Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS produces analgesia without paresthesia and is thought, therefore, not to activate DC axons, leaving its mechanism unclear. Here we show in rats that kilohertz-frequency SCS activates DC axons but causes them to spike less synchronously than conventional SCS. Spikes desynchronize because axons entrain irregularly when stimulated at intervals shorter than their refractory period, a phenomenon we call overdrive desynchronization. Effects of overdrive desynchronization on evoked compound action potentials were verified in simulations, rats, pigs, and a chronic pain patient. Whereas synchronous spiking in DC axons is necessary for paresthesia, asynchronous spiking is sufficient to produce analgesia. Asynchronous activation of DC axons thus produces paresthesia-free analgesia.
Neurons can use different aspects of their spiking to simultaneously represent (multiplex) different features of a stimulus. For example, some pyramidal neurons in primary somatosensory cortex (S1) use the rate and timing of their spikes to, respectively, encode the intensity and frequency of vibrotactile stimuli. Doing so has several requirements. Because they fire at low rates, pyramidal neurons cannot entrain 1:1 with high-frequency (100 to 600 Hz) inputs and, instead, must skip (i.e., not respond to) some stimulus cycles. The proportion of skipped cycles must vary inversely with stimulus intensity for firing rate to encode stimulus intensity. Spikes must phase-lock to the stimulus for spike times (intervals) to encode stimulus frequency, but, in addition, skipping must occur irregularly to avoid aliasing. Using simulations and in vitro experiments in which mouse S1 pyramidal neurons were stimulated with inputs emulating those induced by vibrotactile stimuli, we show that fewer cycles are skipped as stimulus intensity increases, as required for rate coding, and that intrinsic or synaptic noise can induce irregular skipping without disrupting phase locking, as required for temporal coding. This occurs because noise can modulate the reliability without disrupting the precision of spikes evoked by small-amplitude, fast-onset signals. Specifically, in the fluctuation-driven regime associated with sparse spiking, rate and temporal coding are both paradoxically improved by the strong synaptic noise characteristic of the intact cortex. Our results demonstrate that multiplexed coding by S1 pyramidal neurons is not only feasible under in vivo conditions, but that background synaptic noise is actually beneficial.
The axon initial segment (AIS) converts graded depolarization into all-or-none spikes that are transmitted by the axon to downstream neurons. Analog-to-digital transduction and digital signal transmission call for distinct spike initiation properties (filters) and those filters should, therefore, differ between the AIS and distal axon. Here we show that unlike the AIS, which spikes repetitively during sustained depolarization, the axon spikes transiently and only if depolarization reaches threshold before KV1 channels activate. Rate of depolarization is critical. This was shown by optogenetically evoking spikes in the distal axon of CA1 pyramidal neurons using different photostimulus waveforms and pharmacological conditions while recording antidromically propagated spikes at the soma, thus circumventing the prohibitive difficulty of patching intact axons. Computational modeling shows that KV1 channels in the axon implement a high-pass filter that is matched to the axial current waveform associated with spike propagation, thus maximizing the signal-to-noise ratio to ensure high-fidelity transmission of spike-based signals.
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