Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity

Abstract

Background: Pairing sensory or motor events with vagus nerve stimulation (VNS) can reorganize sensory or motor cortex. Repeatedly pairing a tone with a brief period of VNS increases the proportion of primary auditory cortex (A1) responding to the frequency of the paired tone. However, the relationship between VNS intensity and cortical map plasticity is not known.

Objective/hypothesis: The primary goal of this study was to determine the range of VNS intensities that can be used to direct cortical map plasticity.

Methods: The rats were exposed to a 9 kHz tone paired with VNS at intensities of 0.4, 0.8, 1.2, or 1.6 mA.

Results: In rats that received moderate (0.4-0.8 mA) intensity VNS, 75% more cortical neurons were tuned to frequencies near the paired tone frequency. A two-fold effective range is broader than expected based on previous VNS studies. Rats that received high (1.2-1.6 mA) intensity VNS had significantly fewer neurons tuned to the same frequency range compared to the moderate intensity group.

Conclusion: This result is consistent with previous results documenting that VNS is memory enhancing as a non-monotonic relationship of VNS intensity.

Keywords: Auditory cortex; Inverted U function; Plasticity; Vagal nerve stimulation.

Figure 1

Schematic diagram of the VNS-tone train pairing procedure. A 0.5 second, 30 Hz train of 100 μs wide biphasic pulses was delivered to the left vagus nerve via a cuff electrode. Each group received VNS at one of four different intensities: 0.4 mA, 0.8 mA, 1.2 mA, or 1.6 mA. Rats received VNS paired with a 9 kHz tone every 30 s, 300 times during each 2.5 hour session for 20 days. Cortical recordings were made 24 hours after the last pairing session.

Figure 2

Frequency map plasticity in primary auditory cortex. Each polygon represents a single electrode penetration. The characteristic frequency (CF) of each site is indicated in kHz. The red color indicates that the value of the CF is between 8 and 16 kHz. Representative frequency map from a naïve rat (A). Representative frequency map from a rat that received 1.6 mA VNS (B), 0.8 mA VNS (C) or 0.4 mA VNS (D) paired with 9 kHz tones. Moderate VNS-tone pairing reorganizes the frequency map, but intense VNS-tone pairing does not. The scale bar indicates a distance of 0.5 mm. Anterior is shown to the left and dorsal is down.

Figure 3

The percent of A1 sites tuned to each of five 1 octave frequency bins. This demonstrates significant shifting in tuning between 8 to 16 kHz when VNS at 0.4 mA and 0.8 mA is paired with a 9 kHz tone. When the vagus nerve is stimulated at intensities of 1.2 mA and 1.6 mA, there is not a significant shift in tuning between 8 to 16 kHz. Error bars indicate s.e.m. across A1 recording sites.

Figure 4

VNS-tone pairing reorganizes the auditory cortex frequency map as a non-monotonic function of VNS intensity.

Figure 5

Percent of A1 responding to each tone frequency intensity combination for naïve control rats (A), moderate intensity (0.4 mA - 0.8 mA) VNS rats (B), and high intensity (1.2 mA -1.6 mA) VNS rats (C). D) The difference between the percent of A1 responding for moderate VNS rats and control rats reveals the range of tones that evoked a response in more neurons (red) or fewer neurons (blue). White lines delineate the frequency intensity combinations which activate significantly more neurons after VNS pairing with a 9 kHz tone (P<0.05). Black lines delineate significantly decreased responses. E) The difference between the percent of A1 responding in high intensity VNS rats and control rats is also shown. Note that moderate intensity VNS-tone pairing alters the cortical response more than high intensity VNS-tone pairing.

Figure 6

VNS-tone pairing reorganizes the extent of auditory cortex that is activated by suprathreshold tones as a non-monotonic function of VNS intensity. In naïve rats (0 mA), approximately the same percent of A1 area responds to 1-2 kHz 50 dB tones as responds to 8-16 kHz 50 dB SPL tones. After 9 kHz 50 dB SPL tones were paired with moderate VNS (0.4-0.8 mA), more neurons respond to high tones compared to low tones. The shift was less when high VNS intensity (1.2-1.6 mA) was used.

Figure 7

Number of spikes evoked by each combination of tone frequency and intensity in naïve control rats (A), moderate intensity VNS (0.4 mA- 0.8 mA) rats (B), and high intensity VNS (1.2 mA- 1.6 mA) rats (C). D) Difference in the number of spikes evoked by each tone for moderate intensity VNS rats compared to controls. E) Difference in the number of spikes evoked by each tone for high intensity VNS rats compared to controls. As in Figure 5, white and black lines delineate significant increases and decreases, respectively.

Figure 8

The bias in favor of low frequency tones was eliminated by pairing 9 kHz tones with moderate (0.4-0.8 mA) VNS but not with high intensity (1.2-1.6 mA) VNS. The graph plots the difference between the A1 action potentials evoked by 1-2 kHz 50 dB SPL tones and 8-16 kHz 50 dB SPL tones.