Functional integrity of cortical malformations

Epilepsy is one of the most common neurological disorders affecting 0.5-1% of the population. In one third of patients it cannot be controlled adequately with antiepileptic drugs. Drug resistant epilepsy is associated with a high morbidity and significantly increased mortality. Malformations of cortical development (MCD) are increasingly recognised as a major cause for drug resistant epilepsy. Approximately 80% of patients with MCD do not respond to antiepileptic treatment and require surgical intervention. MCD are often localised in functionally eloquent cortical areas conveying sensory-motor, language, emotion or higher cognitive functions. Therefore, a precise knowledge on functional integration of MCD is essential for determining the boundaries of cortical resection in order to achieve seizure freedom without postoperative functional deficits. The gold standard to identify eloquent cortical areas is direct electrical stimulation with implanted subdural or intracerebral depth electrodes, but this method carries a significant morbidity and burden for patients. A non-invasive alternative is a functional MRI (fMRI), which can be used to assess cortical function also in a non-lesional hemisphere (whereas direct cortical stimulation assesses only those brain regions where electrodes are placed). Our previous studies and the results obtained by others, demonstrated functional reorganization of cerebral cortex in some MCD (suggesting a shift of function from malformed cortex to the unaffected areas); or, on the contrary, functional integration of the dysplastic cortices. Preliminary work on few cases with focal cortical dysplasia (FCD) suggests that the developmental neurobiology and histopathology of MCD determine its degree of integration in normally functioning cerebral cortex. The main goal of this study is to assess the integration of different MCD in sensory-motor, language, emotion and memory function with fMRI and cortical direct stimulation and correlate the degree of functional integration with histological and histochemical characteristics in the developmental lesion. The first aim is to assess whether MCD are activated by fMRI paradigms and therefore involved in the functional network. The second aim is to compare the fMRI results with the results of cortical mapping by intracerebral electrodes in those patients who need invasive EEG within the diagnostic needs in the framework of the presurgical assessment. The third aim is to correlate histological and neurochemical features of MCD with the fMRI activation of MCD. The biology and histological features of some MCD (e.g. FCD) determine their fMRI activation and therefore, the functional integrity. We hypothesize, That functional integration of MCD can be identified non-invasively by specific functional neuroimaging (fMRI) characteristics. That there is a tight correlation between the degree of functional integration of the malformed cortex assessed by non-invasive functional neuroimaging and the direct cortical stimulation of the MCD. That functionally integrated MCD will differ histologically and histochemically from those which are not integrated into the normally functioning cerebral cortex.

Cortical malformations result from aberrant development of neurons that comprise cerebral cortex and are commonly associated with epilepsy in children and adults. The aim of this project was to test the involvement of abnormally developed cortex in cerebral function in patients with epilepsy. The results of the study supported our hypothesis that different types of cortical malformations are integrated in cerebral function in different ways. We tested our hypothesis with functional MRI (fMRI) and so called cortical mapping. The former method is non-invasive; the latter is performed through cerebrally implanted electrodes in patients whose epilepsy was not manageable with medications and could be treated by brain surgery. We tested in total 107 patients with fMRI and 16 with cortical mapping. The main result of our project is that cortical malformations due to early developmental damage are not integrated in the cerebral function like language, motor, memory or emotion; whereas cortical malformations due to later developmental injuries harbour important brain functions. These results could have important implications for planning presurgical work-up of patients with cortical malformations in terms of proper placement of cerebral electrodes for cortical mapping. On the other hand, we could avoid unnecessary invasive procedures in patients with functionally integrated cortical malformations. In general, based on our findings, we can better identify patients eligible for successful epilepsy surgery on a non-invasive basis.