Abstracts

Rationale: High frequency stimulation (HFS) has been shown to be effective in the brain to suppress neural activity using deep brain stimulation electrodes for several neuronal disorders such as Parkinson's disease or epilepsy. Yet the effect of these applied currents on neuronal elements is not known and this study focusses on the suppression of axonal pathways by HFS. Methods: Sinusoidal stimulation (sHFS) was applied to the alveus in the hippocampal slice in-vitro either in an intact slice or in isolated alveus. The compound action potentials and the evoked potentials were measured to determine how stimulation could block axons. Channel blockers and potassium concentration were also applied to the tissue to separate the various mechanisms. Results: Five possible mechanisms were investigated: (1) field potential desynchronization, (2) elevated bath potassium, (3) the role of cellular mechanisms , (4) the suppressive effects of the neuromodulator adenosine, and (5) the hyperpolarization-activated (Ih) channel. The results suggest that the suppressive effects of sHFS were not generated by field potential desynchronization. In addition, stratum pyramidale and oriens were not required for the suppressive effects of sHFS on alvear axons. Bath applied potassium ACSF (15 mM K ) in the intact slice as well as the isolated alvear axon field produced significant axonal suppression. The suppressive effect on amplitude, width, and latency of evoked potentials were similar for both bath-applied potassium and sHFS. Finally, the neuromodulator adenosine had no effect on sHFS-mediated suppression of evoked potentials within alvear axons, nor did blocking the hyperpolarization-activated cation (Ih) conductance. Instead, application of Ih blocker ZD7288 (50 ?M) lowered the threshold for complete suppression of the compound action potential using sHFS. Conclusions: These results show that stimulus induced changes in extracellular potassium likely underlie the suppressive effects of direct sHFS on the alveus in-vitro. These data strongly suggest that potassium accumulation plays a crucial role in modulating the activity of axons activated by high frequency stimulation by serving as a neuroprotective mechanism to prevent excess, synchronous neural discharges from propagating throughout neural networks.