Cellular Mechanisms Preventing Sustained Activation of Cortex During Subcortical High-Frequency Stimulation

Abstract

. Kiss. Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation. J Neurophysiol 96: 613-621, 2006. First published March 22, 2006 doi:10.1152/jn.00105.2006. Axonal excitation has been proposed as a key mechanism in therapeutic brain stimulation. In this study we examined how high-frequency stimulation (HFS) of subcortical white matter tracts projecting to motor cortex affects downstream postsynaptic responses in cortical neurons. Whole cell recordings were performed in the primary motor cortex (M1) and ventral thalamus of rat brain slices. In M1, neurons showed only an initial depolarization in response to HFS, after which the membrane potential returned to prestimulation levels. The prolonged suppression of excitation during stimulation was neither associated with GABAergic inhibition nor complete action potential failure in stimulated axons. Instead we found that HFS caused a depression of excitatory synaptic currents in postsynaptic neurons that was specific to the stimulated subcortical input. These data are consistent with the hypothesis that axonal HFS produces a functional deafferentation of postsynaptic targets likely from depletion of neurotransmitter.

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

“…Interestingly, the phase-locked excitatory responses to stimulation that we observed with delays Ͻ2 ms and with relatively low jitter, which could be attributable to antidromic activation, also showed an inability to entrain one to one with high-frequency stimulation. 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).…”

“…In theory, in the case of M1 activity during VPLo DBS, sustained excitation could also be limited by increased inhibition via disynaptic activation of inhibitory interneurons, which may sustain higher firing frequencies (Martina and Jonas 1997) and are less susceptible to conduction failure compared with glutamatergic neurons (Meeks and Mennerick 2004). However, as Iremonger et al (2006) noted, cortical neurons are still unable to follow the high-frequency pattern of stimulation even in the presence of GABA blockade. In addition, at high frequencies of stimulation, synaptic transmission is likely to undergo at least partial vesicle depletion (Anderson et al 2006), which was suggested to shape the cortical response to high-frequency thalamic stimulation in slices using a voltage-sensitive dye (Urbano et al 2002).…”

“…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.…”

Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex

“…Alternatively, there is some evidence for a sparse but direct cortical innervation of the pallidum (Naito and Kita 1994;Smith and Wichmann 2014). The low fidelity of driving observed here (spikes elicited by ϳ6% of shocks) is consistent with a previous study of antidromic activation of cortical neurons during high-frequency stimulation (Iremonger et al 2006). The paucity of stimulation driven high-frequency resonance in our recordings, combined with pronounced and persistent therapeutic effects of GPi-DBS, is inconsistent with the idea that antidromic-driven resonance in cortex is a primary therapeutic mechanism of action for GPi-DBS.…”