and processing, and the application of this multi-modal MR approach in both patients with epilepsy and an animal model of epileptogenesis. We explored in a clinical setting how the cognitive consequences of epilepsy (either due to medication or due to seizures) may be reflected in altered MR tissue characteristics. Furthermore, using an experimental model of febrile convulsions, it was investigated whether neurological abnormalities, possibly linked with epileptogenesis and thus with epilepsy, could be detected by quantitative MR. A general introduction into quantitative MR techniques and epilepsy is given in Chapter 1. Chapter 2 describes a thorough review on absolute quantification of metabolites using spectroscopy, which can substantially improve the diagnostic utility of spectroscopy. Absolute quantification requires more time and expertise than relative quantification, as additional calibrations for concentration determination and spectrum analyses have to be performed. One can only benefit from absolute quantification if all additional reference steps are executed properly; otherwise unwanted additional errors may be introduced. Chapter 3 concerns a clinically relevant reproducibility study of several quantitative MR techniques which was performed on a 3.0 Tesla MR system. Repeated measurements in 10 healthy volunteers were used to establish the reproducibility of quantitative measures derived from different quantitative MR techniques, namely the T2 relaxation time, the apparent diffusion coefficient (ADC), the fractional anisotropy (FA), and metabolite concentrations of N-acetyl-aspartate (NAA), total creatine (tCr), choline (Cho) and myo-inositol (mI). The reproducibility of quantitative brain MR at 3.0 T appeared to be better than, or at least comparable to the reproducibility at 1.5 T. A newly developed statistical image analysis method, which offers considerably increased sensitivity for the detection of subtle signal changes in images of several neurological MR applications, is described in Chapter 4. This method, the regional false discovery rate (FDR) control, increases sensitivity by exploiting the spatially clustered nature of neuroimaging effects. The method was validated, characterized, and compared to some other commonly used methods (uncorrected thresholding, Bonferroni correction, and conventional FDR-control). It was found that the new method showed considerably higher sensitivity as compared to conventional FDR-control. Application of the method to two different neuroimaging applications, revealed substantial improvements compared to the other methods. Quantitative MR (T2 relaxation, diffusion, spectroscopy, and functional MRI) at 1.5 T and neuropsychological assessment was performed in a group of patients with localization related epilepsy and secondarily generalized tonicoclonic seizures (SGTCS) to study cognitive deterioration. Chapter 5 relates to the investigation of the effect of these seizures on microstructural and metabolic changes in brain tissue characteristics. Frontal, but not temporal, MR abnormalities were found to be related to SGTCS. These findings confirm that SGTCS do have a substantial effect on frontal brain function and on the microstructural brain tissue characteristics. This knowledge may help to obtain a better understanding and anticipatory treatment of SGTCS-related cognitive deterioration. In Chapter 6 it was investigated using functional MRI whether a higher number of SGCTS were associated with a functional reorganization of working memory. It was found that high numbers of SGTCS resulted in a decrease in intelligence scores and altered prefrontal brain activation. A shift from frontotemporal to prefrontal activation seemed to have occurred, suggesting that a functional reorganization of working memory is induced by a high number of SGTCS. It remains uncertain if this reorganization reflected compensatory mechanisms, or the underlying pathological processes of cognitive deterioration. In the same patient group it was found in Chapter 7 that the presence of a certain marker for neuronal damage in blood serum (telencephalin) correlates with a decreased frontotemporal activity during an functional MRI memory task.