Epilepsy: Disease and Model to Study Human Brain Function

Introduction Epilepsy is one of the most common neurological disorders, affecting almost 1% of the population. In many patients, a focal onset of seizure activity within the temporal lobe can be detected. Neurophysiological recordings, high-resolution brain imaging and neuropathological analysis of surgical brain specimens identify the hippocampus as the major target structure being affected in patients with temporal lobe epilepsy (TLE). Moreover, removal of this structure during epilepsy surgery is effective in controlling seizures in these patients. Since temporal lobe structures such as the hippocampus are also critically involved in learning and memory formation, clinical and neuropsychological investigations of epilepsy patients open new avenues to study mechanisms of higher order brain functions in human, such as declarative memory processes. Quantitative measurements of neuropsychological deficits in patients with TLE help to generate new concepts on how the information is stored and recalled in the human brain. For instance, our studies have revealed that the hippocampus of the dominant hemisphere contributes significantly to novelty detection during verbal memory formation, an important decisive process linked to long-term memory storage. In addition to neuropsychological, in vivo neurophysiological and imaging studies, the availability of living hippocampal brain tissue following epilepsy surgery allows to analyze cellular and molecular mechanisms of activity-dependent plasticity, ie, long term potentiation. With further advances in clinical and basic neurosciences and high resolution imaging, our understanding of how the human brain is functionally organized and sensory information is processed will continuously increase. Thus, epilepsy constitutes a unique model disease to systematically study human brain function on different levels. Epilepsy and the Functional Anatomy of the Human Brain In 1954 Wilder Penfield and Herbert Jasper published their milestone textbook Epilepsy and the Functional Anatomy of the Human Brain (14). The unique data presented in this publication were based on electrophysiological recordings obtained during epilepsy surgery and local anesthesia of the patient. Until that time, brain stimulation experiments had been carried out only in experimental animals, and non-invasive techniques were not available to characterize eloquent brain regions in humans, ie, motor or speech areas. The result of many hundreds of patients analyzed during epilepsy surgery at the Montreal Institute of Neurology established a coherent functional brain map of the human brain, which is still valid for most instances, replacing and extending previous brain maps derived from postmortem analysis of traumatic brain injury, tumors or stroke. It was the pioneering attitude of Penfield and Jasper to recognize that epilepsy surgery bears remarkable promise to study high order human brain function in conscious human. Today the experimental opportunities associated with epilepsy surgery have extended substantially (2, 8). Experimental analysis is no longer confined to the short period during which surgery and local anesthesia takes place. In many patients, intracerebral electrodes are implanted in order to identify the epileptic focus and/or eloquent brain areas that could be potentially compromised by a surgical intervention (Figure 1). For identification of the epileptic focus, recording spontaneous seizures is essential. During the time period of hospitalization during which patients wait for spontaneous seizures (7-20 days), bioelectrical parameters of specific brain areas, even in the depth of the mesial temporal lobe, and their association with the patient’s neuropsychological ability and behavior can be quantitatively measured. The application of modern neurobiological techniques to human brain specimens from the epileptogenic area resected during epilepsy surgery represent yet another major research avenue (3). Neuropathological examination including immunohistochemical and ultrastructural techniques allow to precisely classify specific disorders underlying focal epileptogenesis (see Blümcke et al, Crino et al, this issue). In addition, living SYMPOSIUM: Pathogenesis and Pathophysiology of Focal Epilepsies