Frequency-dependent antidromic activation in thalamocortical relay neurons: effects of synaptic inputs.

objectiveDeep brain stimulation (DBS) generates action potentials (APs) in presynaptic axons and fibers of passage. The APs may be antidromically propagated to invade the cell body and/or orthodromically transmitted to downstream structures, thereby affecting widespread targets distant from the electrode. Activation of presynaptic terminals also causes trans-synaptic effects, which in turn alter the excitability of the post-synaptic neurons. Our aim was to determine how synaptic inputs affect the antidromic invasion of the cell body. APPROACH: We used a biophysically-based multi-compartment model to simulate antidromic APs in thalamocortical relay (TC) neurons. We applied distributed synaptic inputs to the model and quantified how excitatory and inhibitory inputs contributed to the fidelity of antidromic activation over a range of antidromic frequencies. MAIN

resultsAntidromic activation exhibited strong frequency dependence, which arose from the hyperpolarizing afterpotentials in the cell body and its respective recovery cycle. Low-frequency axonal spikes faithfully invaded the soma, whereas frequent failures of antidromic activation occurred at high frequencies. The frequency-dependent pattern of the antidromic activation masked burst-driver inputs to TC neurons from the cerebellum in a frequency-dependent manner. Antidromic activation also depended on the excitability of the cell body. Excitatory synaptic inputs improved the fidelity of antidromic activation by increasing the excitability, and inhibitory inputs suppressed antidromic activation by reducing soma excitability. Stimulus-induced depolarization of neuronal segments also facilitated antidromic propagation and activation. SIGNIFICANCE: The results reveal that synaptic inputs, stimulus frequency, and electrode position regulate antidromic activation of the cell body during extracellular stimulation. These findings provide a biophysical basis for interpreting the widespread inhibition/activation of target nuclei during DBS.