Expertise Modulates Students' Perception of Pain From a Self-Perspective: Quasi-Experimental Study.

BACKGROUND: Perception of stimuli presented in a virtual dentistry environment affects regions of the brain that are related to pain perception. OBJECTIVE: We investigated whether neural correlates of virtual pain perception are affected by education in dentistry. METHODS: In this functional magnetic resonance imaging study, a sample of 20 dental students and 20 age-matched controls viewed and listened to video clips presenting a dental treatment from the first-person perspective. An anxiety questionnaire was used to assess the level of dental anxiety. Neural correlates of pain perception were investigated through classic general linear model analysis and in-house classification methods. RESULTS: Dental students and naïve controls exhibited similar anxiety levels for invasive stimuli. Invasive dentistry scenes evoked a less affective component of pain in dental students compared with naïve controls (P<.001). Reduced affective pain perception went along with suppressed brain activity in pain matrix regions including the insula, anterior cingulate cortex, and basal ganglia. Furthermore, a substantial reduction of brain activity was observed in motor-related regions, particularly the supplementary motor area, premotor cortex, and basal ganglia. Within this context, a classifier analysis based on neural activity in the nucleus lentiformis could identify dental students and controls on the individual subject level in 85% of the cases (34 out of 40 participants, sensitivity=90%, specificity=80%). CONCLUSIONS: Virtual dental treatment activates pain-related brain regions in controls. By contrast, dental students suppress affective and motor-related aspects of pain. We speculate that dental students learn to control motoric aspects of pain perception during their education because it is a prerequisite for the professional manual treatment of patients. We discuss that a specific set of learning mechanisms might affect perceived self-efficacy of dental students, which in turn might reduce their affective component of pain perception.

Assessment of lingual nerve functions after smoking cessation.

OBJECTIVE: Cigarette smoking is associated with a variety of oral diseases. A previous study showed a reduction of thermal sensitivity in the innervation area of the lingual nerve in smokers possibly caused by a degeneration of thermosensitive receptors as a consequence of smoking. The current study investigates somatosensory changes in ex-smokers. MATERIALS AND METHODS: Sensory functions in innervation areas of lingual nerve were investigated in 40 ex-smokers by psychophysical means. Functions of lingual nerve in 40 ex-smokers were compared to those in 40 smokers and 40 non-smokers. Subjects were investigated using quantitative sensory testing (QST, cold and warm detection, thermal sensory limen, heat and cold pain, and mechanical detection). RESULTS: Significant differences were found in both groups, ex-smokers and smokers compared to non-smokers. Cold (p < .001), warm (ex-smokers: p < .01; smokers: p < .001) detection thresholds and thermal sensory limen (p < .001) showed significantly lower sensitivity in ex-smokers and smokers in comparison to non-smokers. CONCLUSIONS: The lower temperature sensitivity of ex-smokers compared to that in non-smokers indicates a reduction of somatosensory function of the tongue, possibly caused by irreversible nerve degeneration associated with smoking. Influencing factors leading to sensory changes could be modulation of thermo-receptors, demyelination as well as a change of the epithelial structure.

ATP-sensitive muscle afferents activate spinal trigeminal neurons with meningeal afferent input in rat - pathophysiological implications for tension-type headache.

BACKGROUND: Tension-type headache and other primary headaches may be triggered or aggravated by disorders of pericranial muscles, which is possibly due to convergent or collateral afferent input from meningeal and muscular receptive areas. In rodent models high extracellular concentrations of ATP caused muscle nociception and central sensitization of second order neurons. In a rat model of meningeal nociception we asked if spinal trigeminal activity induced by ATP can be modulated by local anaesthesia of distinct muscles. METHODS: Ongoing activity was recorded from spinal trigeminal neurons with afferent input from the cranial dura mater, the temporal muscle and neck muscles. The stable ATP analogue α,ß-methylene adenosine 5'-triphosphate (α,ß-meATP, 10 mM) was injected into the ipsilateral temporal muscle, 30 min later followed by injection of local anaesthetics (lidocaine, 2 %) into the ipsilateral neck muscles and/or the temporal muscle. RESULTS: Injection of α,ß-meATP into the temporal muscle caused progressive increase in ongoing activity of most of the spinal trigeminal neurons within 30 min. Injection of lidocaine into the neck muscles and/or the temporal muscle reduced this activation to previous levels within 10 min. CONCLUSIONS: Distinct spinal trigeminal neurons processing meningeal nociceptive information are under the control of convergent afferent input from several pericranial muscles. Blockade of at least one of these inputs can normalize central trigeminal activity. This may explain why therapeutic manipulations of head muscles can be beneficial in primary headaches.

Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What's in the Pipeline.

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

Innocuous peripheral nerve stimulation shifts stimulus-response function of painful laser stimulation in man.

OBJECTIVES: Electrical peripheral nerve stimulation (PNS) is discussed as an effective neuromodulatory treatment in chronic pain. This human experimental study hypothesized a rightward shift of stimulus-response function as a marker of antinociceptive and analgesic PNS effects. MATERIALS AND METHODS: Innocuous electrical PNS of the left superficial radial nerve trunk evoked paresthesia on the left hand dorsum in 29 healthy volunteers. In this innervation area, laser stimulation was performed before, during, and after PNS. Ten different laser intensities ranging between perception and tolerance thresholds were applied. Cortical laser-evoked potentials (LEP) were recorded, and perceptual ratings were documented. Data were analyzed in low, medium, and high laser intensity categories. Stimulus-response functions were calculated. Laser detection and pain thresholds were interpolated. RESULTS: Interpolated laser thresholds after logarithmic regression were not different from measured thresholds. Laser pain threshold increased during and after PNS. LEP amplitude decreased at medium and high intensities under PNS. Ratings transiently decreased during PNS at medium and high laser intensities. CONCLUSIONS: Modulation of laser pain threshold, perceptual ratings, and LEP indicates a rightward shift of stimulus-response function under PNS. These data emphasize antinociceptive and analgesic effects of PNS in an experimental human model and support its clinical neuromodulative relevance.

Increase in choroidal thickness after blue light stimulation of the blind spot in young adults.

BACKGROUND: Blue light activates melanopsin, a photopigment that is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs). The axons of ipRGCs converge on the optic disc, which corresponds to the physiological blind spot in the visual field. Thus, a blue light stimulus aligned with the blind spot captures the ipRGCs axons at the optic disc. This study examined the potential changes in choroidal thickness and axial length associated with blue light stimulation of melanopsin-expressing ipRGCs at the blind spot. It was hypothesized that blue light stimulation at the blind spot in adults increases choroidal thickness. METHODS: The blind spots of both eyes of 10 emmetropes and 10 myopes, with a mean age of 28 ± 6 years (SD), were stimulated locally for 1-minute with blue flickering light with a 460 nm peak wavelength. Measurements of choroidal thickness and axial length were collected from the left eye before stimulation and over a 60-minute poststimulation period. At a similar time of day, choroidal thickness and axial length were measured under sham control condition in all participants, while a subset of 3 emmetropes and 3 myopes were measured after 1-minute of red flickering light stimulation of the blind spot with a peak wavelength of 620 nm. Linear mixed model analyses were performed to examine the light-induced changes in choroidal thickness and axial length over time and between refractive groups. RESULTS: Compared with sham control (2 ± 1 µm, n = 20) and red light (-1 ± 2 µm, n = 6) stimulation, subfoveal choroidal thickness increased within 60 min after blue light stimulation of the blind spot (7 ± 1 µm, n = 20; main effect of light, p < 0.001). Significant choroidal thickening after blue light stimulation occurred in emmetropes (10 ± 2 µm, p < 0.001) but not in myopes (4 ± 2 µm, p > 0.05). Choroidal thickening after blue light stimulation was greater in the fovea, diminishing in the parafoveal and perifoveal regions. There was no significant main effect of light, or light by refractive error interaction on the axial length after blind spot stimulation. CONCLUSIONS: These findings demonstrate that stimulating melanopsin-expressing axons of ipRGCs at the blind spot with blue light increases choroidal thickness in young adults. This has potential implications for regulating eye growth.

The blink reflex and its modulation - Part 1: Physiological mechanisms.

The blink reflex (BR) is a protective eye-closure reflex mediated by brainstem circuits. The BR is usually evoked by electrical supraorbital nerve stimulation but can be elicited by a variety of sensory modalities. It has a long history in clinical neurophysiology practice. Less is known, however, about the many ways to modulate the BR. Various neurophysiological techniques can be applied to examine different aspects of afferent and efferent BR modulation. In this line, classical conditioning, prepulse and paired-pulse stimulation, and BR elicitation by self-stimulation may serve to investigate various aspects of brainstem connectivity. The BR may be used as a tool to quantify top-down modulation based on implicit assessment of the value of blinking in a given situation, e.g., depending on changes in stimulus location and probability of occurrence. Understanding the role of non-nociceptive and nociceptive fibers in eliciting a BR is important to get insight into the underlying neural circuitry. Finally, the use of BRs and other brainstem reflexes under general anesthesia may help to advance our knowledge of the brainstem in areas not amenable in awake intact humans. This review summarizes talks held by the Brainstem Special Interest Group of the International Federation of Clinical Neurophysiology at the International Congress of Clinical Neurophysiology 2022 in Geneva, Switzerland, and provides a state-of-the-art overview of the physiology of BR modulation. Understanding the principles of BR modulation is fundamental for a valid and thoughtful clinical application (reviewed in part 2) (Gunduz et al., submitted).

Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial.

To elucidate, in a pilot-study, whether noninvasive transcutaneous vagus nerve stimulation (t-VNS) is a safe and tolerable alternative treatment option in pharmacoresistant epilepsy. t-VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients' seizure diaries. For a more reliable assessment of seizure frequency, we carried out prolonged outpatient video-electroencephalography (EEG) monitoring. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t-VNS. The noninvasive t-VNS stimulation is a safe and well-tolerated method for relatively long periods, and might be an alternative treatment option for patients with epilepsy.

P2X7 receptor blockade reverses purinergic facilitation of neck muscle nociception in mice.

INTRODUCTION: Facilitation of neck muscle nociception mediated via purinergic signalling may play a role in the pathophysiology of tension-type headache (TTH). The present study addressed reversal of purinergic facilitation of brainstem nociception via P2X7 antagonist action in anaesthetized mice. METHODS: Following administration of α,ß-meATP (i.m. 20 µL/min, 20 µL each) into semispinal neck muscles, the impact of neck muscle nociceptive input on brainstem processing was monitored by the jaw-opening reflex in anaesthetized mice (n = 20). The hypothesized involvement of the P2X7 receptor in the α,ß-meATP effect was addressed with i.p. (systemic) and i.m. (semispinalis, 20 µL/min, 20 µL each) administration of P2X7 inhibitor A438079 during established facilitation; i.p. saline served as control. RESULTS: α,ß-meATP reliably induced jaw-opening reflex facilitation (256 ± 48% (mean ± SEM), n = 20). I.p. A438079 (150, 300 µmol/kg) completely reversed this α,ß-meATP effect dose-dependently. Neither saline nor intramuscular A438079 (100 µM) altered facilitated brainstem nociceptive processing. DISCUSSION: These data suggest that muscular structures are not directly involved in the P2X7 antagonist-mediated reversal of purinergic facilitation. Instead, involvement of neuronal structures, particularly of the central nervous system, seems more probable. The results from this animal experimental model may point to involvement of purinergic P2X7 receptors in TTH pathophysiology and may suggest potential future targets for its pharmacological treatment.

Impaired somatosensation in tongue mucosa of smokers.

Smoking has been indicated as a risk factor for oral diseases and can lead to altered sense of taste. So far, the effects of sensory changes on the tongue are not investigated. In this study, quantitative sensory testing was used to evaluate somatosensory function in the lingual region. Eighty healthy volunteers were investigated (20 smokers, 20 non-smokers). Subjects were bilaterally tested in innervation areas of lingual nerves. Thresholds of cold and warm detection, cold and heat pain, and mechanical detection were determined. As control for systemic, extraoral effects of smoking, tests were additionally performed in 40 volunteers (20 smokers, 20 non-smokers) on the skin of the chin innervated by the mental branch of the trigeminal nerve. Cold (p < 0.001), warm detection thresholds (p < 0.001), and thermal sensory limen (p < 0.001) showed higher sensitivity in non-smokers as compared to smokers. Heat pain and mechanical detection, as well as all tests in the skin of the chin, showed no significant differences. The impaired temperature perception in smokers indicates a reduction of somatosensory functions in the tongue, possibly caused by nerve degeneration associated with smoking. Possible systemic effects of smoking do not seem to affect extraoral trigeminal branches.

Electrical neurostimulation in glaucoma with progressive vision loss.

BACKGROUND: The retrospective study provides real-world evidence for long-term clinical efficacy of electrical optic nerve stimulation (ONS) in glaucoma with progressive vision loss. METHODS: Seventy glaucoma patients (45 to 86 y) with progressive vision loss despite therapeutic reduction of intraocular pressure (IOP) underwent electrical ONS. Closed eyes were separately stimulated by bipolar rectangular pulses with stimulus intensities up to 1.2 mA sufficient to provoke phosphenes. Ten daily stimulation sessions within 2 weeks lasted about 80 min each. Right before ONS at baseline (PRE), vision loss was documented by static threshold perimetry and compared to the same assessment approximately 1 year afterwards (POST). Mean defect (MD) was defined as primary outcome parameter. Perimetries with a reliability factor (RF) of max. 20% were considered. RESULTS: Perimetry follow-up of 101 eyes in 70 patients fulfilled the criterion of a max. 20% RF. Follow-up was performed on average 362.2 days after ONS. MD significantly decreased from PRE 14.0 dB (median) to POST 13.4 dB (p < 0.01). 64 eyes in 49 patients showed constant or reduced MD as compared to baseline (PRE 13.4 dB vs. POST 11.2 dB). In 37 eyes of 30 patients, MD increased from PRE 14.9 dB to POST 15.6 dB. CONCLUSIONS: Innovative treatments that preserve visual function through mechanisms other than lowering IOP are required for glaucoma with progressive vision loss. The present long-term data document progression halt in more than 63% of affected eyes after ONS and, thus, extend existing evidence from clinical trials.

Heterotopic low-frequency stimulation induces nociceptive LTD within the same central receptive field in man.

Electrical low-frequency stimulation (LFS) evokes long-term depression (LTD) of nociception. Human studies suggested a strictly homotopic organization. This study hypothesizes that even heterotopic LFS evokes LTD within the same receptive field (RF). In 33 healthy volunteers, painful electrical test stimulation and LFS were applied to the low back by a concentric electrode (ExpBack) and to the forearm by a multiarray electrode (ExpArm). Volunteers rated pain perception during test stimulation that was applied before and after LFS. In ExpBack, test stimuli were administered within the right T12 dermatome. LFS was applied heterotopically within the same RF or remote in dermatome T8. In ExpArm, test stimulation was carried out in the center of the RF whereas LFS was applied to the center, margin, or outside the RF. In ExpBack (n = 20), pain ratings decreased significantly stronger in T12 than in T8 dermatome (P < 0.01). In ExpArm (n = 20), LFS to the center of the RF induced a stronger pain reduction than LFS applied outside the RF (P < 0.001). This study demonstrates a heterosynaptic organization of LTD within the same RF. Profound knowledge about RF involvement on LTD seems crucial in order to judge the quality of LFS as a possible neuromodulatory treatment of pain.

Neuronal nitric oxide synthase is involved in the induction of nerve growth factor-induced neck muscle nociception.

BACKGROUND: Neck muscle nociception mediated by nitric oxide may play a role in the pathophysiology of tension-type headache. OBJECTIVE: The present study addresses the involvement of neuronal nitric oxide synthase (nNOS) in the facilitation of neck muscle nociception after local application of nerve growth factor (NGF). METHODS: After administration of NGF into semispinal neck muscles, the impact of neck muscle noxious input on brainstem processing was monitored by the jaw-opening reflex in anesthetized mice. The modulatory effect of preceding and subsequent administration of an inhibitor of neuronal nitric oxide synthase on central facilitation was addressed in a controlled study. RESULTS: With preceding i.p. application of saline or 0.096 mg/kg of the specific nNOS inhibitor Nω-propyl-L-arginine (NPLA), NGF induced a sustained reflex facilitation within 60 minutes. Preceding injection of 0.96 mg/kg or 1.92 mg/kg NPLA completely prevented the potentially facilitatory effect of NGF. Subsequent administration of 0.96 mg/kg NPLA did not affect established NGF-evoked reflex facilitation. Thus, NPLA prevents facilitation of brainstem processing by noxious myofascial input from neck muscles in a dose-dependent manner. CONCLUSION: These findings suggest that nNOS is involved in the induction but not the maintenance of NGF-evoked facilitation of nociception in the brainstem. These results from an experimental animal model may support the idea of NOS and nNOS as potential targets for pharmacological treatment of tension-type headache.

Low-frequency electrical stimulation induces long-term depression in patients with chronic tension-type headache.

Repetitive low-frequency electrical stimulation (LFS) induces pain inhibition in healthy volunteers and in animals, but it is unknown whether it has an analgesic effect in patients with headache. The aim of this study was to investigate if LFS could induce prolonged pain inhibition, called long-term depression (LTD), in patients with chronic tension-type headache (CTTH). Twenty CTTH patients and 20 healthy volunteers were exposed to 20 min LFS (1 Hz) to the forehead. LTD was measured as a decrease in pain response to electrical stimulation in a 1-h post-LFS period following LFS. The LFS induced a significant and stable inhibition of pain (LTD) both in patients with CTTH (post-LFS average decrease in pain rating: 19.6 +/- 3.9%, all P < 0.005, Holm-Sidak) and in healthy controls (30.1 +/- 5.0%, all P < 0.001, Holm-Sidak). During the LFS period, the pain ratings decreased consistently in both groups. In conclusion, a significant and stable pain inhibition (LTD) can be induced in CTTH patients by LFS.

Inhibition of nitric oxide synthases prevents and reverses alpha,beta-meATP-induced neck muscle nociception in mice.

INTRODUCTION: Tension-type headache (TTH) is associated with noxious input from neck muscles. Intravenous administration of the unspecific nitric oxide synthase inhibitor L-NMMA in chronic TTH patients caused analgesia and reduction of neck muscle tenderness. METHODS: The unspecific nitric oxide synthase inhibitor L-NMMA was applied in an experimental model for neck muscle nociception in anesthetized mice (N = 25). RESULTS: Local injection of α,ß-meATP into semispinal neck muscles induced sustained facilitation of brainstem nociception as monitored by the jaw-opening reflex. Preceding intraperitoneal administration of L-NMMA (0.05, 0.1, 1 mg/kg) prevented reflex facilitation evoked by α,ß-meATP in a dose-dependent manner. Intraperitoneal injection of L-NMMA subsequent to intramuscular α,ß-meATP application reversed established brainstem reflex facilitation back to baseline values. DISCUSSION: Both experiments with preceding and subsequent L-NMMA indicate the involvement of nitric oxide synthases in the induction and maintenance of facilitation. However, future experiments will have to address the involvement of various isoenzymes in order to provide for new therapeutic concepts in TTH.

Assessment of trigeminal nerve functions by quantitative sensory testing in patients and healthy volunteers.

PURPOSE: Orofacial sensory dysfunction plays an important role in oral and maxillofacial surgery. Quantitative sensory testing (QST) is a psychophysical approach to evaluate thermal and mechanical somatosensation. PATIENTS AND METHODS: The present human study 1) collected normative QST data in extraoral and intraoral regions, 2) analyzed effects of age, gender, and anatomical sites on QST, and 3) applied QST in 11 patients with iatrogenic inferior alveolar nerve lesions. Sixty (30 male and 30 female) healthy volunteers were tested bilaterally in the innervation areas of infraorbital, mental, and lingual nerves. Ten patients with sensory disturbances in innervation areas of the mental nerve were investigated at 1, 4, and 8 weeks after surgery. Another patient with a complete sensory loss after surgery was repetitively tested within 453 days after primary surgery (dental implant) and subsequent surgical reconstruction of the inferior alveolar nerve by autologous graft. RESULTS: Older subjects were significantly less sensitive than younger subjects for thermal parameters. Thermal detection thresholds in infraorbital and mental regions showed higher sensitivity in women. Sensitivity to thermal stimulation was higher in the infraorbital region than in the mental and lingual regions. QST monitored somatosensory deficits and recovery of inferior alveolar nerve functions in all patients. CONCLUSIONS: Age, gender, and anatomic region affect various QST parameters. QST might be useful in the diagnosis of inferior alveolar nerve disorders in patients. In dentistry, the monitoring of afferent nerve fiber functions by QST might support decisions on further interventions.

Cortical stimulation in pharmacoresistant focal epilepsies.

Pharmacoresistance and adverse drug events designate a considerable group of patients with focal epilepsies that require alternative treatments such as neurosurgical intervention and neurostimulation. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience through intraoperative neurophysiological monitoring in patients. Direct neurostimulation of seizure onset zones in neocortical brain areas may specifically affect neuronal networks involved in epileptiform activity without remarkable adverse influence on physiological cortical processing in immediate vicinity. Noninvasive low-frequency transcranial magnetic stimulation and cathodal transcranial direct current stimulation are suggested to be anticonvulsant; however, potential effects are ephemeral and require effect maintenance by ongoing stimulation. Invasive responsive neurostimulation, chronic subthreshold cortical stimulation, and epicranial cortical stimulation cover a broad range of different emerging technologies with intracranial and epicranial approaches that still have limited market access partly due to ongoing clinical development. Despite significant differences, the present bioelectronic technologies share common mode of actions with acute seizure termination by high-frequency stimulation and long-term depression induced by low-frequency magnetic or electrical stimulation or transcranial direct current stimulation.

Modulatory effects of transcranial direct current stimulation on laser-evoked potentials.

OBJECTIVE: Invasive stimulation of the motor cortex has been used for years to alleviate chronic intractable pain in humans. In our study, we have investigated the effect of transcranial direct current stimulation (tDCS), a noninvasive stimulation method, for manipulating the excitability of cortical motor areas on laser evoked potentials (LEP) and acute pain perception. DESIGNS AND SETTINGS: The amplitude of the N1, N2, and P2 LEP components of 10 healthy volunteers were evaluated prior to and following anodal, cathodal, and sham stimulation of the primary motor cortex. In a separate experiment subjective, pain rating scores of 16 healthy subjects in two perceptual categories (warm sensation, mild pain) were also analyzed. RESULTS: Cathodal tDCS significantly reduced the amplitude of N2 and P2 components compared with anodal or sham stimulation. However, neither of the tDCS types modified significantly the laser energy values necessary to induce moderate pain. In a separate experiment, cathodal stimulation significantly diminished mild pain sensation only when laser-stimulating the hand contralateral to the side of tDCS, while anodal stimulation modified warm sensation. CONCLUSIONS: The possible underlying mechanisms of our findings in view of recent neuroimaging studies are discussed. To our knowledge this study is the first to demonstrate the mild antinociceptive effect of tDCS over the primary motor cortex in healthy volunteers.

Cerebral activations resulting from virtual dental treatment.

Pain, and anxiety of pain, for some people are serious problems in dental treatment. It is a common practical experience that even entering a dental surgery office, or the sound of a dental drill, may evoke vegetative correlates of toothache without any underlying disease. This everyday phenomenon suggests the hypothesis of a corresponding activation of pain-related brain areas by virtual dental treatment. Twenty healthy subjects viewed two different video clips presenting a dental treatment from the first-person perspective (simulation movie) and a moving hand holding an electrical toothbrush (control movie). Using functional magnetic resonance imaging, the cerebral hemodynamic responses that occurred during simulation and control movies were compared. Virtual dental treatment was associated with increased activity in pain-related brain areas such as the cingulate cortex, the insula, and primary and secondary somatosensory cortexes (SI, SII). The brain activation pattern indicates not only affective-motivational but also sensory-discriminative pain components during virtual dental treatment in all volunteers. Volunteers with a higher level of dental anxiety showed stronger activation of SI and SII. This may be a result of their higher anticipation of pain.

Transcutaneous Auricular Vagus Nerve Stimulation.

Invasive vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. Besides recognized clinical efficacy in about 60% of patients, there are major drawbacks such as invasiveness and common side effects including hoarseness, sore throat, shortness of breath, and coughing. Invasive VNS applies electrical stimulation to the left cervical branch of the vagus nerve and excites thick-myelinated afferent nerve fibers. Peripheral vagus nerve afferent volley initiates brainstem activity in the nucleus of the solitary tract and provokes typical brainstem and cerebral activation patterns that mediate the anticonvulsive mode of action. Whereas invasive VNS is an established neuromodulatory treatment in drug-resistant epilepsy, transcutaneous VNS (tVNS) of the auricular branch of the vagus nerve is suggested to be an alternative access path to the same neuronal network without invasiveness. Preclinical and clinical studies indicate that especially the cymba conchae of the auricle is selectively supplied by the auricular branch of the vagus nerve. Recent anatomical data demonstrate existence and quantity of thick-myelinated afferent nerve fibers of the left auricular branch of the vagus nerve that carries 21% of thick-myelinated afferent nerve fibers counted in the left thoracic vagus nerve in humans. Projection of auricular branch of the vagus nerve afferents from the auricle to the nucleus of the solitary tract is known from histochemical and electrophysiological experiments in rodents and confirmed in humans by functional imaging. Cerebral activation patterns triggered by invasive and tVNS resemble each other in appearance. Clinical trials in patients address safety and performance of tVNS and provide evidence for application in drug-resistant epilepsy.