The neural basis of perceived intensity in natural and artificial touch

Abstract

Electrical stimulation of sensory nerves is a powerful tool for studying neural coding because it can activate neural populations in ways that natural stimulation cannot. Electrical stimulation of the nerve has also been used to restore sensation to patients who have suffered the loss of a limb. We have used long-term implanted electrical interfaces to elucidate the neural basis of perceived intensity in the sense of touch. To this end, we assessed the sensory correlates of neural firing rate and neuronal population recruitment independently by varying two parameters of nerve stimulation: pulse frequency and pulse width. Specifically, two amputees, chronically implanted with peripheral nerve electrodes, performed each of three psychophysical tasks-intensity discrimination, magnitude scaling, and intensity matching-in response to electrical stimulation of their somatosensory nerves. We found that stimulation pulse width and pulse frequency had systematic, cooperative effects on perceived tactile intensity and that the artificial tactile sensations could be reliably matched to skin indentations on the intact limb. We identified a quantity we termed the activation charge rate (ACR), derived from stimulation parameters, that predicted the magnitude of artificial tactile percepts across all testing conditions. On the basis of principles of nerve fiber recruitment, the ACR represents the total population spike count in the activated neural population. Our findings support the hypothesis that population spike count drives the magnitude of tactile percepts and indicate that sensory magnitude can be manipulated systematically by varying a single stimulation quantity.

Conflict of interest statement

Competing interests: D.J.T. and the Case Western Reserve University have filed patents on the FINE electrode used in these studies: “Flat interface nerve electrode and a method for use” (US6456866) and “Nerve cuff for implantable electrode” (US8868211 and pending patent application US 14/450,769). D.J.T., M.A.S., the Case Western Reserve University, and the Cleveland Department of Veterans Affairs Medical Center have filed patents for patterned stimulation paradigms: “Methods of treating medical conditions by population based encoding of neural information” (PCT/US2013/075329 with national filings in the United States, Europe, Canada, Australia, and Japan) and “Patterned stimulation intensity for neural stimulation” (PCT/US2014/070435 with national filings due in December 2016).

Copyright © 2016, American Association for the Advancement of Science.

Figures

Fig. 1. Implanted peripheral nerve electrodes deliver stimulation directly to the nerve

Electrical stimulation was delivered by an external stimulator (top left) through percutaneous leads to FINEs implanted on the median, ulnar, and radial nerves of an upper-limb amputee (bottom left). Stimulation consists of trains of square, biphasic, charge-balanced pulses delivered to individual contacts in the eight-channel FINE. The FINE reshapes the nerve and achieves close proximity between the fascicles and the stimulating contacts, improving selectivity. Each electrode contact evokes sensory percepts on small regions of the missing hand of the subject.

Fig. 2. Intensity discrimination performance yields smooth psychometric functions

(A) Discrimination performance as a function of comparison PF. Comparison PF is reported as a percentage of reference PF for one electrode E2.6 and two reference (ref) PFs, 50 and 100 Hz. Points indicate percentage of test stimuli correctly identified as stronger or weaker than the reference over 20 pairwise trials, and the dashed line is the sigmoidal fit to the raw data. (B) Combined discrimination curves from multiple electrode contacts across two subjects under three conditions (PF discrimination, 50-Hz reference, n = 6; PF discrimination, 100-Hz reference, n = 7; PW discrimination, n = 7) (solid line denotes the mean and shaded area denotes the SEM). (Inset) Weber fractions calculated as JND divided by the reference value for the three conditions. Weber fractions were significantly lower for PW than either PF condition (t test, P < 0.001 for both) but did not differ between PF at 50 Hz and PF at 100 Hz (t test, P = 0.61). Open circles denote all data; bars denote the mean and SEM; filled circles correspond to curves in (A). (C) Intensity discrimination performance with variations of both PF and PW averaged across subjects (n = 2). Values indicate the percentage of times that a particular test stimulus was identified as stronger than the reference stimulus (center square). The reference was compared to nine test stimuli that varied in both PW and PF and included combinations of the following: lower than the reference PF level, at the reference PF level, and higher than the reference PF level; lower than the reference PW level, at the reference PW level, and higher than the reference PW level. The high and low PF and PW values were chosen to be slightly greater than or less than one JND, respectively, as determined by testing shown in (A) and (B). The stimulus with the highest PW and PF is in the lower right corner, and the stimulus with the lowest PW and PF is in the upper left. Whenever one or both of the parameters increased, the percentage of times the stimulus was judged stronger than the reference increased.

Fig. 3. Perceived magnitude scales with PW, PF, or both

(A and B) Normalized perceived magnitude as a function of PW(A) or PF (B) for one electrode (E2.7, all other stimulus parameters held constant). Points indicate mean ratings (n= 10); error bars denote the SEM; the colored line is the line of best fit. (C and D) Normalized perceived magnitude as a function of PW (C) or PF (D) averaged across electrodes (n = 4). Shaded areas denote the SEM. (E) Average normalized perceived magnitude as a function of average current for individual electrodes. Manipulations of PW (red), PF (blue), or PW and PF combined (green). Slopes were significantly different depending on stimulation condition (t test, P < 0.001).

Fig. 4. Matching of fingertip indentations on the residual limb to electrical stimuli delivered to the contralateral nerve

(A and B) Indentation depth matched to PW (A) and PF (B) for one electrode (E2.2). Points indicate mean depths (n = 5); error bars denote SEM; the colored line is the line of best fit. (C and D) Normalized indentation depth matched to PW (C) or PF (D), averaged across subjects and electrode contacts (n = 5). Shaded areas denote SEM. (E) Relationship between PF and PW regression slopes for each electrode, where each point represents a different electrode contact (n = 5; correlation analysis, r = 0.96). (F) Indentation depth as a function of average current for each electrode when matched to PW (red) and PF (blue). PW and PF had significantly different effects on matched indentation depth (t test, P < 0.001).

Fig. 5. Graphical representations of hypothesized neural response to stimulation intensity and spike frequency

(A) Recruitment of nerve fibers is hypothesized to increase with increased stimulation intensity (charge per pulse). Arrow indicates the putative location of the perceptual threshold. (B) Neural population firing rate as a function of ACR. Assuming each pulse produces one spike per activated fiber, this yields an approximately linear function. Threshold is assumed to be independent of PF (see fig. S3).

Fig. 6. ACR determines perceived intensity

(A) Intensity discrimination: performance as a function of ACR, accounting for adaptation (see figs. S4 and S5). (Inset) Weber fractions obtained from the three stimulation conditions: PW, PF at 50 Hz, and PF at 100 Hz. Weber fractions were consistent across the stimulation paradigms (t test, P = 0.61, 0.25, and 0.61). (B) Magnitude estimation: perceived intensity as a function of ACR for the PW, PF, and combined PF and PW manipulation, averaged across electrodes (n = 4). The shaded area denotes SEM. (Inset) Comparison of regression slopes obtained when varying PW, PF, or PW and PF for each electrode. Each blue point compares the slope of the PF manipulation to the slope of the combined PW and PF manipulation for a single electrode contact (n = 4). Each red point compares the slope of the PW manipulation to the slope of the combined PW and PF manipulation for a single electrode contact (n = 4). (C) Normalized indentation depth matched for perceived intensity as a function of ACR, averaged across electrodes (n = 5). Shaded area denotes SEM. (Inset) Comparison of regression slopes obtained when varying PF or PW for each electrode (n=5). (D)Magnitude estimates of intensity as a function of the ACR for the PW, PF, and combined PW and PF manipulation for each electrode. Slopes were consistent across stimulation conditions (t test, P>0.05 for all comparisons, except leftmost panel P = 0.0059). (E) Indentation depth matched for perceived intensity as a function of ACR for each electrode. Slopes were consistent across stimulation conditions (t test, P > 0.05 for all).