High frequency stimulation can block axonal conduction

Abstract

High frequency stimulation (HFS) is used to control abnormal neuronal activity associated with movement, seizure, and psychiatric disorders. Yet, the mechanisms of its therapeutic action are not known. Although experimental results have shown that HFS suppresses somatic activity, other data has suggested that HFS could generate excitation of axons. Moreover it is unclear what effect the stimulation has on tissue surrounding the stimulation electrode. Electrophysiological and computational modeling literature suggests that HFS can drive axons at the stimulus frequency. Therefore, we tested the hypothesis that unlike cell bodies, axons are driven by pulse train HFS. This hypothesis was tested in fibers of the hippocampus both in-vivo and in-vitro. Our results indicate that although electrical stimulation could activate and drive axons at low frequencies (0.5 – 25 Hz), as the stimulus frequency increased, electrical stimulation failed to continuously excite axonal activity. Fiber tracts were unable to follow extracellular pulse trains above 50 Hz in-vitro and above 125 Hz in-vivo. The number of cycles required for failure was frequency dependent but independent of stimulus amplitude. A novel in-vitro preparation was developed, in which, the alveus was isolated from the remainder of the hippocampus slice. The isolated fiber tract was unable to follow pulse trains above 75 Hz. Reversible conduction block occurred at much higher stimulus amplitudes, with pulse train HFS (>150 Hz) preventing propagation through the site of stimulation. This study shows that pulse train HFS affects axonal activity by: (1) by disrupting HFS evoked excitation leading to partial conduction block of activity through the site of HFS; and (2) generating complete conduction block of secondary evoked activity, as HFS amplitude is increased. These results are relevant for the interpretation of the effects of HFS for the control of abnormal neural activity such as epilepsy and Parkinson's disease.

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS

“…This finding is consistent with a study in brain slices showing that high-frequency stimulation of the motor thalamus could only entrain antidromic activity within corticothalamic axons at firing rates Ͻ50 Hz (Iremonger et al 2006). Similar findings have been reported for other axonal pathways (Jensen and Durand 2009;Rosenbaum et al 2014;Zheng et al 2011) although some fiber tracts, particularly heavily myelinated tracts, can follow high-frequency stimulation pulse trains (Chomiak and Hu 2007).…”

“…Phase-locked spike activity has also been observed distal to the stimulated target with interpulse interval periods exhibiting increased or decreased probability of spiking that is consistent with activation of axonal efferents yielding putatively monosynaptic (Agnesi et al 2013; Anderson et al 2003;Hashimoto et al 2003;Moran et al 2011;Santaniello et al 2015) and multisynaptic (Kita et al 2005;Montgomery 2006) responses. Although axonal conduction fidelity can be robust for the high-stimulation frequencies that are typical of DBS therapy (ϳ80 -185 Hz) (Chomiak and Hu 2007;Windels et al 2003), several studies have shown axonal conduction and synaptic conduction failure (Chomiak and Hu 2007;Iremonger et al 2006;Jensen and Durand 2009;Rosenbaum et al 2014;Zheng et al 2011) with high-frequency stimulation.We hypothesized that 1) the fidelity of spike entrainment to high-frequency stimulation depends on the circuit-level connections to or from current clinical targets of DBS and that 2) the phase-locked spike activity in upstream and downstream cell populations is not stationary over time, with excitatory pathways exhibiting less stationarity than inhibitory pathways. To evaluate the fidelity of frequency entrainment to DBS, we introduce a simple but intuitive measurement called the effective pulse fraction (EPF) representing the number of single-unit spikes, within a phase of an interpulse interval, that are induced or suppressed by stimuli divided by the number of stimulus pulses used to entrain the cell.…”

“…Phase-locked spike activity has also been observed distal to the stimulated target with interpulse interval periods exhibiting increased or decreased probability of spiking that is consistent with activation of axonal efferents yielding putatively monosynaptic (Agnesi et al 2013; Anderson et al 2003;Hashimoto et al 2003;Moran et al 2011;Santaniello et al 2015) and multisynaptic (Kita et al 2005;Montgomery 2006) responses. Although axonal conduction fidelity can be robust for the high-stimulation frequencies that are typical of DBS therapy (ϳ80 -185 Hz) (Chomiak and Hu 2007;Windels et al 2003), several studies have shown axonal conduction and synaptic conduction failure (Chomiak and Hu 2007;Iremonger et al 2006;Jensen and Durand 2009;Rosenbaum et al 2014;Zheng et al 2011) with high-frequency stimulation.…”

Modulation of local field potentials by high-frequency stimulation of afferent axons in the hippocampal CA1 region

“…This is consistent with previous studies suggesting that an increase of action potential¯rings of single neurons can increase the power of LFP (Ray & Maunsell, 2011). The increase of MUA during HFS could be attributed to attenuated actions of the stimulation pulses resulting from a partial blockage of the Scha®er collaterals by HFS (Jensen & Durand, 2009;Feng et al, 2013). The attenuated actions of HFS could activate scattered¯rings of individual pyramidal cells but might not be strong enough to activate a large population of the cells simultaneously.…”

Effects of hippocampal high‐frequency electrical stimulation in memory formation and their association with amino acid tissue content and release in normal rats

“…On the other hand, the HFS-induced prolonged release of GABA could result from a delayed increasing recruitment of GABAergic fibers close to the target and GABAergic inputs from other brain regions (Windels et al, 2000(Windels et al, , 2003, or inhibition of presynaptic GABA transporters (GAT), resulting in the reduced reuptake of GABA and then, its increases in the synaptic cleft (Li et al, 2004). Prior studies have shown that HFS suppresses somatic neuronal activity (Beurrier et al, 2001;Lian et al, 2003) and blocks axonal conduction (Jensen and Durand, 2009). These inhibitory effects of HFS have been associated with reduction in excitability of neurons, increased inhibitory neurotransmission, and depression of excitatory neurotransmission (Boraud et al, 1996;Durand and Bikson, 2001).…”