A broad and overarching goal of clinical neurosciences is to develop a mechanistic account of neural processes within a specific anatomical functional network that explains a specific clinical phenotype. There is a fundamental gap in understanding how seizures and epileptic pathological activity (i.e., not only seizures but also epileptic activity such as high frequency oscillations) affect a patient?s cognition. A core part of human cognition is the ability to remember. While the mechanisms of memory functions and their relationship with medial temporal lobe structures have been investigated in detail, and there is a wealth of information on memory dysfunction in temporal lobe epilepsy, it is yet to be known how memory functions are affected during epileptic discharges and seizures. It also remains unknown whether focal temporal lobe seizures are able to impair goal-oriented task performance. In clinical practice, we classify seizures based on whether the patient remembers the events or not, and yet we have no mechanistic understanding of what happens to the patient?s memory during seizures and how seizures impact memory for preceding and subsequent experiences. Likewise, we know little about the nature of cognitive deficits during postictal state. The goal of the proposed project is to overcome methodological limitations and test goal-directed behavior and memory in patients with MTL epilepsy. The objective here is to characterize the relationship between epileptic activities and goal-oriented task performance and memory processing. The central hypothesis of the project is that epileptic activities in the MTL will not only affect memory processing at the time of their occurrence but will also have retrograde effects by disturbing the consolidation of memory items presented before the occurrence of epileptic pathological activity and they will also have an anterograde lasting effect on encoding, consolidation and retrieval of memory items after they have disappeared. This conceptual framework is based on recent published preliminary data. The conceptual framework combined with our novel approach present an innovative platform to address the existing gap of knowledge. The proposed research is significant because it will serve as a systematic investigation to provide clear evidence about the nature of memory impairments caused by epileptic activity in the MTL. This will guide future work to design interventions in order to reduce the deleterious effects of pathological epileptic activity using novel neuromodulation methods. Our long-term ambition is that in patients implanted with chronic neuromodulation devices we use our evidence to design novel means by which we not only control seizures but more importantly reverse the cognitive deficits or even enhance the reserve functions of the epileptic tissue by silencing ongoing pathological epileptic discharges that we confirm to be toxic to human cognition.
The proposed research is the first scientific exploratory project to study the effects of temporal lobe seizures and epileptic activity such as epileptic high frequency oscillations (HFOs) and spikes on performance in a goal directed experimental task and memory functions. The proposed research is relevant to public health and the NIH?s mission because a better understanding of the deleterious effects of seizures and spontaneous epileptic activity (e.g., HFOs) on memory function in temporal lobe epilepsy can guide us devise better treatment strategies for these patients to prevent further memory loss in patients with temporal lobe epilepsy - and even ambitiously aim at enhancing their memory function using future neuromodulation devices.
