A roadmap to solve outstanding questions and challenges
Using more standardized pupillometric setups, such as the one introduced in this study, opens up exciting possibilities. Pupil responses to touch can be used to investigate at which level tactile stimulation is processed. For instance, if tactile stimuli elicit a pupil response without explicit conscious perception, it implies that the stimulus is only implicitly processed, a dissociation that resembles a condition termed numbsense (Gallace & Spence, 2008; Rossetti et al., 1995). To gain further insight into the patterns of pupil response for consciously and unconsciously perceived stimuli, measuring pupil responses after tactile stimulation on numbed skin using local anesthesia could be employed. While it has been shown that pupil responses scale with the intensity of nociceptive stimuli (Chapman et al., 1999; Sabourdin et al., 2018; Wildemeersch et al., 2018) and with the concentration of administered analgesia (Aissou et al., 2012; Larson et al., 1997), there is a gap in understanding pupil response after non-noxious tactile stimulation on a body location under local anesthesia. Alternatively, paradigms could be used in which the stimuli are presented at the threshold of detection (Gusso et al., 2022) or in which attention for the stimulated location is manipulated. The resulting findings could contribute to a better understanding of (subtypes of) tactile hypo- and hypersensitivity in pathologies such as chronic pain (fibromyalgia, complex regional pain syndrome) and autism spectrum disorder, and neuropsychological disorders such as tactile neglect and extinction following brain damage. Potentially, characteristics of the pupil response following tactile stimulation may be used to index the level of (residual) processing of touch, and consequently predict recovery or outcomes of rehabilitation therapy.
The differences observed in pupil responses across the three stimulated body locations in our study were in line with the known patterns of subjective tactile sensitivity (Weinstein, 1968). The pupillometric index could be used to expand these findings and create a “pupil-based homunculus” – where pupil responses serve as a detailed map, mirroring the processing intensity of tactile sensation in the brain. This could potentially lead to novel insights on the underlying neural mechanisms of differences in tactile sensitivity of different body parts. Whilst our results show clear evidence of stronger pupil dilation to stimulation to more subjectively sensitive body parts and stronger stimulation, at this point, we cannot elucidate which mechanical receptor types drove these effects the strongest. However, the systematic variation of stimulation frequency at constant amplitude might allow to narrow down this question, as different types of mechanoreceptors have different frequency ranges to which they are most sensitive (Delhaye et al., 2018). For instance, Meissner’s Corpuscles reportedly respond strongest to stimulation in the band of 10 to 50 Hz (Piccinin, MA, Miao, JH, Schwartz, 2022), whilst Pacinian Corpuscles should respond stronger to stimulation at much higher frequencies such as 250 Hz (Talbot et al., 1968). A straightforward prediction is therefore that matching stimulation intensities trigger certain receptor types specifically. Comparing pupil responses to these different frequencies at constant amplitude could therefore allow to make inferences about relative receptor distributions/proportions.
While the current method effectively shows the predicted differences between conditions at a group level, substantial individual variability poses a challenge. To enhance the method for both research and clinical use, it is crucial to optimize the signal-to-noise ratio, and obtain a measure that ideally encompasses a low number of trials and is still reliable.