Biology subjects

Olausson, H.

Publications and source records attributed to Olausson, H..

16 recordsLinked to original sources

bioRxiv2026

Rapid peripheral reprogramming of myelinated afferents drives human hyperalgesia

A small burn can render a large area of skin painfully tender. This widespread hyperalgesia protects injured tissue and is typically attributed to altered spinal cord mechanisms. Whether peripheral sensory afferents directly interact to contribute to hyperalgesia remains unclear. Using single-unit microneurography, we recorded cutaneous afferents before and after inducing localized TRPV1-mediated inflammatory flare. This triggered minutes-scale reweighting of transcriptomically defined TRPV1- afferents, with divergent effects among myelinated (A{beta}-range) classes: tactile receptors showed reduced responsiveness, whereas mechano-nociceptors underwent sensitization. These changes paralleled diminished tactile sensitivity and intensified mechanical pain. Recruitment of mechanically silent branches in A{beta}-range mechano-nociceptors produced wide-field amplification of peripheral nociceptive signaling beyond the inflamed site. These findings suggest that rapid peripheral crosstalk from TRPV1+ afferents reprograms TRPV1- A{beta}-afferents and drives human hyperalgesia.

neuroscience↗

bioRxiv2026

Oxytocin Modulation of Spinal Circuits Drives Therapeutic Benefits of Massage

Across social species, social touch enhances well-being and reduces pain -- two seemingly distinct benefits that enhance survival. Yet where and how the nervous system integrates these functions, and whether a single mechanism could serve both, remains unknown. Here we show that massage triggers oxytocin release, which shapes both pain and touch reward at the earliest stage of central processing -- the spinal cord -- through a single, state-dependent circuit mechanism. We report that in humans, massage enhances well-being, effects that correlate with endogenous oxytocin release. In mice, gentle touch activates hypothalamic oxytocin neurons that project directly to the spinal dorsal horn. Genetic manipulation of spinal oxytocin circuits alters behavioral responses to both gentle touch and noxious stimuli. Spinal calcium imaging and slice electrophysiology reveal that oxytocin acts on both excitatory and inhibitory spinal neurons to sculpt the relative activity of spinal ascending systems that convey both social touch and pain to the brain. Extending these findings to humans, we show that oxytocin receptors are also expressed on spinal excitatory and inhibitory neurons, and that endogenous oxytocin during massage correlates with altered spinal touch processing. Thus, spinal oxytocin signaling provides an evolutionarily conserved mechanism for the therapeutic benefits of massage.

neuroscience↗

bioRxiv2025

Hierarchical organization of mechano-nociceptive pathways revealed by activity labeling

Noxious mechanical stimuli give rise to distinct percepts, from sharp cutaneous pain to diffuse visceral discomfort, yet the nociceptor ensembles that underlie these differences remain poorly defined. We mapped the peripheral architecture of nociceptive signaling by combining in vivo activity labeling of pelvic nerve afferents with single-cell RNA sequencing. Noxious stimuli recruited diverse classes of mechano-nociceptors, but stimulus type exerted modest influence on the composition of activated ensembles. Instead, tissue identity imposed the dominant organizational structure: stimulation of cutaneous and deep pelvic tissues engaged distinct subsets of both myelinated and unmyelinated neurons, revealing a clear domain-level division. Within this architecture, we identified a bladder-innervating myelinated nociceptor subtype with distinctive molecular features, illustrating an additional layer of refinement. Functional imaging and anatomical tracing corroborated this multilevel organization. These findings reveal a hierarchical organization of peripheral mechanical pain encoding, in which mechano-nociceptor populations are differentially engaged according to tissue domain and organ context.

neuroscience↗

bioRxiv2025

Central role for fast nociceptors in mechanical nocifensive behavior and sensitization

Nociceptors, primary afferent nerve fibers that signal noxious stimuli, are broadly divided into slowly conducting unmyelinated C fibers and fast-conducting myelinated A fibers. Whereas C-nociceptors have been extensively studied, considerably less is known about the function of A-nociceptors. To address this gap, we developed an intersectional genetic approach for robust and selective interrogation and manipulation of mechanically responsive A-nociceptors (A-MNs) in mice. Optogenetic A-MN stimulation induced rapid and precise withdrawal reflexes as well as place aversion and facial expression changes consistent with pain affect, while inhibition strongly impaired mechanical nociceptive withdrawal reflexes, demonstrating that A-MNs are necessary and sufficient for rapid avoidance of noxious mechanical stimuli. Prolonged A-MN activation induced mechanical allodynia and central sensitization. In a rare individual lacking thickly myelinated A{beta} fibers, mechanical withdrawal reflexes were completely absent, and pain perception reduced. Together, these findings identify fast-conducting mechano-nociceptors as essential drivers of nocifensive behaviors in mice and humans.

neuroscience↗

bioRxiv2025

A fast nociceptive subsystem mediating rapid reflexive behavior but not affective pain

Spinal nociceptive withdrawal reflexes are widely believed to rely on unmyelinated and thinly myelinated nociceptive fibers that also signal affective and motivational aspects of pain. Here we discover a population of myelinated mechanoreceptive nociceptor that forms free nerve endings as well as circumferential endings around hair follicles, and exclusively terminate in the deep spinal dorsal horn. Optogenetic activation of these fibers triggers rapid withdrawal reflexes that are precise and selective for the targeted limb, while silencing increases the threshold of mechanical nociceptive withdrawal reflexes. By contrast, optogenetic stimulation of the fibers is not associated with place aversion nor with changes in facial expression. Thus, we conclude that this nerve fiber population is uniquely positioned to rapidly respond to mechanical threats via selective withdrawal of the targeted body part, whereas other fast and slow nociceptive pathways are required for affective-motivational aspects of pain.

neuroscience↗

bioRxiv2025

Tactile Illusion Reveals Central Neural Basis for Touch Pleasantness

C-low threshold mechanoreceptors (C-LTMRs) have been highlighted in mediating the pleasantness of slow, caressing touch. This has given rise to the "Affective Touch Hypothesis," which posits that velocity tuning of C-LTMRs underpins pleasantness perception. The known activation preferences of C-LTMRs have been used as a proxy for pleasant touch, yet recent findings have raised questions about the necessity of this peripheral mechanism. This project explored the peripheral and central mechanisms in affective touch through comparing two motion-conditions: gentle brushing-like motion and apparent motion, an illusory perception of movement produced by successive touches along the skin. We used this illusion to examine whether previously established velocity tuning of true lateral motion is observed in apparent motion, when local information provided to individual peripheral afferents is held constant. The sole dependence on peripheral modulation predicts that the characteristic inverted-U-shaped relationship between velocity and pleasantness, regularly associated with C-LTMRs, would only be observed for brushing-like motion. Central modulation would instead predict a more similar relationship between the motion-conditions. To investigate this, pleasantness-ratings and velocity-ratings were collected across different velocities (0.1-30cm/s, N=23) for both conditions. Linear and quadratic regression analyses were performed and for both conditions adding a quadratic term improved the overall model fit, reaching significance (p<0.001). The quadratic term coefficients were negative for both conditions, displaying an inverted-U-shape. Further analyses revealed that motion-condition did not significantly alter the relationship between stimulus-velocity and pleasantness. These findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs. Key pointsO_LIC-low threshold mechanoreceptors (C-LTMRs) have been shown to display a unique inverted-U-shaped relationship between firing frequencies and stroking velocity, which is not seen with any other cutaneous afferents C_LIO_LIAn inverted-U-shaped relationship is also observed between perceived touch pleasantness and stroking velocity, giving rise to a hypothesis which posits that the velocity tuning of C-LTMRs underpins the perception of pleasant touch C_LIO_LIWe compared traditional stroking (brushing-like motion) to an illusory perception of movement produced by successive touches along the skin (apparent motion) to examine if similar velocity-dependent pleasantness patterns would be observed when information provided to individual peripheral afferents is held constant C_LIO_LIIn our experiment, the type of motion did not significantly alter the relationship between perceived pleasantness and stimulus-velocity C_LIO_LIThese findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs C_LI

neuroscience↗

bioRxiv2023

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 A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} 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.

neuroscience↗

bioRxiv2023

Human foot outperforms the hand in mechanical pain discrimination

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterised. Here, we measured the capacity for mechanical pain discrimination using a twoalternative 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 characterise the relationship between peripheral neural and perceptual processes, we recorded singleunit 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 single primary afferents. 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. Significance StatementStandard clinical practice for diagnosing neuropathies and pain disorders often involves assessing thresholds for pain or light touch. The ability to discriminate between different stimulus intensities is a separate but equally important sensory function, however this is not typically assessed in the clinic, and so studying this may provide insights into pain signalling mechanisms. Here, we investigated the ability of healthy individuals to discriminate between different forces of painful indentation. We found that the foot was better at this than the hand. This difference could not be explained by the firing activity of peripheral nociceptors (pain-signalling neurons) between the two regions, suggesting that mechanisms other than nociceptor sensitivity are involved.

neuroscience↗

bioRxiv2023

The role of cutaneous Aβ fibers in human nocifensive functions: Nerve block study on painful withdrawal reflex responses

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency A{beta}-mediated response, considered tactile, and a longer-latency A{delta}-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to A{beta} tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of A{beta} fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current intensity required to evoke the NWR was magnitude higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the A{beta}-mediated tuning fork sensation was lost while A{delta}-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current intensities, the reflex could not be evoked despite a two-fold increase in the pre-block current intensity and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of A{beta}-fiber inputs in pain and reflex signaling.

neuroscience↗

bioRxiv2023

Mechanoreceptive Aβ primary afferents discriminate naturalistic social touch inputs at a functionally relevant time scale

Interpersonal touch is an important part of our social and emotional interactions. How these physical, skin-to-skin touch expressions are processed in the peripheral nervous system is not well understood. From single-unit microneurography recordings in humans, we evaluated the capacity of six subtypes of cutaneous afferents to differentiate perceptually distinct social touch expressions. By leveraging conventional statistical analyses and classification analyses using convolutional neural networks and support vector machines, we found that single units of multiple A{beta} subtypes, especially slowly adapting type II (SA-II) and fast adapting hair follicle afferents (HFA), can reliably differentiate the skin contact of those expressions at accuracies similar to those perceptually. Rapidly adapting field (Field) afferents exhibit lower accuracies, whereas C-tactile (CT), fast adapting Pacinian corpuscles (FA-II), and muscle spindle (MS) afferents can barely differentiate the expressions, despite responding to the stimuli. We then identified the most informative firing patterns of SA-II and HFA afferents spike trains, which indicate that an average duration of 3-4 s of firing provides sufficient discriminative information. Those two subtypes also exhibit robust tolerance to shifts in spike-timing of up to 10 ms. A greater shift in spike-timing, however, drastically compromises an afferents discrimination capacity, and can change a firing patterns envelope to resemble that of another expression. Altogether, the findings indicate that SA-II and HFA afferents differentiate the skin contact of social touch at time scales relevant for such interactions, which is 1-2 orders of magnitude longer than those relevant for discriminating non-social touch inputs.

neuroscience↗

bioRxiv2023

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons - critical information to decipher their functions - are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the existence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identifying high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma sequencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-specific properties.

neuroscience↗

bioRxiv2022

Get a new perspective on EEG: Convolutional neural network encoders for parametric t-SNE.

Backgroundt-distributed stochastic neighbor embedding (t-SNE) is a method for reducing high-dimensional data to a low-dimensional representation and is mostly used for visualizing data. In parametric t-SNE, a neural network learns to reproduce this mapping. When used for EEG analysis, the data is usually first transformed into a set of features, but it is not known which features are optimal. New methodThe principle of t-SNE was used to train convolutional neural network (CNN) encoders to learn to produce both a high- and a low-dimensional representation, eliminating the need for feature engineering. A simple neighbor distribution based on ranked distances was used for the high-dimensional representation instead of the traditional normal distribution. To evaluate the method, the Temple University EEG Corpus was used to create three datasets with distinct EEG characters: 1) wakefulness and sleep, 2) interictal epileptiform discharges, and 3) seizure activity. ResultsThe CNN encoders for the three datasets produced low-dimensional representations of the datasets with a global and local structure that conformed well to the EEG characters and generalized to new data. Comparison to existing methodsCompared to parametric t-SNE for either a short-time Fourier transforms or wavelet representation of the datasets, the developed CNN encoders performed equally well but generally produced a higher degree of clustering. ConclusionsThe developed principle is promising and could be further developed to create general tools for exploring relations in EEG data, e.g., visual summaries of recordings, and trends for continuous EEG monitoring. It might also be used to generate features for other types of machine learning.

neuroscience↗

bioRxiv2022

Investigations into an overlooked early component of painful nociceptive withdrawal reflex responses in humans

IntroductionThe role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Ad-fiber range consistent with the canonical view that "fast pain" is signaled by Ad nociceptors. We recently demonstrated that human skin is equipped with ultrafast (A{beta} range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception. MethodsWe revisited our earlier work on NWR measurements in which, following convention, only those reflex responses were selected that were in the presumed Ad range (taken to be latencies [≥]90 ms in that study). In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings. ResultsIn both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings to reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range. DiscussionWe found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. We predict these might be signaled by the ultrafast nociceptors, warranting further investigation.

neuroscience↗

bioRxiv2021

A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

Numerous microneurography studies in the human peroneal nerve have suggested that CT afferents are lacking in the more distal parts of the limbs. Here we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves, with the most distal receptive fields located on the proximal phalanx of the third finger for the superficial branch of the radial nerve, and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial, radial and peroneal nerves. Moreover, we found that while CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared to C nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, including a lack of responsiveness to heat, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.

neuroscience↗

bioRxiv2020

Virtual EEG-electrodes: Convolutional neural networks as a method for upsampling or restoring channels

BackgroundIn clinical practice, EEGs are assessed visually. For practical reasons, recordings often need to be performed with a reduced number of electrodes and artifacts make assessment difficult. To circumvent these obstacles, different interpolation techniques can be utilized. These techniques usually perform better for higher electrode densities and values interpolated at areas far from electrodes can be unreliable. Using a method that learns the statistical distribution of the cortical electrical fields and predicts values may yield better results. New MethodGenerative networks based on convolutional layers were trained to upsample from 4 or 14 channels or to dynamically restore single missing channels to recreate 21 channel EEGs. 5,144 hours of data from 1,385 subjects of the Temple University Hospital EEG database were used for training and evaluating the networks. Comparison with Existing MethodThe results were compared to spherical spline interpolation. Several statistical measures were used as well as a visual evaluation by board certified clinical neurophysiologists. Overall, the generative networks performed significantly better. There was no difference between real and network generated data in the number of examples assessed as artificial by experienced EEG interpreters whereas for data generated by interpolation, the number was significantly higher. In addition, network performance improved with increasing number of included subjects, with the greatest effect seen in the range 5 - 100 subjects. ConclusionsUsing neural networks to restore or upsample EEG signals is a viable alternative to interpolation methods.

neuroscience↗

bioRxiv2019

Spinal signaling of C-fiber mediated pleasant touch in humans

C-tactile afferents form a distinct channel that encodes pleasant tactile stimulation. Prevailing views indicate they project, as with other unmyelinated afferents, in lamina I-spinothalamic pathways. However, we found that spinothalamic ablation in humans, whilst profoundly impairing pain, temperature and itch, had no effect on pleasant touch perception. Only discriminative touch deficits were seen. These findings preclude privileged C-tactile-lamina I-spinothalamic projections and imply integrated hedonic and discriminative spinal processing from the body.

physiology↗