Brain-body physiology: Local, reflex, and central communication.

Behavior is tightly synchronized with bodily physiology. Internal needs from the body drive behavior selection, while optimal behavior performance requires a coordinated physiological response. Internal state is dynamically represented by the nervous system to influence mood and emotion, and body-brain signals also direct responses to external sensory cues, enabling the organism to adapt and pursue its goals within an ever-changing environment. In this review, we examine the anatomy and function of the brain-body connection, manifested across local, reflex, and central regulation levels. We explore these hierarchical loops in the context of the immune system, specifically through the lens of immunoception, and discuss the impact of its dysregulation on human health.

Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem.

Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc.

Airway Protection-A Role for Vagal P2RY1 Receptors.

Recent events bring the importance of respiratory health to the forefront of our collective attention. In this issue of Cell, a new study by Prescott and Umans et al. reveals how a dedicated laryngeal sensory motor reflex circuit protects our airways from aspirated foods or liquids.

Reflex principles of immunological homeostasis.

The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases.

Sensory Neurons Drive Anticipatory Immunity.

Sensory neurons have recently emerged as critical mediators of immunity. Cohen et al. (2019) demonstrate that peripheral neurons utilize reflex arcs in order to rapidly condition the immune response in skin adjacent to the site of infection. This nerve reflex arc generates anticipatory immunity for more effective elimination of the pathogen if later exposed.

Consolidating roles of neuroimmune reflexes: specificity of afferent, central, and efferent signals in homeostatic immune networks.

Neural reflexes occupy a central role in physiological homeostasis. The vagus nerve is a major conduit for transmitting afferent and efferent signals in homeostatic reflex arcs between the body and the brain. Recent advances in neuroscience, immunology, and physiology have revealed important vagus nerve mechanisms in suppressing inflammation and treating rheumatoid arthritis and other autoimmune conditions. Numerous clinical trials indicate that there is significant benefit to vagus nerve stimulation therapy. Although many questions are still unanswered, it will be important, even necessary, to pursue answers that will be useful in guiding interventions to modulate immunological and physiological homeostasis.

A vagal reflex evoked by airway closure.

Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function1,2. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax or airway compression. Here we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, whereas ablating NEBs or vagal PVALB neurons eliminated gasping in response to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of Piezo2 in NEBs eliminated responses to airway closure. NEBs were dispensable for the Hering-Breuer inspiratory reflex, which indicated that discrete terminal structures detect airway closure and inflation. Similar to the involvement of Merkel cells in touch sensation3,4, NEBs are PIEZO2-expressing epithelial cells and, moreover, are crucial for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.

Vagal sensory neurons mediate the Bezold-Jarisch reflex and induce syncope.

Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders1. The Bezold-Jarisch reflex (BJR), first described2,3 in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown. Here we leveraged single-cell RNA-sequencing data and HYBRiD tissue clearing4 to show that VSNs that express neuropeptide Y receptor Y2 (NPY2R) predominately connect the heart ventricular wall to the area postrema. Optogenetic activation of NPY2R VSNs elicits the classic triad of BJR responses-hypotension, bradycardia and suppressed respiration-and causes an animal to faint. Photostimulation during high-resolution echocardiography and laser Doppler flowmetry with behavioural observation revealed a range of phenotypes reflected in clinical syncope, including reduced cardiac output, cerebral hypoperfusion, pupil dilation and eye-roll. Large-scale Neuropixels brain recordings and machine-learning-based modelling showed that this manipulation causes the suppression of activity across a large distributed neuronal population that is not explained by changes in spontaneous behavioural movements. Additionally, bidirectional manipulation of the periventricular zone had a push-pull effect, with inhibition leading to longer syncope periods and activation inducing arousal. Finally, ablating NPY2R VSNs specifically abolished the BJR. Combined, these results demonstrate a genetically defined cardiac reflex that recapitulates characteristics of human syncope at physiological, behavioural and neural network levels.

Spicy Immunity: Pain to Gain.

The skin is densely innervated with nociceptive neurons specialized in detecting noxious and painful stimuli. In a recent issue of Cell, Cohen et al. report that activation of cutaneous nociceptive neurons leads to a nerve-reflex action that is sufficient to provide a danger signal that triggers regional immunity to fight a microbial challenge.

A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis.

Somatosensory autonomic reflexes allow electroacupuncture stimulation (ES) to modulate body physiology at distant sites1-6 (for example, suppressing severe systemic inflammation6-9). Since the 1970s, an emerging organizational rule about these reflexes has been the presence of body-region specificity1-6. For example, ES at the hindlimb ST36 acupoint but not the abdominal ST25 acupoint can drive the vagal-adrenal anti-inflammatory axis in mice10,11. The neuroanatomical basis of this somatotopic organization is, however, unknown. Here we show that PROKR2Cre-marked sensory neurons, which innervate the deep hindlimb fascia (for example, the periosteum) but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal-adrenal axis. Low-intensity ES at the ST36 site in mice with ablated PROKR2Cre-marked sensory neurons failed to activate hindbrain vagal efferent neurons or to drive catecholamine release from adrenal glands. As a result, ES no longer suppressed systemic inflammation induced by bacterial endotoxins. By contrast, spinal sympathetic reflexes evoked by high-intensity ES at both ST25 and ST36 sites were unaffected. We also show that optogenetic stimulation of PROKR2Cre-marked nerve terminals through the ST36 site is sufficient to drive the vagal-adrenal axis but not sympathetic reflexes. Furthermore, the distribution patterns of PROKR2Cre nerve fibres can retrospectively predict body regions at which low-intensity ES will or will not effectively produce anti-inflammatory effects. Our studies provide a neuroanatomical basis for the selectivity and specificity of acupoints in driving specific autonomic pathways.

PIEZO2 in sensory neurons and urothelial cells coordinates urination.

Henry Miller stated that "to relieve a full bladder is one of the great human joys". Urination is critically important in health and ailments of the lower urinary tract cause high pathological burden. Although there have been advances in understanding the central circuitry in the brain that facilitates urination1-3, there is a lack of in-depth mechanistic insight into the process. In addition to central control, micturition reflexes that govern urination are all initiated by peripheral mechanical stimuli such as bladder stretch and urethral flow4. The mechanotransduction molecules and cell types that function as the primary stretch and pressure detectors in the urinary tract mostly remain unknown. Here we identify expression of the mechanosensitive ion channel PIEZO2 in lower urinary tract tissues, where it is required for low-threshold bladder-stretch sensing and urethral micturition reflexes. We show that PIEZO2 acts as a sensor in both the bladder urothelium and innervating sensory neurons. Humans and mice lacking functional PIEZO2 have impaired bladder control, and humans lacking functional PIEZO2 report deficient bladder-filling sensation. This study identifies PIEZO2 as a key mechanosensor in urinary function. These findings set the foundation for future work to identify the interactions between urothelial cells and sensory neurons that control urination.

Identifying essential factors for energy-efficient walking control across a wide range of velocities in reflex-based musculoskeletal systems.

Humans can generate and sustain a wide range of walking velocities while optimizing their energy efficiency. Understanding the intricate mechanisms governing human walking will contribute to the engineering applications such as energy-efficient biped robots and walking assistive devices. Reflex-based control mechanisms, which generate motor patterns in response to sensory feedback, have shown promise in generating human-like walking in musculoskeletal models. However, the precise regulation of velocity remains a major challenge. This limitation makes it difficult to identify the essential reflex circuits for energy-efficient walking. To explore the reflex control mechanism and gain a better understanding of its energy-efficient maintenance mechanism, we extend the reflex-based control system to enable controlled walking velocities based on target speeds. We developed a novel performance-weighted least squares (PWLS) method to design a parameter modulator that optimizes walking efficiency while maintaining target velocity for the reflex-based bipedal system. We have successfully generated walking gaits from 0.7 to 1.6 m/s in a two-dimensional musculoskeletal model based on an input target velocity in the simulation environment. Our detailed analysis of the parameter modulator in a reflex-based system revealed two key reflex circuits that have a significant impact on energy efficiency. Furthermore, this finding was confirmed to be not influenced by setting parameters, i.e., leg length, sensory time delay, and weight coefficients in the objective cost function. These findings provide a powerful tool for exploring the neural bases of locomotion control while shedding light on the intricate mechanisms underlying human walking and hold significant potential for practical engineering applications.

Temporal dynamics of the sensorimotor convergence underlying voluntary limb movement.

Descending motor drive and somatosensory feedback play important roles in modulating muscle activity. Numerous studies have characterized the organization of neuronal connectivity in which descending motor pathways and somatosensory afferents converge on spinal motor neurons as a final common pathway. However, how inputs from these two pathways are integrated into spinal motor neurons to generate muscle activity during actual motor behavior is unknown. Here, we simultaneously recorded activity in the motor cortices (MCx), somatosensory afferent neurons, and forelimb muscles in monkeys performing reaching and grasping movements. We constructed a linear model to explain the instantaneous muscle activity using the activity of MCx (descending input) and peripheral afferents (afferent input). Decomposition of the reconstructed muscle activity into each subcomponent indicated that muscle activity before movement onset could first be explained by descending input from mainly the primary motor cortex and muscle activity after movement onset by both descending and afferent inputs. Descending input had a facilitative effect on all muscles, whereas afferent input had a facilitative or suppressive effect on each muscle. Such antagonistic effects of afferent input can be explained by reciprocal effects of the spinal reflex. These results suggest that descending input contributes to the initiation of limb movement, and this initial movement subsequently affects muscle activity via the spinal reflex in conjunction with the continuous descending input. Thus, spinal motor neurons are subjected to temporally organized modulation by direct activation through the descending pathway and the lagged action of the spinal reflex during voluntary limb movement.

Effect of a False Inertial Cue in the Velocity-Storage Circuit on Head Posture and Inertia Perception.

The velocity-storage circuit participates in the vestibulopostural reflex, but its role in the postural reflex requires further elucidation. The velocity-storage circuit differentiates gravitoinertial information into gravitational and inertial cues using rotational cues. This implies that a false rotational cue can cause an erroneous estimation of gravity and inertial cues. We hypothesized the velocity-storage circuit is a common gateway for all vestibular reflex pathways and tested that hypothesis by measuring the postural and perceptual responses from a false inertial cue estimated in the velocity-storage circuit. Twenty healthy human participants (40.5 ± 8.2 years old, 6 men) underwent two different sessions of earth-vertical axis rotations at 120°/s for 60 s. During each session, the participants were rotated clockwise and then counterclockwise with two different starting head positions (head-down and head-up). During the first (control) session, the participants kept a steady head position at the end of rotation. During the second (test) session, the participants changed their head position at the end of rotation, from head-down to head-up or vice versa. The head position and inertial motion perception at the end of rotation were aligned with the inertia direction anticipated by the velocity-storage model. The participants showed a significant correlation between postural and perceptual responses. The velocity-storage circuit appears to be a shared neural integrator for the vestibulopostural reflex and vestibular perception. Because the postural responses depended on the inertial direction, the postural instability in vestibular disorders may be the consequence of the vestibulopostural reflex responding to centrally estimated false vestibular cues.SIGNIFICANCE STATEMENT The velocity-storage circuit appears to participate in the vestibulopostural reflex, which stabilizes the head and body position in space. However, it is still unclear whether the velocity-storage circuit for the postural reflex is in common with that involved in eye movement and perception. We evaluated the postural and perceptual responses to a false inertial cue estimated by the velocity-storage circuit. The postural and perceptual responses were consistent with the inertia direction predicted in the velocity-storage model and were correlated closely with each other. These results show that the velocity-storage circuit is a shared neural integrator for vestibular-driven responses and suggest that the vestibulopostural response to a false vestibular cue is the pathomechanism of postural instability clinically observed in vestibular disorders.

The Orienting Reflex Reveals Behavioral States Set by Demanding Contexts: Role of the Superior Colliculus.

Sensory stimuli can trigger an orienting reflex (response) by which animals move the head to position their sensors (e.g., eyes, pinna, whiskers). Orienting responses may be important to evaluate stimuli that call for action (e.g., approach, escape, ignore), but little is known about the dynamics of orienting responses in the context of goal-directed actions. Using mice of either sex, we found that, during a signaled avoidance action, the orienting response evoked by the conditioned stimulus (CS) consisted of a fast head movement containing rotational and translational components that varied substantially as a function of the behavioral and underlying brain states of the animal set by different task contingencies. Larger CS-evoked orienting responses were associated with high-intensity auditory stimuli, failures to produce the appropriate signaled action, and behavioral states resulting from uncertain or demanding situations and the animal's ability to cope with them. As a prototypical orienting neural circuit, we confirmed that the superior colliculus controls and codes the direction of spontaneous exploratory orienting movements. In addition, superior colliculus activity correlated with CS-evoked orienting responses, and either its optogenetic inhibition or excitation potentiated CS-evoked orienting responses, which are likely generated downstream in the medulla. CS-evoked orienting responses may be a useful probe to assess behavioral and related brain states, and state-dependent modulation of orienting responses may involve the superior colliculus.SIGNIFICANCE STATEMENT Humans and other animals produce an orienting reflex (also known as orienting response) by which they rapidly orient their head and sensors to evaluate novel or salient stimuli. Spontaneous orienting movements also occur during exploration of the environment in the absence of explicit, salient stimuli. We monitored stimulus-evoked orienting responses in mice performing signaled avoidance behaviors and found that these responses reflect the behavioral state of the animal set by contextual demands and the animal's ability to cope with them. Various experiments involving the superior colliculus revealed a well-established role in spontaneous orienting but only an influencing effect over orienting responses. Stimulus-evoked orienting responses may be a useful probe of behavioral and related brain states.

Kv2 channels contribute to neuronal activity within the vagal afferent-nTS reflex arc.

Diversity in the functional expression of ion channels contributes to the unique patterns of activity generated in visceral sensory A-type myelinated neurons versus C-type unmyelinated neurons in response to their natural stimuli. In the present study, Kv2 channels were identified as underlying a previously uncharacterized delayed rectifying potassium current expressed in both A- and C-type nodose ganglion neurons. Kv2.1 and 2.2 appear confined to the soma and initial segment of these sensory neurons; however, neither was identified in their central presynaptic terminals projecting onto relay neurons in the nucleus of the solitary tract (nTS). Kv2.1 and Kv2.2 were also not detected in the peripheral axons and sensory terminals in the aortic arch. Functionally, in nodose neuron somas, Kv2 currents exhibited frequency-dependent current inactivation and contributed to action potential repolarization in C-type neurons but not A-type neurons. Within the nTS, the block of Kv2 currents does not influence afferent presynaptic calcium influx or glutamate release in response to afferent activation, supporting our immunohistochemical observations. On the other hand, Kv2 channels contribute to membrane hyperpolarization and limit action potential discharge rate in second-order neurons. Together, these data demonstrate that Kv2 channels influence neuronal discharge within the vagal afferent-nTS circuit and indicate they may play a significant role in viscerosensory reflex function.NEW & NOTEWORTHY We demonstrate the expression and function of the voltage-gated delayed rectifier potassium channel Kv2 in vagal nodose neurons. Within sensory neurons, Kv2 channels limit the width of the broader C-type but not narrow A-type action potential. Within the nucleus of the solitary tract (nTS), the location of the vagal terminal field, Kv2 does not influence glutamate release. However, Kv2 limits the action potential discharge of nTS relay neurons. These data suggest a critical role for Kv2 in the vagal-nTS reflex arc.

Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats.

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9- to 13-week interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. KEY POINTS: Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination. We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.

The vestigial pinna-orienting system in humans briefly suppresses superior auricular muscle activity during reflexive orienting toward auditory stimuli.

The vestigial pinna-orienting system in humans is capable of increasing the activity of several auricular muscles in response to lateralized transient auditory stimuli. For example, transient increases in electromyographic activity in the posterior auricular muscle (PAM) to an attention-capturing stimulus have been documented. For the current study, surface electromyograms (EMGs) were recorded from the PAMs and superior auricular muscles (SAMs) of 10 normal-hearing participants. During the experiments, lateralized transient auditory stimuli, such as a crying baby, a shattering vase, or the participant's first names, were presented. These transient stimuli were either presented in silence or when participants actively listened to a podcast. Although ipsilateral PAM activity increased in response to transient stimuli, the SAM displayed the opposite behavior, i.e., a brief, ipsilateral suppression of activity. This suppression of ipsilateral SAM activity was more frequent on the right (75%) than left side (35%), whereas an ipsilateral PAM increase was roughly equal in prevalence on the two sides (left: 90%, right: 95%). During the active listening task, SAM suppression on the right ear was significantly larger in response to ipsilateral stimuli, compared with contralateral ones (P = 0.002), whereas PAM activity increased significantly (P = 0.002). Overall, this study provides evidence of a systematic transient suppression of the SAM during exogenous attention. This could suggest a more complex system than previously assumed, as the presence of synchronized excitatory and inhibitory components in different auricular muscles points toward a coordinated attempt at reflexively orienting the pinna toward a sound.NEW & NOTEWORTHY This study provides evidence that two auricular muscles in humans, the posterior and superior auricular muscles (PAM, SAM), react fundamentally different to lateralized transient auditory stimuli, especially during active listening. Although the PAM reacts with a transient increase in ipsilateral activity, ongoing ipsilateral SAM activity is briefly suppressed at the same time. This indicates the presence of a more complex and nuanced pinna-orienting system, with synchronized excitatory and inhibitory components in humans, than previously suspected.

Forelimb movements contribute to hindlimb cutaneous reflexes during locomotion in cats.

During quadrupedal locomotion, interactions between spinal and supraspinal circuits and somatosensory feedback coordinate forelimb and hindlimb movements. How this is achieved is not clear. To determine whether forelimb movements modulate hindlimb cutaneous reflexes involved in responding to an external perturbation, we stimulated the superficial peroneal nerve in six intact cats during quadrupedal locomotion and during hindlimb-only locomotion (with forelimbs standing on stationary platform) and in two cats with a low spinal transection (T12-T13) during hindlimb-only locomotion. We compared cutaneous reflexes evoked in six ipsilateral and four contralateral hindlimb muscles. Results showed similar occurrence and phase-dependent modulation of short-latency inhibitory and excitatory responses during quadrupedal and hindlimb-only locomotion in intact cats. However, the depth of modulation was reduced in the ipsilateral semitendinosus during hindlimb-only locomotion. Additionally, longer-latency responses occurred less frequently in extensor muscles bilaterally during hindlimb-only locomotion, whereas short-latency inhibitory and longer-latency excitatory responses occurred more frequently in the ipsilateral and contralateral sartorius anterior, respectively. After spinal transection, short-latency inhibitory and excitatory responses were similar to both intact conditions, whereas mid- or longer-latency excitatory responses were reduced or abolished. Our results in intact cats and the comparison with spinal-transected cats suggest that the absence of forelimb movements suppresses inputs from supraspinal structures and/or cervical cord that normally contribute to longer-latency reflex responses in hindlimb extensor muscles.NEW & NOTEWORTHY During quadrupedal locomotion, the coordination of forelimb and hindlimb movements involves central circuits and somatosensory feedback. To demonstrate how forelimb movement affects hindlimb cutaneous reflexes during locomotion, we stimulated the superficial peroneal nerve in intact cats during quadrupedal and hindlimb-only locomotion as well as in spinal-transected cats during hindlimb-only locomotion. We show that forelimb movement influences the modulation of hindlimb cutaneous reflexes, particularly the occurrence of long-latency reflex responses.

Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity.

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS-induced suppression of the NWR and parasympathetic activation. We applied either 3.0 mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10 min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10 min after: p = .008, 30 min after: p = .008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p = .003; Post 30: p = .001). The present results of this single-blinded study demonstrate the pain-suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain-suppressing effect of taVNS after its application.