Warm Stimuli Research Articles

Disentangling the spinal mechanisms of illusory heat and burning sensations in the thermal grill illusion.

The thermal grill illusion (TGI), a phenomenon in which the juxtaposition of innocuous warm and cold temperatures on the skin elicits a burning sensation, offers a unique perspective to how pain occurs in response to harmless stimuli. We investigated the role of the spinal cord in the generation of the TGI across 2 experiments (total n = 80). We applied heat and cold stimuli to dermatomes, areas of skin innervated by a single spinal nerve, that mapped onto adjacent or nonadjacent spinal segments. Enhanced warm and burning ratings during the TGI were observed when cold and warm stimuli were confined within the same dermatome. Furthermore, we found the spatial organisation of warm and cold stimuli within and across dermatomes affected TGI perception. Perceived warmth and burning intensity increased when the cold stimulus projected to the segment more caudal to the warm stimulus, whereas perceived cold during the TGI decreased compared with the opposite spatial arrangement. This suggests that the perception of TGI is enhanced when cold afferents are projected to spinal segments positioned caudally in relation to those receiving warm afferents. Our results indicate distinct interaction of sensory pathways based on the segmental arrangement of afferent fibres and are consistent with current interpretations of the spread and integration of thermosensory information along the spinal cord.

10 kHz spinal cord stimulation improves metrics of spinal sensory processing in a male STZ rat model of diabetes

To explore why clinical 10 kHz spinal cord stimulation (10 kHz SCS) might improve neurological function in a model of painful diabetic neuropathy (PDN), the short-term behavioral, electrophysiological, and histological effects of 10 kHz SCS were studied using adult male streptozotocin (STZ)-induced diabetic Sprague-Dawley rats. Four testing groups were established: Naïve controls (N = 8), STZ controls (N = 7), STZ+Sham SCS (N = 9), and STZ+10 kHz SCS (N = 11). After intraperitoneal injection (60 mg/kg) of STZ caused the rats to become hyperglycemic, SCS electrodes were implanted in the dorsal epidural space over the L5-L6 spinal segments in the STZ+Sham SCS and STZ+10 kHz SCS groups and were stimulated for 14 days. The von Frey filament paw withdrawal threshold was measured weekly. At termination, animals were anesthetized and the electrophysiologic response of dorsal horn neurons (receptive field size, vibration, radiant warmth) of the ipsilateral foot was measured. Tissue from the plantar paw surface was obtained post-euthanization for intraepidermal nerve fiber density measurements. In comparison to other control groups, while no significant effect of 10 kHz SCS on peripheral intraepidermal nerve fiber density was observed, 10 kHz SCS ‘normalized’ the central neural response to vibration, receptive field, and paw withdrawal threshold, and elevated the neural response to tissue recovery from warm stimuli. These results suggest that short-term, low intensity 10 kHz SCS operates in the spinal cord to ameliorate compromised sensory processing, and may compensate for reduced peripheral sensory functionality from chronic hyperglycemia, thereby treating a broader spectrum of the sensory symptoms in diabetic neuropathy.

Response of the human choroid to short-term changes in eyelid and periocular temperature

ABSTRACT Clinical relevance Choroidal thickness measurement is gaining popularity in clinical practice and research as an early indicator of myopia progression. Understanding the influence of temperature on choroidal thickness changes will improve the reliability of the measures. Background It has been suggested that environmental temperature may affect choroidal thickness and blood flow, with potential implications for ocular disease and refractive development. This study investigates the effect of changes in eyelid/ocular adnexa temperature on choroidal thickness. Methods In a paired-eye study, 20 young, healthy subjects received a warm stimulus (heat pack) over one closed eye and simultaneously a cold stimulus (ice pack) over the other for 10 min. Eyelid temperatures were monitored with thermal probes, and optical coherence tomography scans of the retina and choroid were taken before and after heating and cooling, and then every 5 min during a 15-min recovery period. Retinal and choroidal thicknesses were measured across the macular region (6 mm), including the subfoveal (1 mm), parafoveal (1–3 mm), and perifoveal (3–5 mm) regions, and compared between the cooled and warmed eyes. Results When the thermal stimuli were applied, eyelid surface temperatures changed predictably and remained significantly different (by approximately 10–15°C) between the eyes after 2 min (p < .001). Relative to the warmed eye, macular choroidal thickness in the cooled eye increased significantly after 10 min of treatment (p = .004). This choroidal thickening response occurred in the subfoveal, parafoveal, and perifoveal regions (all p < .05). Upon removal of the thermal stimuli, choroidal thickness rapidly returned to the baseline and was no longer different between the cooled and warmed eye (p = .641). Conclusion Cooling the anterior eye by application of a cold stimulus directly onto the closed eyelid caused a small but significant increase in choroidal thickness relative to warming the anterior eye, demonstrating that the choroid can modulate its thickness rapidly and transiently in response to local temperature changes.

Greater severity of depressive symptoms is associated with changes to perceived sweating, preferred ambient temperature, and warmth-seeking behavior

ABSTRACT The thermosensory system is relevant to both the conceptualization and treatment of depression. There is evidence that depression is associated with changes in thermoregulatory functioning, and that thermosensory pathways can be recruited to influence affect and reduce depressive symptoms. In this study, we investigated the relationship between severity of depressive symptoms and changes to measures of subjective experiences associated with thermoregulatory processes as well as the relationship between severity of depressive symptoms and affective responses to warm stimuli, specifically frequency of warmth-seeking behavior. Participants (N = 529) completed measures of depressive symptoms, subjective experiences associated with thermoregulatory processes (i.e., perceived sweating and preferred ambient temperature) and frequency of warmth-seeking behavior (e.g., long hot baths, saunas, etc.). We demonstrate that, controlling for age and gender, greater severity of depressive symptoms is associated with greater perceived sweating and lower preferred ambient temperature. Furthermore, we demonstrate that greater severity of depressive symptoms is associated with more frequent warmth-seeking behavior, and that something other than thermal preference (i.e., stated preference for warmer temperature) is driving this behavior. These data highlight the importance of incorporating the thermoregulatory system in our conceptualization of the pathophysiology of depression and support the potential to recruit thermosensory pathways to target depressive symptoms.

A novel methodology to demonstrate vestibulo-ocular reflex using caloric stimulation in undergraduate physiology laboratory.

The study aims to develop a novel methodology to demonstrate the vestibulo-ocular reflex (VOR) and nystagmus by caloric stimulation in an undergraduate medical physiology laboratory. The experimental setup involved two sets of electrodes: one set positioned laterally to both eyes, and another set positioned vertically over either the right or left eye. The caloric method is used to stimulate ears, which involves irrigation of warm (44°C) and cold (30°C) water into the ears while maintaining a temperature difference of approximately ±7°C from the body temperature. The changes in chorioretinal potential were calibrated to angular displacement by a two-point calibration method, and angular velocity was derived after taking the first-time derivative. The results obtained from the digital data acquisition system were compared to the traditional instrument used in our Otorhinolaryngology Department [Interacoustics Videonystagmography (VNG) System for hospitals, medical grade] for the normal subject's data. No significant differences in angular velocity were noted (P > 0.05). The cold stimuli elicit a more pronounced VOR compared to the warm stimuli. It has been consistently observed that the onset of nystagmus occurs approximately 20 s after irrigation, reaching its peak intensity between 45 and 90 s, and gradually diminishing until it ceases after approximately 200 s. Our developed methodology enables the recording and quantification of nystagmus using easily accessible equipment. This study serves the goal of visualizing the physiological process of VOR and thereby fulfills the goal of an effective teaching tool for demonstrating to undergraduate medical students.NEW & NOTEWORTHY We developed a novel methodology to demonstrate and visualize the most common and important physiological phenomenon like the vestibulo-ocular reflex as a teaching module for undergraduate students.

Combined transcranial magnetic stimulation and electroencephalography reveals alterations in cortical excitability during pain.

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n=29), multiple sustained thermal stimuli were administered to the forearm, with the first, second, and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures, respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45 ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n=10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

Severity of depressive symptoms moderates the sympathoinhibitory effect of local skin warming following exposure to a social stressor

Depression is the leading cause of disease burden globally. Existing antidepressant treatments that target the central nervous system have limited efficacy and come at the cost of significant side effects. Thus, there is growing interest in novel therapeutic interventions for the prevention and treatment of depression, including interventions that target interoceptive signaling. The thermosensory system may hold particular promise, given evidence that depression is associated with impairments in thermosensory functioning, and that whole-body hyperthermia produces an antidepressant effect in patients with major depressive disorder. In this study, we investigated whether the severity of depressive symptoms in a non-clinical population moderated the effect of local skin warming on subjective and physiological stress responses following exposure to an acute social stressor. Following exposure to the stressor, participants (N = 90) rested their arm on a heat blanket that was either turned on (local skin warming condition) or left off (control condition). We demonstrate that local skin warming increased fingertip temperature, a marker of reduced sympathetic nervous system activity, but only for participants with high levels of depressive symptoms. While local skin warming also inhibited salivary alpha amylase, severity of depressive symptoms did not moderate this effect, and no effect was found for electrodermal activity. These data highlight the importance of incorporating peripheral physiology in our conceptualization of the pathophysiology of depression and show that changes in sympathetic nervous system activity may underpin the antidepressant effect of warm stimuli.

A Novel Mechanism for T1R-Independent Taste Responses to Concentrated Sugars.

Recent findings from our laboratory demonstrated that the rostral nucleus of the solitary tract (rNST) retains some responsiveness to sugars in double-knock-out mice lacking either the T1R1+T1R3 (KO1+3) or T1R2+T1R3 (KO2+3) taste receptor heterodimers. Here, we extended these findings in the parabrachial nucleus (PBN) of male and female KO1+3 mice using warm stimuli to optimize sugar responses and employing additional concentrations and pharmacological agents to probe mechanisms. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Similar to the NST, there were no "sugar-best" neurons in KO1+3 mice. Nevertheless, 1000 mm glucose activated nearly 55% of PBN neurons, with responses usually occurring in neurons that also displayed acid and amiloride-insensitive NaCl responses. In wild-type (WT) mice, concentrated sugars activated the same electrolyte-sensitive neurons but also "sugar-best" cells. Regardless of genotype, phlorizin, an inhibitor of the sodium-glucose co-transporter (SGLT), a component of a hypothesized alternate glucose-sensing mechanism, did not diminish responses to 1000 mm glucose. The efficacy of concentrated sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III taste bud cells. Dorzolamide had no effect on sugar-elicited responses in WT sugar-best PBN neurons but strongly suppressed them in WT and KO1+3 electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type III taste bud cells.SIGNIFICANCE STATEMENT Since the discovery of Tas1r receptors for sugars and artificial sweeteners, evidence has accrued that mice lacking these receptors maintain some behavioral, physiological, and neural responsiveness to sugars. But the substrate(s) has remained elusive. Here, we recorded from parabrachial nucleus (PBN) taste neurons and identified T1R-independent responses to hyperosmotic sugars dependent on carbonic anhydrase (CA) and occurring primarily in neurons broadly responsive to NaCl and acid, implying an origin from Type III taste bud cells. The effectiveness of different sugars in driving these T1R-independent responses did not correlate with their efficacy in driving licking, suggesting they evoke a nonsweet sensation. Nevertheless, these salient responses are likely to comprise an adequate cue for learned preferences that occur in the absence of T1R receptors.

Spatial summation of cold and warm detection: Evidence for increased precision when brisk stimuli are delivered over larger area

Cold and warm stimuli delivered over a larger skin area tend to be more easily detected/elicit stronger sensations, a phenomenon referred to as spatial summation. The aim of the present study was to clarify how stimulation area affects thermal detection processes by evaluating whether increasing the stimulation area simply reduces the detection threshold or also reduces the uncertainty of the detection process.Psychometric functions were fitted to the detection performance of 16 healthy subjects. Stimuli (duration: 200 ms; rate of change: 300 °C/s) were delivered to the volar forearm using a Peltier-effect contact thermode and three different stimulation surfaces (23 mm2, 69 mm2, and 116 mm). Stimulation intensities were selected trial-by-trial by the psi marginal method to optimize estimation of slope and threshold parameters of the psychometric function. The raw data (100 stimulus–response pairs per subject per surface and per modality) was used to fit group-level hierarchical models of cold and warm detection, allowing to assess the effect of stimulation surface and account for inter-individual variability.Increasing stimulation area led to a compression of the psychometric function towards baseline skin temperature (reduced threshold and steeper slope), suggesting that spatial summation reflects a change in the precision of the neural representation of the stimulus which in turn influences the ability of the nervous system to distinguish true stimuli from sensory noise. Regardless of area, with the stimulation settings used in this study, cold detection appeared easier than warm detection, possibly because of structural and functional differences between cold- and warm-sensitive afferents.

Hypocapnia attenuates local skin thermal perception to innocuous warm and cool stimuli in normothermic resting humans.

When one is exposed to a stressful situation in their daily life, a common response is hyperventilation. Although the physiological significance of stress-induced hyperventilation remains uncertain, this response may blunt perception of the stress-inducing stimulus. This study examined the effects of voluntary hyperventilation and resultant hypocapnia on the local skin thermal detection threshold in normothermic resting humans. Local skin thermal detection thresholds were measured in 15 young adults (three females) under three breathing conditions: 1) spontaneous breathing (Control trial), 2) voluntary hypocapnic hyperventilation (HH trial), and 3) voluntary normocapnic hyperventilation (NH trial). Local skin thermal detection thresholds were measured using thermostimulators containing a Peltier element that were attached to the forearm and forehead. The temperature of the probe was initially equilibrated to the skin temperature, then gradually increased or decreased at a constant rate (±0.1 °C/s) until the participants felt warmth or coolness. The difference between the initial skin temperature and the local skin temperature at which the participant noticed warmth/coolness was assessed as an index of the local skin warm/cool detection threshold. Local detection of warm and cool stimuli did not differ between the Control and NH trials, but it was blunted in the HH trial as compared with the Control and NH trials, except for detection of warm stimuli on the forearm. These findings suggest that hyperventilation-induced hypocapnia, not hyperventilation per se, attenuates local skin thermal perception, though changes in responses to warm stimuli may not be clearly perceived at some skin areas (e.g., forearm).

Serum neurofilament light chain: a novel biomarker for early diabetic sensorimotor polyneuropathy

Aims/hypothesisNo established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood biomarker of neuroaxonal damage in several neurodegenerative diseases, represents a potential biomarker for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN and nerve dysfunction in individuals recently diagnosed with diabetes.MethodsThis cross-sectional study included 423 adults with type 1 and type 2 diabetes and known diabetes duration of less than 1 year from the prospective observational German Diabetes Study cohort. NFL was measured in serum samples of fasting participants in a multiplex approach using proximity extension assay technology. DSPN was assessed by neurological examination, nerve conduction studies and quantitative sensory testing. Associations of serum NFL with DSPN (defined according to the Toronto Consensus criteria) were estimated using Poisson regression, while multivariable linear and quantile regression models were used to assess associations with nerve function measures. In exploratory analyses, other biomarkers in the multiplex panel were also analysed similarly to NFL.ResultsDSPN was found in 16% of the study sample. Serum NFL levels increased with age. After adjustment for age, sex, waist circumference, height, HbA1c, known diabetes duration, diabetes type, cholesterol, eGFR, hypertension, CVD, use of lipid-lowering drugs and use of non-steroidal anti-inflammatory drugs, higher serum NFL levels were associated with DSPN (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p<0.0001), slower motor (all p<0.0001) and sensory (all p≤0.03) nerve conduction velocities, lower sural sensory nerve action potential (p=0.0004) and higher thermal detection threshold to warm stimuli (p=0.023 and p=0.004 for hand and foot, respectively). There was no evidence for associations between other neurological biomarkers and DSPN or nerve function measures.Conclusions/interpretationOur findings in individuals recently diagnosed with diabetes provide new evidence associating higher serum NFL levels with DSPN and peripheral nerve dysfunction. The present study advocates NFL as a potential biomarker for DSPN.Graphical abstract

Reliability of Monothermal Caloric Test as Screening Test of Vestibular System

This retrospective study completed at a tertiary care center aimed to assess the monothermal caloric test (MCT) as a screening test, using the bithermal caloric test (BCT) as a reference. Additionally, it attempts to measure the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a fixed inter-auricular difference (IAD) value for both cold and warm stimuli using water irrigation. Medical records of 259 patients referred for vestibular symptoms who underwent BCT with water irrigation were reviewed. Patients with bilateral vestibular weakness and caloric tests using air irrigation were excluded. BCT showed 40.9% unilateral weakness. Two formulas were used to determine the monothermal caloric asymmetry (MCA-1 and MCA-2). The measurement of agreement Kappa between the two formulas in comparison with BCT revealed moderate agreement at 0.54 and 0.53 for hot and cold stimulation, respectively. The monothermal warm stimulating test (MWST) using MCA-2 showed better results, with a sensitivity of 80%, specificity of 91%, PPV of 83.1%, and NPV of 89.2%. Thirty-four patients had horizontal spontaneous nystagmus (HSN) with a mean velocity of 2.25°/s. These patients showed better sensitivity but lower specificity after adjustment of HSN using the MCA-2 formula at warm temperatures. Therefore, they should complete the caloric test with cold irrigation to perform the BCT. MCT is efficient as a screening test if the warm stimulus is used with the MCA-2 formula fixed at 25%. If present, HSNs should be adjusted. Negative IAD (normal) in the absence or presence of adjusted HSN or slow-phase eye velocity ≤ 6°/s at each right and left warm stimulation should be accomplished by the BCT.

A robust quantitative approach for laser speckle contrast imaging perfusion analysis revealed anomalies in the brain blood flow in offspring mice of preeclampsia.

Microcirculation analysis of the brain cortex is challenging because surface perfusion varies rapidly in small space-time regions and is bone protected. The laser speckle contrast imaging (LSCI) technique allows analyzing in vivo brain vascular perfusion generating a large amount of data that requires sophisticated data analytics, making researchers invest much effort in processing. Our research question was whether the reduced placental perfusion model (RUPP) of preeclampsia (PE) was associated with impaired blood perfusion in the offspring's brains. We aimed to develop a robust numerical approach that mainly consisted of applying a signal-processing tool for calculating optimal segmentation and piece-wise fits of the offspring's brain perfusion signals obtained from the LSCI technique. We combined this tool with the usual statistical analysis, implementing both in Matlab software. We performed brain perfusion measurements from offspring (five days postnatal, P5) of control pregnant dams (sham, n=13) and of RUPP dams (RUPP, n=7) using the Pericam® PSI-HR system at a basal condition and after thermal stimuli (warm and cold). We found that pups of RUPP mice exhibited significant differences in perfusion and vascular response to thermal stimuli compared to the sham mice. These differences were associated with high data variability in the Sham group, while in the RUPP group, perfusion looks "stiffer." Data also suggest sex-dimorphism in the vascular response since female pups in the Sham group but not male pups showed statistically significant differences in response to the warm stimulus. Again, this sex-related difference was absent in pups of RUPP mice. In conclusion, we present a robust quantitative approach for LSCI measurements that revealed anomalies in the brain blood flow in offspring of the RUPP model of PE.

Warm hands, warm hearts: An investigation of physical warmth as a prepared safety stimulus.

Recent work has demonstrated that social support figures seem to be particularly robust inhibitors of the Pavlovian fear response. Specifically, social support figures appear to act as prepared safety stimuli, stimuli that have played an important role in mammalian survival and are thus less easily associated with threat and more able to inhibit the fear response. Given some of the shared behavioral and neural consequences of both social support and physical warmth, as well as the importance of physical warmth for mammalian survival, we conducted a series of examinations designed to examine whether physical warmth is also a prepared safety stimulus. In two studies conducted in human adults, we examined whether a physically warm stimulus was less readily associated with threat (compared to soft or neutral stimuli; Study 1) and was able to inhibit the fear response elicited by other threatening cues (compared to neutral stimuli; Study 2). Results showed that physical warmth resisted association with threat (Study 1) and not only inhibited the fear response but also led to lasting inhibition even after the warm stimulus was removed (Study 2). Together, these studies indicate that physical warmth, like social support, meets the requirements of being a prepared safety stimulus, and they pave the way for future work to clarify the properties that enable cues in this category to naturally inhibit fear responding. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Thermal grill illusion of pain in patients with chronic pain: a clinical marker of central sensitization?

The thermal grill illusion of pain (TGIP) is a paradoxical burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode ("thermal grill") consisting of interlaced heated and cooled bars. Its neurophysiological mechanisms are unclear, but TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, through the involvement of N-methyl- d -aspartate receptors. However, few studies have investigated TGIP in patients with chronic pain and its clinical relevance is uncertain. We hypothesized that the TGIP would be increased in comparison with controls in patients with fibromyalgia or irritable bowel syndrome, which are regarded as typical "nociplastic" primary pain syndromes related to changes in central pain processing. We compared the sensations elicited by a large range of combinations of temperature differentials between the warm and cold bars of a thermal grill applied to the hand between patients with fibromyalgia (n = 30) or irritable bowel syndrome (n= 30) and controls (n = 30). The percentage of TGIP responses and the intensity and unpleasantness of TGIP were significantly greater in patients than controls. Furthermore, positive correlations were found between TGIP intensity and clinical pain intensity and between TGIP intensity and the cold pain threshold measured on the hand. These results are consistent with our working hypothesis of shared mechanisms between TGIP and clinical pain mechanisms in patients with nociplastic chronic pain syndromes and suggest that TGIP might represent a clinical marker of central sensitization in these patients.

When cooling of the skin is perceived as warmth: Enhanced paradoxical heat sensation by pre-cooling of the skin in healthy individuals

ABSTRACT A paradoxical heat sensation (PHS) is the misperception of warmth when the skin is cooled. PHS is uncommon in healthy individuals but common in patients with neuropathy and is associated with reduced thermal sensitivity. Identifying conditions that contribute to PHS may indirectly help us understand why some patients experience PHS. We hypothesized that pre-warming increased the number of PHS and that pre-cooling had minimal effect on PHS. We tested 100 healthy participants’ thermal sensitivity on the dorsum of their feet by measuring detection and pain thresholds to cold and warm stimuli and PHS. PHS was measured using the thermal sensory limen (TSL) procedure from the quantitative sensory testing protocol of the German Research Network on Neuropathic Pain and by using a modified TSL protocol (mTSL). In the mTSL we examined the participants’ thermal detection and PHS after pre-warming of 38°C and 44°C and pre-cooling of 26°C and 20°C. Compared to a baseline condition, the number of PHS responders was significantly increased after pre-cooling (20°C: RR = 1.9 (1.1; 3.3), p = 0.023 and 26°C: RR = 1.9 (1.2; 3.2), p = 0.017), but not significantly after pre-warming (38°C: RR = 1.5 (0.86; 2.8), p = 0.21 and 44°C: RR = 1.7 (.995; 2.9), p = 0.078). Pre-warming and pre-cooling increased the detection threshold of both cold and warm temperatures. We discussed these findings in relation to thermal sensory mechanisms and possible PHS mechanisms. In conclusion, PHS and thermosensation are closely related and pre-cooling can induce PHS responses in healthy individuals.

Effect of delayed photobiomodulation therapy on neurosensory recovery in patients with mandibular nerve neurotmesis following traumatic mandibular fracture: A randomized triple-blinded clinical trial.

There is a possibility of neurotmesis of the inferior alveolar nerve (IAN) in mandibular fractures, which leads to neurosensory impairment. In this study, we aimed to investigate the efficacy of photobiomodulation therapy (PBMT) in patients with neurotmesis following trauma and mandibular fracture. This triple-blind randomized trial was carried out on patients who suffered neurotmesis of the IAN following mandibular angle and body fracture at least for 6months. In the intervention group, laser irradiation was applied with a low-level GaAlAs diode laser (continuous wave of 810nm wavelength, power of 200mW, and energy density of 12-14J/cm2). In the control group, the laser probe was turned off and placed on the affected area. LLLT was done for 12 sessions (2 times/week for 6weeks). Light touch sensations, two-point discrimination, thermal discrimination (cold and warm stimulus), electric pulp test (EPT), and oral health impact profile (OHIP)-14 questionnaire were performed before the intervention, immediately after each PBMT session, and after 3, 6, 9 and 12months. In both groups, 3 and 23 patients were female and male, respectively. The results showed significantly improved light (cotton swab), light (wooden cotton swab), and sharp (dental needle) touch sensations, and two-point discrimination test in the PBMT group after the 10th, 11th, 10th, and 10th session, respectively. Two-way repeated measure ANOVA revealed that the trend of light touch sensation with cotton swab and two-point discrimination test was statistically significant (p-value=0.002 and 0.001, respectively). The results of OHIP-14 test showed a significantly higher mean in the PBMT group 3months after PBMT. There was no statistically significant difference in EPT and thermal discrimination tests regarding the patients' group. PBMT could be an effective treatment for late post-traumatic nerve neurotmesis following a traumatic mandibular fracture.

FV 2 A new neurophysiological test protocol for the assessment of the somatosensory nervous system – from the laboratory to clinical application

During clinical routine diagnostics, the integrity of the somatosensory nervous system is assessed by somatosensory-evoked potentials (SEPs), analyzing Aβ-fiber function, the posterior funiculus, brainstem, and the somatosensory cortex (Muzyka and Estephan 2019). Nevertheless, SEPs cannot provide diagnostic information on small fibers (Cruccu et al. 2004), which form around 80% of the somatosensory nervous system. These small fibers are subdivided into heat-sensitive Aδ-fibers (AMH II), mechanosensitive Aδ-fibers (AMH I), cold-sensitive Aδ-fibers, and C-fibers (mediating noxious and warm stimuli; Gasser 1941). Therefore, a combination of specific tests is required to gain a complete electrophysiological assessment of the somatosensory nervous system or to detect loss of function for specific nerve fiber subtypes. Loss of function of specific subtypes of somatosensory nerve fibers are found in neuropathic disorders, such as polyneuropathy (Bönhof et al. 2017), radiculopathy (Carlstedt 2008; Cavanaugh et al. 1997), traumatic nerve injury (Rotshenker 2011), and others (Gomatos and Rehman 2021). Large-fiber neuropathies only affect thickly myelinated nerve fibers (such as hypocobalaminemia-associated neuropathies; (Franques et al. 2019; Stabler 2013)), while other neuropathic disorders begin by an affection of small fibers (Aδ- and C-fibers), such as chemotherapy-induced polyneuropathy (Timmins et al. 2020). Some neuropathies involve specific subtypes of small nerve fibers, such as a loss of function of cold-mediating Aδ-fibers during the early stage of Fabry‘s disease (Onishi and Dyck 1974). Here, we present a novel neurophysiological test protocol, which assesses a major part of the somatosensory nervous system by recording evoked potentials of touch, pinprick, vibration, heat/heat pain, cold, and warm stimuli. This test protocol was applied on healthy subjects in a first step and then transferred to patients with painful radiculopathy and painful polyneuropathy in a second step. The EP-measurements were compared to clinical data, nerve conduction studies as well as Quantitative Sensory Testing. We found several promising analogies to clinical features of the tested patients, which motivates us and hopefully other researchers to continue on this path with the goal to form a reliable and valid electrophysiological sensory tool that could be used as an outcome measure for future neurophysiological studies and in clinical routine diagnostics.

Distinct spatio-temporal and spectral brain patterns for different thermal stimuli perception

Understanding the human brain’s perception of different thermal sensations has sparked the interest of many neuroscientists. The identification of distinct brain patterns when processing thermal stimuli has several clinical applications, such as phantom-limb pain prediction, as well as increasing the sense of embodiment when interacting with neurorehabilitation devices. Notwithstanding the remarkable number of studies that have touched upon this research topic, understanding how the human brain processes different thermal stimuli has remained elusive. More importantly, very intense thermal stimuli perception dynamics, their related cortical activations, as well as their decoding using effective features are still not fully understood. In this study, using electroencephalography (EEG) recorded from three healthy human subjects, we identified spatial, temporal, and spectral patterns of brain responses to different thermal stimulations ranging from extremely cold and hot stimuli (very intense), moderately cold and hot stimuli (intense), to a warm stimulus (innocuous). Our results show that very intense thermal stimuli elicit a decrease in alpha power compared to intense and innocuous stimulations. Spatio-temporal analysis reveals that in the first 400 ms post-stimulus, brain activity increases in the prefrontal and central brain areas for very intense stimulations, whereas for intense stimulation, high activity of the parietal area was observed post-500 ms. Based on these identified EEG patterns, we successfully classified the different thermal stimulations with an average test accuracy of 84% across all subjects. En route to understanding the underlying cortical activity, we source localized the EEG signal for each of the five thermal stimuli conditions. Our findings reveal that very intense stimuli were anticipated and induced early activation (before 400 ms) of the anterior cingulate cortex (ACC). Moreover, activation of the pre-frontal cortex, somatosensory, central, and parietal areas, was observed in the first 400 ms post-stimulation for very intense conditions and starting 500 ms post-stimuli for intense conditions. Overall, despite the small sample size, this work presents novel findings and a first comprehensive approach to explore, analyze, and classify EEG-brain activity changes evoked by five different thermal stimuli, which could lead to a better understanding of thermal stimuli processing in the brain and could, therefore, pave the way for developing a real-time withdrawal reaction system when interacting with prosthetic limbs. We underpin this last point by benchmarking our EEG results with a demonstration of a real-time withdrawal reaction of a robotic prosthesis using a human-like artificial skin.

Painful cold-heat segmental pulse stimulation provokes the thermal pain illusion

Purpose/Aim The thermal grill illusion is a paradoxical pain sensation induced by simultaneous exposure to spatially separated, non-painful, cold, and warm stimuli. This study aimed to determine whether paradoxical sensations are also evoked by simultaneous exposure to painful cold-heat stimuli and whether the mechanism involves modulation by segmental and extra-segmental spatial integration. Materials and Methods Sensory perceptions were triggered by simultaneous application of painful cold-heat pulse stimuli using a developed bedside tool equipped with quantitative thermal stimulator devices. Four conditions were investigated: (1) one device placed on the forearm (condition 1, control); (2) two devices placed on the forearm (condition 2, ipsilateral segmental integration); (3) two devices placed on the forearm and ipsilateral thigh (condition 3, extra-segmental integration); and (4) two devices placed bilaterally on the forearms (condition 4, contralateral segmental integration). The evoked perceptions of paradoxical heat sensation and the loss of cold or heat sensation were evaluated. Results The aforementioned phenomena were experienced by 11(35.4%), 3(9.7%), 3(9.7%), and 0(0.0%) subjects for conditions 1–4, respectively. Fisher's exact test revealed significant differences (p=.001) among the four conditions. However, Bonferroni post hoc analysis revealed significant differences only between conditions 1 and 4 (p=.005). Conclusions Simultaneous painful cold–heat pulse stimulation can induce paradoxical sensations similar to those shown for non-painful thermal (cold and heat) stimuli. They were predominantly evoked by ipsilateral integration. Paradoxical sensations have diagnostic value, and quantifying them using a simple bedside tool may be useful in the clinical setting.