Human Thalamus in Propagation of Temporal Lobe Seizures and Memory Formation

PROJECT SUMMARY The clinical potential of neuromodulation of the anterior nucleus of the thalamus (ANT) in patients with refractory epilepsy is becoming evident. Nevertheless, this approach exhibits limited effectiveness and, in some patients, gives rise to unwanted side effects, including memory impairments. Recent preliminary evidence suggests that other thalamic nuclei may be engaged earlier and more prominently than the ANT during seizure propagation. To date, however, our understanding of seizure propagation through the human thalamus and the mechanisms of memory deficits introduced by ANT neuromodulation remains poorly understood. The goal of the proposed project is to address the existing gaps of knowledge by examining how two key subregions of the human thalamus (ANT and pulvinar) are connected with other brain structures (Aim 1), how seizures involve the two thalamic subregions differently and how the map of cortico-thalamic ictal propagation matches the intrinsic connectivity maps identified in the same individuals (Aim 2). We will also study the spatiotemporal dynamics of electrophysiological activity within ANT and between ANT and the hippocampus during an experimental paradigm of memory encoding. By applying direct electrical stimulation of the ANT (using conventional DBS parameters) we will determine the causal relevance of ANT to different aspects of human memory processing. Given our track record with intracranial research, we confidently aim to recruit patients with multisite thalamic recordings to test specific sets of hypotheses. The promise of the proposed project is to create a comprehensive map of cortico-thalamo-cortical electrophysiological causal effective connections in the human brain, its concordance with resting state fMRI connectivity, the thalamic routes of propagation for seizures originating from the temporal lobes, and whether these could be predicted by the resting state fMRI maps. Data from the memory experiment coupled with causal manipulation of the ANT will provide (hitherto missing) mechanistic and causal knowledge about the mode of ANT function during memory encoding in the human brain. Information gathered will be of relevant to future studies investigating the merits of personalizing the thalamic targets for treating patients suffering from refractory epilepsy.