Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons.

Mechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury in mice. Mice in which TrkB-Cre-expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB-positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.

Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System.

Focused ultrasound has been shown to stimulate excitable cells, but the biophysical mechanisms behind this phenomenon remain poorly understood. To provide additional insight, we devised a behavioral-genetic assay applied to the well-characterized nervous system of Caenorhabditis elegans nematodes. We found that pulsed ultrasound elicits robust reversal behavior in wild-type animals in a pressure-, duration-, and pulse protocol-dependent manner. Responses were preserved in mutants unable to sense thermal fluctuations and absent in mutants lacking neurons required for mechanosensation. Additionally, we found that the worm's response to ultrasound pulses rests on the expression of MEC-4, a DEG/ENaC/ASIC ion channel required for touch sensation. Consistent with prior studies of MEC-4-dependent currents in vivo, the worm's response was optimal for pulses repeated 300-1000 times per second. Based on these findings, we conclude that mechanical, rather than thermal, stimulation accounts for behavioral responses. Further, we propose that acoustic radiation force governs the response to ultrasound in a manner that depends on the touch receptor neurons and MEC-4-dependent ion channels. Our findings illuminate a complete pathway of ultrasound action, from the forces generated by propagating ultrasound to an activation of a specific ion channel. The findings further highlight the importance of optimizing ultrasound pulsing protocols when stimulating neurons via ion channels with mechanosensitive properties.SIGNIFICANCE STATEMENT How ultrasound influences neurons and other excitable cells has remained a mystery for decades. Although it is widely understood that ultrasound can heat tissues and induce mechanical strain, whether or not neuronal activation depends on heat, mechanical force, or both physical factors is not known. We harnessed Caenorhabditis elegans nematodes and their extraordinary sensitivity to thermal and mechanical stimuli to address this question. Whereas thermosensory mutants respond to ultrasound similar to wild-type animals, mechanosensory mutants were insensitive to ultrasound stimulation. Additionally, stimulus parameters that accentuate mechanical effects were more effective than those producing more heat. These findings highlight a mechanical nature of the effect of ultrasound on neurons and suggest specific ways to optimize stimulation protocols in specific tissues.

Oral sensory dysfunction following radiotherapy.

OBJECTIVES/HYPOTHESIS: To assess differences in oral tactile sensation between subjects who have undergone radiation therapy (XRT) compared to healthy controls. STUDY DESIGN: Cross-sectional cohort comparison. METHODS: Thirty-four subjects with a history of XRT were compared with 23 healthy controls. There was no difference in age (P = .23), but there were slightly more males in the XRT cohort (P = .03). The mean (standard deviation) time after XRT completion was 3.84 (4.84) years. Fifty-six percent of the XRT cohort received chemotherapy. Using our previously validated methodology to measure oral tactile sensory threshold quantitatively with Cheung-Bearelly monofilaments, sensory thresholds of four subsites (anterior tongue, buccal mucosa, posterior tongue, soft palate) were compared for the two cohorts. RESULTS: Site-by-site comparisons showed higher forces were required for stimulus detection at all four subsites among subjects in the XRT cohort compared to healthy controls. Mean force in grams for XRT versus control cohorts were: anterior tongue, 0.39 (1.0) versus 0.02 (0.01); buccal mucosa, 0.42 (0.95) versus 0.06 (0.05); posterior tongue, 0.76 (1.46) versus 0.10 (0.07); and soft palate, 0.86 (1.47) versus 0.08 (0.05) (P < .001 for all comparisons). Combining all four subsites into a single metric to assess an overall level of oral tactile dysfunction, the XRT cohort had reduced sensation by 18.7 dB (P < .001). CONCLUSIONS: After radiation therapy, the oral cavity and oropharynx exhibit global tactile sensory dysfunction, manifested by increased tactile forces required for stimulus detection. The magnitude of sensory impairment is 18.7 dB. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:2282-2286, 2017.

Whole body vibration at different exposure frequencies: infrared thermography and physiological effects.

The aim of this study was to investigate the effects of whole body vibration (WBV) on physiological parameters, cutaneous temperature, tactile sensitivity, and balance. Twenty-four healthy adults (25.3 ± 2.6 years) participated in four WBV sessions. They spent 15 minutes on a vibration platform in the vertical mode at four different frequencies (31, 35, 40, and 44 Hz) with 1 mm of amplitude. All variables were measured before and after WBV exposure. Pressure sensation in five anatomical regions and both feet was determined using Von Frey monofilaments. Postural sway was measured using a force plate. Cutaneous temperature was obtained with an infrared camera. WBV influences the discharge of the skin touch-pressure receptors, decreasing sensitivity at all measured frequencies and foot regions (P ≤ 0.05). Regarding balance, no differences were found after 20 minutes of WBV at frequencies of 31 and 35 Hz. At 40 and 44 Hz, participants showed higher anterior-posterior center of pressure (COP) velocity and length. The cutaneous temperature of the lower limbs decreased during and 10 minutes after WBV. WBV decreases touch-pressure sensitivity at all measured frequencies 10 min after exposure. This may be related to the impaired balance at higher frequencies since these variables have a role in maintaining postural stability. Vasoconstriction might explain the decreased lower limb temperature.

Lower-level laser therapy improves neurosensory disorders resulting from bilateral mandibular sagittal split osteotomy: a randomized crossover clinical trial.

Bilateral sagittal split osteotomy (BSSO) is a technique commonly used to correct mandibular disproportion but many patients experience hypoaesthesia of the inferior alveolar nerve (IAN). The purpose of this study was to verify the effectiveness of using a low-level laser therapy protocol after BSSO. The 10 patients in our study, who underwent BSSO with Le Fort I osteotomy and had low-level laser therapy on one side of the jaw, were evaluated over a period of 60 days. The data for the treated and non-treated sides were compared post-operatively. At 15, 30 and 60 days after surgery, when sensitivity was recovered on both sides. On the treated side, recovery was faster and was almost complete at the time of the last evaluation. We suggest that this lower-level laser therapy protocol can improve tissue response and accelerate the recovery of neurosensory disorders following BSSO. (NCT01530100).

Intense focused ultrasound can reliably induce sensations in human test subjects in a manner correlated with the density of their mechanoreceptors.

Sensations generated by intense focused ultrasound (iFU) can occur cutaneously and/or at depth, in contrast to other forms of stimulation (e.g., heat, electricity), whose action usually occurs only at the skin surface, or mechanical stimulation (e.g., von Frey hairs, calibrated forceps, tourniquets) that compress and thus stimulate all tissue. Previous work on iFU stimulation has led to the hypothesis that the tactile basis of iFU stimulation should correlate with the density of mechanoreceptors at the site of iFU stimulation. Here we tested that hypothesis, correlating a "two-point" neurological examination-a standard measure of superficial mechanoreceptor density-with the intensity of superficially applied iFU necessary to generate sensations with high sensitivity and specificity. We applied iFU at 1.1 MHz for 0.1 s to the fingertip pads of 17 test subjects in a blinded fashion and escalated intensities until they consistently observed iFU-induced sensations. Most test subjects achieved high values of sensitivity and specificity, doing so at values of spatially and temporally averaged intensity measuring <100 W/cm(2). Moreover, the test subjects' sensitivity to iFU stimulation correlated with the density of mechanoreceptors as determined by a standard two-point discrimination neurological examination, consistent with earlier hypotheses.

Effect of the interaction between light and touch stimuli on inducing curling seminal roots in rice seedlings.

Root development is sensitive to environmental stimuli. We have recently reported that the light signal could promote the helical growth of seminal roots and drive the wavy root morphology in rice (Oryza sativa L.) young seedlings. The light-stimulated wavy roots were mostly performed in indica-type rice varieties (e.g. Taichung Native 1; TCN1) but not in japonica rice (e.g. Tainung 67; TNG67). Here, we demonstrated that the light-driven circumutation trajectory of TCN1 seminal roots could be changed if the seedling roots were grown in the medium containing high concentration of Phytagel. The data showed the root morphology would be modulated from wavy to curling when the Phytagel concentration was increased to 2%. However, the touch-stimulated curling root phenotype could not be performed in dark. In addition, the touch-induced curling roots were not appeared in the TNG67 rice cultivar. Although touch stimuli could not induce wavy/curling root phenotype in dark, it could modify the light-promoted helical growth to conduct curling roots in TCN1 rice seedlings. Thus, it was suggested that there is a crosstalk mechanism between touching-induced root curling and light-stimulated root waving.

Laser modulation of heat and capsaicin receptor TRPV1 leads to thermal antinociception.

Er,Cr:YSGG lasers are used clinically in dentistry. The advantages of laser therapy include minimal thermal damage and the alleviation of pain. This study examined whether the Er,Cr:YSGG laser has in vivo and in vitro antinociceptive effects in itself. In capsaicin-evoked acute licking/shaking tests and Hargreaves tests, laser irradiation with an aerated water spray suppressed nociceptive behavior in mice. Laser irradiation attenuated TRPV1 activation by capsaicin in Ca(2+) imaging experiments with TRPV1-overexpressing cells and cultured trigeminal neurons. Therefore, the laser-induced behavioral changes are probably due to the loss of TRPV1 activity. TRPV4 activity was also attenuated, but limited mechanical antinociception by the laser was observed. The laser failed to alter the other receptor functions, which indicates that the antinociceptive effect of the laser is dependent on TRPV1. These results suggest that the Er,Cr:YSGG laser has analgesic effects via TRPV1 inhibition. Such mechanistic approaches may help define the laser-sensitive pain modality and increase its beneficial uses.

Millimeter wave effects on electrical responses of the sural nerve in vivo.

Millimeter wave (MMW, 42.25 GHz)-induced changes in electrical activity of the murine sural nerve were studied in vivo using external electrode recordings. MMW were applied to the receptive field of the sural nerve in the hind paw. We found two types of responses of the sural nerve to MMW exposure. First, MMW exposure at the incident power density >/=45 mW/cm(2) inhibited the spontaneous electrical activity. Exposure with lower intensities (10-30 mW/cm(2)) produced no detectable changes in the firing rate. Second, the nerve responded to the cessation of MMW exposure with a transient increase in the firing rate. The effect lasted 20-40 s. The threshold intensity for this effect was 160 mW/cm(2). Radiant heat exposure reproduced only the inhibitory effect of MMW but not the transient excitatory response. Depletion of mast cells by compound 48/80 eliminated the transient response of the nerve. It was suggested that the cold sensitive fibers were responsible for the inhibitory effect of MMW and radiant heat exposures. However, the receptors and mechanisms involved in inducing the transient response to MMW exposure are not clear. The hypothesis of mast cell involvement was discussed.

A high-voltage bipolar transconductance amplifier for electrotactile stimulation.

This paper describes a high-performance transconductance amplifier specifically designed for electrotactile (electrocutaneous) stimulation. It enables voltages up to +/-600 V to be produced at the output that will allow the psychophysiological performance associated with stimulation of the fingertip using various stimulation waveforms to be studied more thoroughly. The design has a transconductance of up to 20 mA/V, an 8.8-Momega output resistance, and can provide output currents up to +/-20 mA. A complete schematic diagram is presented along with a discussion of theory of operation and safety issues as well as performance and derating plots from the implemented design.

Transcranial direct current stimulation disrupts tactile perception.

The excitability of the cerebral cortex can be modulated by various transcranial stimulation techniques. Transcranial direct current stimulation (tDCS) offers the advantage of portable equipment and could, therefore, be used for ambulatory modulation of brain excitability. However, modulation of cortical excitability by tDCS has so far mostly been shown by indirect measures. Therefore, we examined whether tDCS has a direct behavioral/perceptional effect. We compared tactile discrimination of vibratory stimuli to the left ring finger prior to, during and after tDCS applied for 7 min at 1-mA current intensity in 13 subjects. Stimulation was pseudorandomized into cathodal, anodal and sham conditions in a within-subject design. The active electrode was placed over the corresponding somatosensory cortex at C4 according to the 10-20 EEG system and the reference electrode at the forehead above the contralateral orbita. Cathodal stimulation compared with sham induced a prolonged decrease of tactile discrimination, while anodal and sham stimulation did not. Thus, cortical processing can be modulated in a behaviorally/perceptually meaningful way by weak transcranial current stimulation applied through portable technology. This finding offers a new perspective for the treatment of conditions characterized by alterations of cortical excitability.

Visual enhancing of tactile perception in the posterior parietal cortex.

The visual modality typically dominates over our other senses. Here we show that after inducing an extreme conflict in the left hand between vision of touch (present) and the feeling of touch (absent), sensitivity to touch increases for several minutes after the conflict. Transcranial magnetic stimulation of the posterior parietal cortex after this conflict not only eliminated the enduring visual enhancement of touch, but also impaired normal tactile perception. This latter finding demonstrates a direct role of the parietal lobe in modulating tactile perception as a result of the conflict between these senses. These results provide evidence for visual-to-tactile perceptual modulation and demonstrate effects of illusory vision of touch on touch perception through a long-lasting modulatory process in the posterior parietal cortex.

[Influence of body size on the electric current perception threshold]. / Einfluss der Körpermasse auf die elektrische Wahrnehmbarkeitsschwelle.

Although the threshold for electric current perception is of great importance for safety considerations and safety regulations, important aspects remain unsolved, e.g. the role of age or body size. In the present study measurements of the perception threshold were performed in 790 persons aged between 18 and 82 years randomly selected from the general population. For the first time, the composition and size of the sample were selected such as to allow extrapolation to the general population. The results reveal not only statistically significant gender differences in the perception threshold but also statistically significant relationships between perception threshold and body size. The assumption that the differences in body size between men and women are responsible for the gender-specific difference in electric current perception threshold was not confirmed in this study.

Merkel cells are not the mechanosensory transducers in the touch dome of the rat.

The identity of the mechanosensory transducing elements in the vertebrate touch receptors that contain Merkel cell-neurite complexes is unknown. The Merkel cells, however, have long been the favoured candidates. We have now selectively eliminated the Merkel cells from rat touch domes by first loading them with quinacrine, and then irradiating the domes with near-UV light. Mechanical stimulation of these domes revealed a range of mechanosensory function, evaluated qualitatively, that varied from non-responsive to normal. Since irradiation eliminated the quinacrine fluorescence, the status of the Merkel cells was evaluated by EM. In both responsive and unresponsive domes fixed for EM immediately following irradiation, the Merkel cells and associated nerve endings appeared to be normal. After 2 or more days, even in domes that continued to be normally responsive, there was a striking reduction in the normal complement of about 90 Merkel cells, and most of the remaining Merkel cells appeared to be degenerating. However, numerous 'isolated' (Merkel cell-free) nerve endings remained in the basal epidermis. A few of these nerve endings showed signs of damage, but in the non-responsive domes abnormal nerve endings were routinely observed. The EM studies did not exclude the possibility that a few surviving innervated Merkel cells, or even one such, had escaped detection and were responsible for a persisting mechanosensitivity. To resolve this issue a mechanical stimulating technique with a spatial resolution of 55 microns was used to map the mechanosensory profile of a single responsive dome irradiated 2.75 days earlier. This dome was then serially sectioned for EM study. Only seven Merkel cells had survived which appeared to be both viable and innervated, but almost all of the tested sites were normally responsive. When the correlation was made, seven of these sites were located 55-100 microns away from the nearest surviving Merkel cell, four were 110-165 microns away, and three were more than 165 microns away. Even when allowance is made for errors in the positioning of the stimulus, the responses at the last seven sites cannot be attributed to the presence of underlying Merkel cells. We conclude that mechanosensory transduction within touch domes is not a function of the Merkel cells, but must reside in the associated nerve endings.

Modification of acoustic and tactile startle by single microwave pulses.

Single microwave pulses at 1.25 GHz were delivered to the head and neck of male Long-Evans rats as a prestimulus to acoustic and tactile startle. For acoustic startle, pulses averaging 0.96 microsecond in duration were tested with two specific absorption rate (specific absorption) ranges, 15.0-30.0 kW/kg (16.0-44.2 mJ/kg) and 35.5-86.0 kW/kg (66.6-141.8 mJ/kg), delivered 201, 101, 51, 3, and 1 ms before and 1 ms after onset of a startling noise. The low-intensity pulse did not affect peak amplitude, integral, or latency of the whole-body startle response. The high-intensity pulse at 101 and 51 ms inhibited the startle response by decreasing peak amplitude and integral; at 201 and 51 ms latency was increased. The high-intensity pulse at 1 ms enhanced the startle response by increasing peak amplitude and at 3 ms by increasing integral. For tactile startle, either microwave pulses averaging 7.82 microseconds in duration and 55.9-113.3 kW/kg (525.0-1055.7 mJ/kg) or 94 dB SPL clicks were delivered 157, 107, 57, and 7 ms before and 43 ms after onset of a startling air burst. The microwave pulse at 57 ms inhibited the startle response by decreasing peak amplitude; at 157, 107, 57, and 7 ms it increased latency. The microwave pulse at 43 ms after onset enhanced the startle response by increasing peak amplitude. The acoustic click at 157 and 57 ms inhibited the startle response by decreasing peak amplitude; at 157,2 107, and 57 ms it increased latency.(ABSTRACT TRUNCATED AT 250 WORDS)

Early postnatal x-irradiation of the hippocampus and discrimination learning in adult rats.

Rats with X-irradiation-produced degranulation of the hippocampal dentate gyrus were trained in the acquisition and reversal of simultaneous visual and tactile discriminations in a T-maze. These experiments employed the same treatment, apparatus, and procedure but varied in task difficulty. In the brightness and roughness discriminations, the irradiated rats were not handicapped in acquiring or reversing discriminations of low or low-moderate task difficulty. However, these rats were handicapped in acquiring and reversing discriminations of moderate and high task difficulty. In a Black/White discrimination, in which the stimuli were restricted to the goal-arm walls, the irradiated rats were handicapped in the acquisition (low task difficulty) and reversal (moderate task difficulty) phases of the task. These results suggest that the irradiated rats were not handicapped when the noticeability of the stimuli was high, irrespective of modality used, but were handicapped when the noticeability of the stimuli was low. In addition, these results are consistent with the hypothesis that rats with hippocampal damage are inattentive due to hyperactivity.