Human Foot Outperforms the Hand in Mechanical Pain Discrimination.

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterized. Here, we measured the capacity for mechanical pain discrimination using a two-alternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes-Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterize the relationship between peripheral nociceptor activity and pain perception, we recorded single-unit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of individual nociceptors. We found no significant difference in the discrimination performance of either the myelinated or unmyelinated class of nociceptors between skin regions. This suggests the possibility that other factors such as skin biophysics, receptor density or central mechanisms may underlie these regional differences.

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aß deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aß input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Perceived tactile intensity at a fixed primary afferent spike rate varies with the temporal pattern of spikes.

The perceived intensity of a vibrotactile stimulus is thought to depend on single-neuron firing rates (rate coding) and the number of active afferents (population coding). Unaddressed until now is whether the temporal relation of individual spikes also conveys information about tactile intensity. We used cutaneous electro-tactile stimulation to investigate how the temporal structure of a fixed number of spikes in a 1-s train influenced the perception of intensity. Four mean spike rates spanning the flutter and vibratory hum range (36 Hz, 60 Hz; 120 Hz, 180 Hz) were tested, with spikes grouped into a regular pattern, or bursts of 2-6 spikes spaced 3 ms apart. To link a putative neural code to perception, perceived intensity was assessed in 16 human participants (aged 20-45; 4 females) using the psychophysical paradigm of magnitude estimation. Compound sensory nerve action potentials were recorded to assess any stimulus variation in afferent recruitment. The temporal structuring of a fixed number of spikes into periodic bursts of multiple spikes altered perceived intensity as a function of burst spike count. The largest increase was seen at 36 Hz, where the bursts of six spikes were rated 2.1 times stronger than the regularly spaced spikes [95% confidence interval (CI): 1.9-2.3]. The true increase is likely larger as temporal structuring of spikes into bursts had some negative effect on afferent recruitment. We conclude that the perceived intensity can be modulated by changing temporal features of afferent discharge even when normalized for the number of recruited afferents.NEW & NOTEWORTHY Structuring a fixed number of spikes into temporal burst patterns evoke gradations of perceived intensity with burst spike count, emphasizing the importance of spike timing in primary afferents for shaping perception. This forms the basis for new strategies in communicating a range of intensity information to users of neural interfaces by simply varying the timing of spikes in nonspecific primary afferents using fixed-charge electric pulses, without requiring alterations in stimulation current or mean pulse frequency.

Auditory clicks elicit equivalent temporal frequency perception to tactile pulses: A cross-modal psychophysical study.

Both hearing and touch are sensitive to the frequency of mechanical oscillations-sound waves and tactile vibrations, respectively. The mounting evidence of parallels in temporal frequency processing between the two sensory systems led us to directly address the question of perceptual frequency equivalence between touch and hearing using stimuli of simple and more complex temporal features. In a cross-modal psychophysical paradigm, subjects compared the perceived frequency of pulsatile mechanical vibrations to that elicited by pulsatile acoustic (click) trains, and vice versa. Non-invasive pulsatile stimulation designed to excite a fixed population of afferents was used to induce desired temporal spike trains at frequencies spanning flutter up to vibratory hum (>50 Hz). The cross-modal perceived frequency for regular test pulse trains of either modality was a close match to the presented stimulus physical frequency up to 100 Hz. We then tested whether the recently discovered "burst gap" temporal code for frequency, that is shared by the two senses, renders an equivalent cross-modal frequency perception. When subjects compared trains comprising pairs of pulses (bursts) in one modality against regular trains in the other, the cross-sensory equivalent perceptual frequency best corresponded to the silent interval between the successive bursts in both auditory and tactile test stimuli. These findings suggest that identical acoustic and vibrotactile pulse trains, regardless of pattern, elicit equivalent frequencies, and imply analogous temporal frequency computation strategies in both modalities. This perceptual correspondence raises the possibility of employing a cross-modal comparison as a robust standard to overcome the prevailing methodological limitations in psychophysical investigations and strongly encourages cross-modal approaches for transmitting sensory information such as translating pitch into a similar pattern of vibration on the skin.

The burst gap is a peripheral temporal code for pitch perception that is shared across audition and touch.

When tactile afferents were manipulated to fire in periodic bursts of spikes, we discovered that the perceived pitch corresponded to the inter-burst interval (burst gap) in a spike train, rather than the spike rate or burst periodicity as previously thought. Given that tactile frequency mechanisms have many analogies to audition, and indications that temporal frequency channels are linked across the two modalities, we investigated whether there is burst gap temporal encoding in the auditory system. To link this putative neural code to perception, human subjects (n = 13, 6 females) assessed pitch elicited by trains of temporally-structured acoustic pulses in psychophysical experiments. Each pulse was designed to excite a fixed population of cochlear neurons, precluding place of excitation cues, and to elicit desired temporal spike trains in activated afferents. We tested periodicities up to 150 Hz using a variety of burst patterns and found striking deviations from periodicity-predicted pitch. Like the tactile system, the duration of the silent gap between successive bursts of neural activity best predicted perceived pitch, emphasising the role of peripheral temporal coding in shaping pitch. This suggests that temporal patterning of stimulus pulses in cochlear implant users might improve pitch perception.

The Relationship Between Tactile Intensity Perception and Afferent Spike Count is Moderated by a Function of Frequency.

It has been suggested that tactile intensity perception can be explained by a linear function of spike rate weighted by afferent type. Other than relying on mathematical models, verifying this experimentally is difficult due to the frequency tuning of different afferent types and changes in population recruitment patterns with vibrotactile frequency. To overcome these complexities, we used pulsatile mechanical stimuli which activate the same afferent population regardless of the repetition rate (frequency), generating one action potential per pulse. We used trains of different frequencies (20-200 Hz) to investigate perceived intensity. Subjects' magnitude ratings increased with pulse rate up to ∼100 Hz and plateaued beyond this frequency. This was true regardless of pulse amplitude, from small pulses that exclusively activated Pacinian (PC) afferents, to pulses large enough to activate other afferents including slowly adapting. Electrical stimulation, which activates afferents indiscriminately, plateaued at a similar frequency, although not in all subjects. As the plateauing did not depend on indentation magnitude and hence on afferent weights, we propose that the contribution of spike count to intensity perception is weighted by a function of frequency. This may explain why fine textures evoking high frequency vibrations of a small magnitude do not feel disproportionally intense.

Burst gap code predictions for tactile frequency are valid across the range of perceived frequencies attributed to two distinct tactile channels.

Perceived frequency of vibrotactile stimuli can be divided into two distinctive cutaneous sensations-flutter (<60 Hz) and vibratory hum (>60 Hz), mediated by two different tactile afferent types [fast adapting type I (FA1) and fast adapting type II (FA2), respectively]. We recently demonstrated a novel form of neural coding in the human tactile system, where frequency perception of stimulus pulses grouped into periodic bursts in the flutter range depended on the duration of the silent gap between bursts, rather than the periodicity or mean impulse rate. Here, we investigated whether this interburst interval could also explain the perceived frequency of electrocutaneous pulse patterns delivered at frequencies above the flutter range. At stimulus rates of 50 to 190 pulses/s, the burst gap model correctly predicted the perceived frequency. This shows that the burst gap code represents a general coding strategy that spans the range of frequencies traditionally attributed to two different tactile channels.NEW & NOTEWORTHY We present evidence for a generalized frequency processing strategy on tactile afferent inputs that is shared across a broad range of frequencies extending beyond the flutter range, supporting the notion that spike timing has an important role in shaping tactile perception.

Temporal patterns in electrical nerve stimulation: Burst gap code shapes tactile frequency perception.

We have previously described a novel temporal encoding mechanism in the somatosensory system, where mechanical pulses grouped into periodic bursts create a perceived tactile frequency based on the duration of the silent gap between bursts, rather than the mean rate or the periodicity. This coding strategy may offer new opportunities for transmitting information to the brain using various sensory neural prostheses and haptic interfaces. However, it was not known whether the same coding mechanisms apply when using electrical stimulation, which recruits a different spectrum of afferents. Here, we demonstrate that the predictions of the burst gap coding model for frequency perception apply to burst stimuli delivered with electrical pulses, re-emphasising the importance of the temporal structure of spike patterns in neural processing and perception of tactile stimuli. Reciprocally, the electrical stimulation data confirm that the results observed with mechanical stimulation do indeed depend on neural processing mechanisms in the central nervous system, and are not due to skin mechanical factors and resulting patterns of afferent activation.

Tapping Into the Language of Touch: Using Non-invasive Stimulation to Specify Tactile Afferent Firing Patterns.

The temporal pattern of action potentials can convey rich information in a variety of sensory systems. We describe a new non-invasive technique that enables precise, reliable generation of action potential patterns in tactile peripheral afferent neurons by brief taps on the skin. Using this technique, we demonstrate sophisticated coding of temporal information in the somatosensory system, that shows that perceived vibration frequency is not encoded in peripheral afferents as was expected by either their firing rate or the underlying periodicity of the stimulus. Instead, a burst gap or silent gap between trains of action potentials conveys frequency information. This opens the possibility of new encoding strategies that could be deployed to convey sensory information using mechanical or electrical stimulation in neural prostheses and brain-machine interfaces, and may extend to senses beyond artificial encoding of aspects of touch. We argue that a focus on appropriate use of effective temporal coding offers more prospects for rapid improvement in the function of these interfaces than attempts to scale-up existing devices.