Atypical language lateralisation associated with right fronto-temporal grey matter increases - a combined fMRI and VBM study in left-sided mesial temporal lobe epilepsy patients

Labudda K, Mertens M, Janszky J, Bien CG, Woermann FG. Atypical language lateralisation associated with right fronto-temporal grey matter increases - a combined fMRI and VBM study in left-sided mesial temporal lobe epilepsy patients. NeuroImage. 2012;59(1):728-737.By combining language functional magnetic resonance imaging and voxel-based morphometry in patients with left-sided mesial temporal lobe epilepsy and hippocampal sclerosis, we studied whether atypical language dominance is associated with temporal and/or extratemporal cortical changes. Using verbal fluency functional magnetic resonance imaging for language lateralisation, we identified 20 patients with left-sided mesial temporal lobe epilepsy with hippocampal sclerosis and atypical language lateralisation. These patients were compared with a group of 20 matched left-sided mesial temporal lobe epilepsy patients who had typical language lateralisation. Using T1-weighted 3D images of all patients and voxel-based morphometry. we compared grey matter volumes between the groups of patients. We also correlated grey matter volumes with the degree of atypical language activation. Patients with atypical language lateralisation had increases of grey matter volumes, mainly within right-sided temporo-lateral cortex (x =59, y = 16, z = 1,T= 6.36, p<.001 corrected), and less significantly within frontal brain regions compared to patients with typical language lateralisation. The degree of atypical fronto-temporal language activation (measured by lateralisation indices and relative functional magnetic resonance imaging activity) was correlated with right-sided temporal and frontal grey matter volumes. Patients with atypical language lateralisation did not differ in terms of language performance from patients with typical language dominance. Atypical language lateralisation in patients with left-sided mesial temporal lobe epilepsy was associated with increased grey matter volume within the non-epileptic right temporal and frontal lobe. Grey matter increases associated with atypical language might represent morphological changes underlying functional reorganisation of the language network. This hard-wired reorganised atypical language network seems to be suitable to support language functions. (C) 2011 Elsevier Inc. All rights reserved

Episodic Memory in Temporal Lobe Epilepsy

Individuals with temporal lobe epilepsy (TLE) have significant material specific episodic memory impairments with greater verbal and visual memory deficits accompanying left and right TLE respectively. More recently, however, widespread cognitive deficits have been described in patients with TLE in keeping with morphological and functional abnormalities that extend beyond the temporal lobes. Functional magnetic resonance imaging (fMRI) has demonstrated reorganisation of memory encoding networks within the temporal lobe in TLE, but little is known of the extra-temporal networks in these patients. Memory fMRI as a tool for predicting memory decline after anterior temporal lobe resection has been explored but a clinically applicable algorithm has yet to be defined. Fewer studies have described the changes in the memory encoding networks after temporal lobe surgery. This thesis presents methodological developments and novel applications to describe the pre-operative and post-operative verbal and visual memory networks in those with unilateral TLE. Pre-operatively, I investigated extra-temporal areas of memory reorganisation in left and right TLE patients, quantitatively compared to healthy controls. Novel findings include the ‘efficiency’ of extra-temporal reorganisation to successful memory formation. Next, using clinical parameters such as age at onset of epilepsy, epilepsy duration and seizure frequency as continuous regressors, I described the factors affecting verbal and visual memory reorganisation in TLE. In a separate pre-operative study, I used an alternative fMRI analysis method, multi-voxel pattern analysis (MVPA) that focuses on the patterns of activity across voxels 4 in specific brain regions that are associated with individual memory traces. I used MVPA-fMRI to assess the functional integrity of the hippocampi and other medial temporal lobe structures in patients with unilateral TLE. Next, I explored the predictive ability of temporal and extra-temporal activations in predicting post-operative verbal memory decline in left and right TLE patients and described a method of using memory fMRI as a clinically applicable tool in patients who had anterior temporal lobe resection. Finally, I explored memory encoding network plasticity four and 12 months after anterior temporal lobe resection. In this study, controls were also scanned at similar time intervals to patients. I report for the first time, dynamic changes in the memory encoding network four and 12 months after surgery, relative to changes in controls. Novel findings also include the efficiency of these post-operative networks. In this thesis, I also discuss methodological constraints, clinical applications and future directions

Asymmetry of planum temporale constrains interhemispheric language plasticity in children with focal epilepsy.

Reorganization of eloquent cortex enables rescue of language functions in patients who sustain brain injury. Individuals with left-sided, early-onset focal epilepsy often show atypical (i.e. bilateral or right-sided) language dominance. Surprisingly, many patients fail to show such interhemispheric shift of language despite having major epileptogenic lesions in close proximity to eloquent cortex. Although a number of epilepsy-related factors may promote interhemispheric plasticity, it has remained unexplored if neuroanatomical asymmetries linked to human language dominance modify the likelihood of atypical lateralization. Here we examined the asymmetry of the planum temporale, one of the most striking asymmetries in the human brain, in relation to language lateralization in children with left-sided focal epilepsy. Language functional magnetic resonance imaging was performed in 51 children with focal epilepsy and left-sided lesions and 36 healthy control subjects. We examined the association of language laterality with a range of potential clinical predictors and the asymmetry of the length of the planum temporale. Using voxel-based methods, we sought to determine the effect of lesion location (in the affected left hemisphere) and grey matter density (in the unaffected right hemisphere) on language laterality. Atypical language lateralization was observed in 19 patients (38%) and in four controls (11%). Language laterality was increasingly right-sided in patients who showed atypical handedness, a left perisylvian ictal electroencephalographic focus, and a lesion in left anterior superior temporal or inferior frontal regions. Most striking was the relationship between rightward asymmetry of the planum temporale and atypical language (R = 0.70, P < 0.0001); patients with a longer planum temporale in the right (unaffected) hemisphere were more likely to have atypical language dominance. Voxel-based regression analysis confirmed that increased grey matter density in the right temporo-parietal junction was correlated with right hemisphere lateralization of language. The length of the planum temporale in the right hemisphere was the main predictor of language lateralization in the epilepsy group, accounting for 48% of variance, with handedness accounting for only a further 5%. There was no correlation between language lateralization and planum temporale asymmetry in the control group. We conclude that asymmetry of the planum temporale may be unrelated to language lateralization in healthy individuals, but the size of the right, contra-lesional planum temporale region may reflect a 'reserve capacity' for interhemispheric language reorganization in the presence of a seizure focus and lesions within left perisylvian regions

Cognitive functional MRI in temporal lobe epilepsy

Anterior temporal lobe resections (ATLR) provide an effective treatment option for patients with medically refractory temporal lobe epilepsy (TLE) rendering up to 70% of them seizure free. The goal of epilepsy surgery is to remove the brain areas generating the seizures without causing neuropsychological deficits such as language or memory dysfunction. Furthermore up to 60% of patients with TLE suffer from emotional disturbances following surgery. The principle aim of the work presented in this thesis was to improve presurgical evaluation of patients with TLE by using cognitive functional MRI (fMRI) to non-invasively localise brain areas that are essential for processing cognitive function such as language and memory function and emotional and social behaviour. 150 consecutive patients and 40 healthy controls were included in our experiments. Different fMRI paradigms for the evaluation of cognitive functions have been implemented on a 3 Tesla scanner. All subjects underwent language and memory fMRI and standard neuropsychological assessment; those patients who proceeded to have temporal lobe surgery were reinvestigated 4 months following ATLR. We studied the efficiency of reorganisation of language and memory function due to the underlying disease and in particular following ATLR. Amygdala fMRI was used to investigate potential implications on emotional and social outcome. A major part of the work included in this thesis has concentrated on the use of fMRI for the exploration and prediction of postoperative complications such as language and memory impairment but also emotional disturbances. When used in concert with other MR imaging modalities the results of these methods can be used to improve surgical strategies tailored to individual patients with regard to functional outcome, by virtue of definition of epileptic cerebral areas that need to be resected and eloquent areas that need to be spared

Translation of Novel Imaging Techniques into Clinical Use for Patients with Epilepsy

Temporal lobe epilepsy is the most common focal epilepsy. Up to 40% of patients are refractory to medication. Anterior temporal lobe resection (ATLR) is an effective treatment but damage to the optic radiation can result in a visual field deficit (VFD) that precludes driving, a key goal of surgery. Diffusion tensor imaging tractography allows the in vivo delineation of white matter tracts such as the optic radiation. This thesis addresses the role of optic radiation tractography in planning and subsequently improving the safety of epilepsy surgery. I show how tractography assists risk stratification and surgical planning in patients with lesions near the optic radiation and assess the utility of different tractography methods for surgical planning. To derive the greatest benefit, tractography information should be available during surgery which requires correction for intraoperative brain shift and other sources of image distortion. I apply software developed at UCL in a clinical population underlying ATLR to show that postoperative imaging can predict the VFD and then use this software in real time during surgery in an intraoperative MRI suite. Updated anatomical scans can be acquired during surgery and tractography data accurately mapped on to these and displayed on the operating microscope display. I demonstrate that this image guidance allows the neurosurgeon to avoid significant VFD without affecting the seizure outcome. Diffusion imaging can also probe tissue microstructure. I explore how structural changes within the frontoparietal working memory network and temporal lobes are related to working memory impairment in TLE. I describe the structural changes that occur following ATLR showing both Wallerian degeneration and structural plasticity. Finally, I show how a novel diffusion model (NODDI) could aid the clinical assessment of patients with focal cortical dysplasia. The emphasis throughout this thesis is how diffusion imaging can be clinically useful and address clinically relevant outcomes

The effects of genes, antiepileptic drugs and risk of death on functional anatomy and cognitive networks in epilepsy

Epilepsy is one of the most common neurological disorders. Apart from seizures, patients are also affected by epilepsy comorbidities, such as cognitive impairment, side effects of antiepileptic drugs, and an increased risk of dying from sudden death. Within epilepsy research, recent efforts have been made to identify reliable biomarkers to advance the understanding of disease-mechanisms, to individualize and optimize treatment and side-effect profiles and to enhance prediction of treatment success and disease progression. Biomarkers are objective measures of a normal or pathological biological process and, in the context of this PhD, neuroimaging biomarkers ideally enable in vivo measurements of (i) disease activity, (ii) treatment effects and (iii) risk of comorbidities and mortality. Employing functional and structural neuroimaging techniques, we studied potential neuroimaging biomarkers in three different domains of epilepsy. In the first project, we explored fMRI endophenotypes in a prototype of a genetic generalised epilepsy syndrome, namely juvenile myoclonic epilepsy (JME). Endophenotypes are heritable traits, closer related to the genotype than the final phenotype and are found frequently in non-affected family members of patients. Our study revealed potential functional endophenotypes and support a genetically determined neurodevelopmental disease mechanism in JME. The second project investigated fMRI markers of antiepileptic drug effects on cognitive networks in patients with refractory epilepsy. In two retrospective studies employing fMRI cognitive tasks, we isolated task- and medication-specific effects on working memory and language networks for Levetiracetam (study 1) and Topiramate and Zonisamide (study 2). In the third project, we employed Voxel-Based-Morphometry in a retrospective analysis of structural imaging of patients who had died of sudden unexpected death in epilepsy (SUDEP) or were at high or low risk of SUDEP. We identified structural markers of high SUDEP risk, and discussed that these were at least partially specific, i.e. independent of disease progression and load

Advanced clinical MRI for better outcome in epilepsy surgery. Focusing on fMRI and prediction of verbal memory decline.

Abstract Aim: The aim of the thesis was to evaluate the use of advanced MRI technology to improve results of epilepsy surgery, with focus on language and memory functions. Methods: In paper I, 25 patients with drug-resistant epilepsy were retrospectively included in the study for having been referred to high resolution 3T MRI with and without surface coils. The surface coils were placed over the suspected epileptogenic zone. The efficacy of the coils was assessed and graded in relation to their placement. In papers II, III and IV, a functional MRI (fMRI) paradigm, including both a verbal encoding task and a visuospatial task, was designed and implemented. The medial temporal lobe (MTL) for memory and the anterior language area were studied. In paper III, a standard word generation fMRI paradigm was also included. In these three studies, the test was performed in 15 healthy right handed subjects (paper II), 6 patients with drug-resistant temporal lobe epilepsy (TLE) with mixed handedness and 10 controls (paper III) and 14 TLE patients eligible for resective surgery (paper IV), respectively. A bootstrap algorithm was used to calculate lateralization indices (LI) and LI-curves. In paper IV, a clinical risk assessment score was created from collected clinical data. Additional value from fMRI LI was correlated to post-surgical memory decline. Results: Surface coil 3T MRI did not contribute to detection of previously undiagnosed lesions. In 20% of patients, 3T MRI, compared with previous 1.0-1.5T MRI, provided new information about cortical lesions. The fMRI paradigm visualized memory-related activity in the MTL and provided information regarding language processes. LI and LI-curves for memory at group level were consistent with previous studies, but a variety of activation effects were found at the individual level. LI-curves added complementary information for individual subjects with uncharacteristic results. The verbal encoding task provided information on verbal memory, which had equal lateralization as language in right-handed subjects, but not always in left-handed subjects and TLE patients. Bilateral fMRI language representation was seen in 2 right TLE patients who later suffered verbal memory decline post-operatively. Conclusion: High resolution 3T MRI is valuable for lesion detection, but surface coils do not provide further crucial information. The fMRI paradigm activates memory and language areas that can be studied at an individual level using LIcurves. Analysis of language patterns seems to be important for prediction of memory outcome in both left and right TLE. fMRI indices may identify an unexpected high risk for post-operative verbal memory decline in right TLE patients

Imaging brain networks in focal epilepsy: a prospective study of the clinical application of simultaneous EEG-fMRI in pre-surgical evaluation

Epilepsy is a common disorder with significant associated morbidity and mortality. Despite advances in treatment, there remain a minority of people with pharmacoresistant focal epilepsy for whom surgery may be beneficial. It has been suggested that not enough people are offered surgical treatment, partly owing to the fact that current non-invasive techniques do not always adequately identify the seizure onset zone so that invasive EEG is required. EEG-fMRI is an imaging technique, developed in the 1990s (Ives, Warach et al. 1993) which identifies regions of interictal epileptiform discharge associated haemodynamic changes, that are concordant with the seizure onset zone in some patients (Salek-Haddadi, Diehl et al. 2006). To date there has been no large scale prospective comparison with icEEG and postoperative outcome. This thesis presents a series of experiments, carried out in a cohort of patients scanned using EEG-fMRI as part of a multi-centre programme, designed to investigate the relationship between EEG-fMRI and intracranial EEG and to assess its potential role in pre-surgical evaluation of patients with focal epilepsy. The results suggested that positive, localised IED-related BOLD signal changes were sensitive for the seizure onset zone, as determined on icEEG, both in patients neocortical epilepsies, but were not predictive of outcome. Widespread regions of positive IEDrelated BOLD signal change were associated with widespread or multifocal abnormalities on icEEG and poor outcome. Patterns of haemodynamic change, identified using both data driven and EEG derived modeling approaches, correspond to regions of seizure onset on icEEG, but improvements for modeling seizures are required. A study of a single seizure in a patient who underwent simultaneous icEEGfMRI, showed similar findings.. An exploratory investigation of fMRI-DCM in EEG-fMRI, suggested it can provide information about seizure propagation and this opens new avenues for the non-invasive study of the epileptic network and interactions with function