The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies

Despite the significant differences in pathological background of neurodegenerative diseases,epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer 'sdisease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shownthat the risk of developing epilepsy is three to six times higher in patients with MS compared tothe general population. In this context, understanding the pathological processes underlying thisconnection will allow for the targeting of the common and shared pathological pathways involvedin both conditions, which may provide a new avenue in the management of neurological disorders.This review provides an outlook of what is known so far about the bidirectional association betweenepilepsy and M

Revealing a brain network endophenotype in families with idiopathic generalised epilepsy

Idiopathic generalised epilepsy (IGE) has a genetic basis. The mechanism of seizure expression is not fully known, but is assumed to involve large-scale brain networks. We hypothesised that abnormal brain network properties would be detected using EEG in patients with IGE, and would be manifest as a familial endophenotype in their unaffected first-degree relatives. We studied 117 participants: 35 patients with IGE, 42 unaffected first-degree relatives, and 40 normal controls, using scalp EEG. Graph theory was used to describe brain network topology in five frequency bands for each subject. Frequency bands were chosen based on a published Spectral Factor Analysis study which demonstrated these bands to be optimally robust and independent. Groups were compared, using Bonferroni correction to account for nonindependent measures and multiple groups. Degree distribution variance was greater in patients and relatives than controls in the 6-9 Hz band (p = 0.0005, p = 0.0009 respectively). Mean degree was greater in patients than healthy controls in the 6-9 Hz band (p = 0.0064). Clustering coefficient was higher in patients and relatives than controls in the 6-9 Hz band (p = 0.0025, p = 0.0013). Characteristic path length did not differ between groups. No differences were found between patients and unaffected relatives. These findings suggest brain network topology differs between patients with IGE and normal controls, and that some of these network measures show similar deviations in patients and in unaffected relatives who do not have epilepsy. This suggests brain network topology may be an inherited endophenotype of IGE, present in unaffected relatives who do not have epilepsy, as well as in affected patients. We propose that abnormal brain network topology may be an endophenotype of IGE, though not in itself sufficient to cause epilepsy

The effects of the 15q11.2 BP1-BP2 copy number variant on white matter microstructure

Altered white matter structure has been consistently reported in neurodevelopmental disorders. A key question is whether genetic risk variants that are associated with neurodevelopmental disorders, are also associated with changes in white matter. The 15q11.2 BP1-BP2 copy number variant (CNV) is emerging as a recognised syndrome and has been associated with several neurodevelopmental disorders, including autism spectrum disorders (ASD) and schizophrenia. The cytoplasmic FMR1 interacting protein 1 (CYFIP1), a gene in this region, is involved in two distinct complexes, known to regulate actin cytoskeleton dynamics and protein translation - mechanisms that are crucial in white matter dynamics. This thesis describes a translational project combining a diverse set of multidisciplinary experiments to investigate the effects of the 15q11.2 BP1BP2 CNV on white matter microstructure. In Chapters 3 and 4, using diffusion tensor imaging (DTI) methods, I demonstrate a link between 15q11.2 BP1-BP2 CNV dosage and altered white matter microstructure in human carriers, where bidirectional CNV dosage leads to opposite changes in white matter measures. In Chapters 5, 6 and 7, using a novel Cyfip1 haploinsufficiency rat model to model the low dosage of CYFIP1 in 15q11.2 BP1-BP2 deletion carriers, I investigate how this gene could contribute to the phenotype seen in Chapters 3 and 4. Combining DTI, histology and in vitro methods, I report that Cyfip1 haploinsufficiency leads to thinning of the myelin sheath in the corpus callosum, and suggest that these changes are caused by abnormal mechanisms involving myelin basic protein distribution in mature oligodendrocytes. In conclusion, these results show that variations at the 15q11.2 BP1-BP2 chromosomal region lead to white matter abnormalities, and suggest that Cyfip1 influences myelination in the central nervous system in a rat model, providing an insight into a possible contribution made by low dosage of CYFIP1 to 15q11.2 BP1-BP2 deletion associated phenotypes

New MR imaging techniques in epilepsy

This thesis is concerned with the application of three magnetic resonance (MR) techniques in epilepsy: i.) Fluid attenuated inversion recovery prepared (FLAIR) imaging, ii.) diffusion imaging including diffusion tensor imaging (DTI) and iii.) serial and high resolution imaging of the hippocampus. I assessed the clinical value of fast FLAIR in epilepsy in a study involving 128 patients and of 3D FLAIR in a study involving 10 patients. The conspicuity of neocortical lesions and hippocampal sclerosis was increased. New lesions were detected in 5% of patients. The extent of low grade tumours was best assessed on 3D fast FLAIR images. Fast FLAIR was inferior to standard MR techniques for identifying and heterotopia. I applied newly developed, experimental diffusion imaging techniques. In eight studies using different diffusion imaging techniques involving a total of 50 patients and 54 control subjects I investigated the mobility of water molecules in the human epileptic brain in vivo. I used spin echo diffusion imaging in two studies, echo planar imaging (EPI) based DTI in four studies and EPI diffusion imaging in a patient during focal status epilepticus. Finally, in a preliminary study I attempted to use EPI diffusion imaging as a contrast to visualise transient changes associated with frequent lateralizing spikes. Our findings were: i.) diffusion is increased in hippocampal sclerosis suggesting a loss of structural organization and expansion of the extracellular space, ii.) displaying the directionality (anisotropy) of diffusion is superior to standard imaging to visualise tracts, iii.) anisotropy is reduced in the pyramidal tract in patients with hemiparesis and iv.) in the optic radiation in patients with hemianopia after temporal lobectomy suggesting wallerian degeneration, v.) both developmental and acquired structural abnormalities have a lower anisotropy than normal white matter, vi.) diffusion abnormalities in blunt head trauma are widespread and may include regions which are normal on standard imaging, indicating micro structural damage suggestive of diffuse axonal injury, vii.) focal status epilepticus can be associated with a reduced difflision in the affected cortex, viii.) diffusion imaging may be useful as a contrast for event-related (spike triggered) functional MR imaging. With serial MRI I demonstrated hippocampal volume loss in a patient after generalized status epilepticus and with high resolution imaging of an anatomical specimen and a control subject I showed hippocampal layers on MR images. The results presented in this thesis emphasised the flexibility of MR imaging and its ability to demonstrate abnormalities in vivo. FLAIR imaging is now part of the clinical work up of patients with epilepsy. Diffusion imaging has been shown to be superior to standard imaging to visualise tracts which has far-reaching implications for neurological applications. Diffusion imaging also provides an exciting window to study cerebral micro structure in vivo. Serial imaging allows for the first time the visualisation of temporal changes and high resolution imaging has the prospect of demonstrating hippocampal layers in vivo. MR imaging is a constantly progressing technique. It is hoped that this thesis will help to formulate hypotheses for new MR experiments to study the relationship of dysfunction and structural abnormalities

The structural plasticity of white matter networks following anterior temporal lobe resection

Anterior temporal lobe resection is an effective treatment for refractory temporal lobe epilepsy. The structural consequences of such surgery in the white matter, and how these relate to language function after surgery remain unknown. We carried out a longitudinal study with diffusion tensor imaging in 26 left and 20 right temporal lobe epilepsy patients before and a mean of 4.5 months after anterior temporal lobe resection. The whole-brain analysis technique tract-based spatial statistics was used to compare pre- and postoperative data in the left and right temporal lobe epilepsy groups separately. We observed widespread, significant, mean 7%, decreases in fractional anisotropy in white matter networks connected to the area of resection, following both left and right temporal lobe resections. However, we also observed a widespread, mean 8%, increase in fractional anisotropy after left anterior temporal lobe resection in the ipsilateral external capsule and posterior limb of the internal capsule, and corona radiata. These findings were confirmed on analysis of the native clusters and hand drawn regions of interest. Postoperative tractography seeded from this area suggests that this cluster is part of the ventro-medial language network. The mean pre- and postoperative fractional anisotropy and parallel diffusivity in this cluster were significantly correlated with postoperative verbal fluency and naming test scores. In addition, the percentage change in parallel diffusivity in this cluster was correlated with the percentage change in verbal fluency after anterior temporal lobe resection, such that the bigger the increase in parallel diffusivity, the smaller the fall in language proficiency after surgery. We suggest that the findings of increased fractional anisotropy in this ventro-medial language network represent structural reorganization in response to the anterior temporal lobe resection, which may damage the more susceptible dorso-lateral language pathway. These findings have important implications for our understanding of brain injury and rehabilitation, and may also prove useful in the prediction and minimization of postoperative language deficits

Imaging functional and structural networks in the human epileptic brain

Epileptic activity in the brain arises from dysfunctional neuronal networks involving cortical and subcortical grey matter as well as their connections via white matter fibres. Physiological brain networks can be affected by the structural abnormalities causing the epileptic activity, or by the epileptic activity itself. A better knowledge of physiological and pathological brain networks in patients with epilepsy is critical for a better understanding the patterns of seizure generation, propagation and termination as well as the alteration of physiological brain networks by a chronic neurological disorder. Moreover, the identification of pathological and physiological networks in an individual subject is critical for the planning of epilepsy surgery aiming at resection or at least interruption of the epileptic network while sparing physiological networks which have potentially been remodelled by the disease. This work describes the combination of neuroimaging methods to study the functional epileptic networks in the brain, structural connectivity changes of the motor networks in patients with localisation-related or generalised epilepsy and finally structural connectivity of the epileptic network. The combination between EEG source imaging and simultaneous EEG-fMRI recordings allowed to distinguish between regions of onset and propagation of interictal epileptic activity and to better map the epileptic network using the continuous activity of the epileptic source. These results are complemented by the first recordings of simultaneous intracranial EEG and fMRI in human. This whole-brain imaging technique revealed regional as well as distant haemodynamic changes related to very focal epileptic activity. The combination of fMRI and DTI tractography showed subtle changes in the structural connectivity of patients with Juvenile Myoclonic Epilepsy, a form of idiopathic generalised epilepsy. Finally, a combination of intracranial EEG and tractography was used to explore the structural connectivity of epileptic networks. Clinical relevance, methodological issues and future perspectives are discussed

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques