Abstracts

Rationale: Direct brain stimulation has fully emerged as a therapy and a clinical tool for mapping of eloquent cortex, and for neuromodulation attempts at stopping seizures. In contrast, the effect of electrical stimulation remains poorly understood, mostly due to the inability to capture and quantify the high variability in the responses of stimulated neurons. As a result, new therapeutic and clinical applications of brain stimulation are introduced without a clear understanding of the mechanisms necessary for the determination of clinical efficacy or safety of these interventions. Methods: We developed a high-cell density (10³cells/mm³) computer model of a cortical volume that allows for quantification of presynaptic elements of cortical neurons that are activated by electrical stimulation. Realistic multicompartmental cell models (Traub et al. 2005) previously used to study high frequency oscillation, sleep spindles, and epileptogenic bursts have been implemented in the GENESIS simulator. The model consists of layers of a 3d representation of cells arranged in anatomically realistic fashion inside a 5x5x4 mm volume of gray matter that is modeled as an uniform, isotropic conductive medium subjected to an electric field generated by a disk electrode (2.3 mm diameter). Results: The initiation of APs takes place predominantly in axon initial segments or in axon branch terminals. Coincident APs initiations in more than one axonal compartment were less frequent and occurred mostly in axon terminals. The total number of recruited cells by single current pulse exhibits an S-shape growth as the amplitude of the applied current to the electrode increases. The site of initiation of APs in the axon depends on the orientation of the cell relative to the electrode, and the amplitude and polarization of an applied current. The 3d structure of a cell's main dendritic arbor has a significant effect on the initial segment excitation threshold. The anodal-cathodal pulse sequence was more effective in cell recruitment, however the increase in the number of recruited cells was selective with respect to the number of cells recruited solely the in axonal terminals (on average 45-70%). There were significant (up to 0.5 ms) time delays in in propagation of APs initiated in one axon terminal to non-activated axonal branches and associated with these delays latencies in the occurrence of both APs (duplets) in axon terminals. Conclusions: After the axon initial segment, axon terminals are the location where APs can originate regardless of the state of the initial segment (sup- or sub-threshold activation, or hyperpolarization). The 3d structure of the proximal dendritic arbor has an impact on the axon initial segment polarization. APs initiated at axon terminals generate AP duplets and there are latencies in the arrival of these AP duplets at various axon terminals in a given cell. This temporal variability of presynaptic AP arrival can contribute to desynchronizaton of the neural activity and therefore may underlay desynchronization or the anti-epileptic effects of stimulation. Supported by ARO Grant W911NF-12-1-0418