Insular Cortical Thickness in Patients With Somatoform Pain Disorder: Are There Associations With Symptom Severity and Childhood Trauma?

BACKGROUND: Studies show significant alterations in insular cortical thickness in patients with somatoform pain disorder (SPD). Additionally, associations between childhood maltreatment and morphometric alterations in insular cortex have been observed. Since patients with SPD often report about adverse childhood experiences, we were interested in the interrelationship of exposure to childhood maltreatment and insular cortical thickness in patients with SPD. METHODS: Fifteen adult patients with SPD (ICD-10 F 45.40/41, DSM-Code 307.80) and thirteen healthy adult controls underwent T1-weighted MR brain imaging. In the voxel-based morphometry (VBM) analysis we compared whole brain cortical thickness between patients and controls using a Student's two-sampled t-test (p < .05). Then we performed a secondary analysis to detect differences in cortical thickness levels in the insular cortex between both groups. For further analysis of differences in insular cortical thickness we used gender, age, depressive symptoms [Patient Health Questionnaire (PHQ)-9], and whole brain cortical thickness as nuisance covariates. Subsequently we explored associations between insular cortical thickness, symptom severity (PHQ-15) and past experiences of childhood maltreatment (CTQ) in both groups. RESULTS: Patients showed reduced insular cortical thickness in a subregion of right Brodmann area (BA) 13 (anterior part of the insular cortex), whereas whole brain cortical thickness did not differ between groups. The between-group difference in the identified insular subregion of right BA 13 was not diminished by any of the covariates. This implies that the reduction in cortical thickness in the identified insular subregion might be due to a specific group effect. The effect sizes indicate that the group of patients experienced more childhood maltreatment than the control group. Nonetheless, significant correlations of insular cortical thickness with symptom severity and childhood maltreatment in the total collective could not be demonstrated for the group of patients. CONCLUSIONS: Our data suggest that alterations in the identified insular subregion of right BA 13 are associated with somatoform pain, independent of gender, age, or coincident depression levels. To identify significant associations of insular cortical thickness and experiences of childhood maltreatment in patients with SPD investigations within larger samples are highly recommended.

Neural mechanisms of perceptive and affective processing of body stimuli in anorexia nervosa - are there developmental effects?

Different components of body image processing seem to be reflected by different neural mechanisms. A core symptom of Anorexia nervosa (AN) is a disturbance of body image with correlates found on a neural level. The present study focuses on the neural processing of visual body stimuli of different weight categories in adolescent and adult AN patients. Thirty-three adolescents aged 12-18 years (15 AN patients, 18 control participants) and 36 adult women (19 AN patients, 17 control participants) underwent functional magnetic resonance imaging (fMRI) while performing a perceptive and an affective body image task involving photographic stimuli of women belonging to different BMI categories. Differential effects on activation, depending on the BMI of the women shown in the pictures, were found in frontal brain regions, the thalamus, the caudate and the fusiform gyrus. Group effects differentiating between AN patients and control participants were seen mainly in the caudate and insula. No significant developmental effect was seen. During a perceptive task, diminished activation of regions involved in perceptive and evaluative functions as well as emotional reasoning was seen in AN. During an affective task there was a tendency towards activation differences reflecting reduced ability of size estimation and impaired integration of visual and body perception with emotions.

Neural processing of food and emotional stimuli in adolescent and adult anorexia nervosa patients.

BACKGROUND: A constant preoccupation with food and restrictive eating are main symptoms of anorexia nervosa (AN). Imaging studies revealed aberrant neural activation patterns in brain regions processing hedonic and reward reactions as well as-potentially aversive-emotions. An imbalance between so called "bottom-up" and "top-down" control areas is discussed. The present study is focusing on neural processing of disease-specific food stimuli and emotional stimuli and its developmental course in adolescent and adult AN patients and could offer new insight into differential mechanisms underlying shorter or more chronic disease. METHODS: 33 adolescents aged 12-18 years (15 AN patients, 18 control participants) and 32 adult women (16 AN patients, 16 control participants) underwent functional magnetic resonance imaging (fMRI, 3T high-field scanner) while watching pictures of high and low-calorie food and affective stimuli. Afterwards, they rated subjective valence of each picture. FMRI data analysis was performed using a region of interest based approach. RESULTS: Pictures of high-calorie food items were rated more negatively by AN patients. Differences in activation between patients and controls were found in "bottom up" and "top down" control areas for food stimuli and in several emotion processing regions for affective stimuli which were more pronounced in adolescents than in adults. CONCLUSION: A differential pattern was seen for food stimuli compared to generally emotion eliciting stimuli. Adolescents with AN show reduced processing of affective stimuli and enhanced activation of regions involved in "bottom up" reward processing and "top down" control as well as the insula with regard to food stimuli with a focus on brain regions which underlie changes during adolescent development. In adults less clear and less specific activation differences were present, pointing towards a high impact that regions undergoing maturation might have on AN symptoms.

The Brain Network of Itch Distraction.

is missing (Commentary).

Brain mechanisms of abnormal temperature perception in cold allodynia induced by ciguatoxin.

OBJECTIVE: Cold allodynia occurs as a major symptom of neuropathic pain states. It remains poorly treated with current analgesics. Ciguatoxins (CTXs), ichthyosarcotoxins that cause ciguatera, produce a large peripheral sensitization to dynamic cold stimuli in Aδ-fibers by activating sodium channels without producing heat or mechanical allodynia. We used CTXs as a surrogate model of cold allodynia to dissect the framework of cold allodynia-activated central pain pathways. METHODS: Reversible cold allodynia was induced in healthy male volunteers by shallow intracutaneous injection of low millimolar concentrations of CTX into the dorsal skin of the forefoot. Cold and warm stimuli were delivered to the treated and the control site using a Peltier-driven thermotest device. Functional magnetic resonance imaging (fMRI) scans were acquired with a 3T MRI scanner using a blood oxygen level-dependent (BOLD) protocol. RESULTS: The CTX-induced substantial peripheral sensitization to cooling stimuli in Aδ-fibers is particularly retrieved in BOLD changes due to dynamic temperature changes and less during constant cooling. Brain areas that responded during cold allodynia were almost always located bilaterally and appeared in the medial insula, medial cingulate cortex, secondary somatosensory cortex, frontal areas, and cerebellum. Whereas these areas also produced changes in BOLD signal during the dynamic warming stimulus on the control site, they remained silent during the warming stimuli on the injected site. INTERPRETATION: We describe the defining feature of the cold allodynia pain percept in the human brain and illustrate why ciguatera sufferers often report a perceptual temperature reversal. ANN NEUROL 2017;81:104-116.

Improved quantification of important beer quality parameters based on nonlinear calibration methods applied to FT-MIR spectra.

During the production process of beer, it is of utmost importance to guarantee a high consistency of the beer quality. For instance, the bitterness is an essential quality parameter which has to be controlled within the specifications at the beginning of the production process in the unfermented beer (wort) as well as in final products such as beer and beer mix beverages. Nowadays, analytical techniques for quality control in beer production are mainly based on manual supervision, i.e., samples are taken from the process and analyzed in the laboratory. This typically requires significant lab technicians efforts for only a small fraction of samples to be analyzed, which leads to significant costs for beer breweries and companies. Fourier transform mid-infrared (FT-MIR) spectroscopy was used in combination with nonlinear multivariate calibration techniques to overcome (i) the time consuming off-line analyses in beer production and (ii) already known limitations of standard linear chemometric methods, like partial least squares (PLS), for important quality parameters Speers et al. (J I Brewing. 2003;109(3):229-235), Zhang et al. (J I Brewing. 2012;118(4):361-367) such as bitterness, citric acid, total acids, free amino nitrogen, final attenuation, or foam stability. The calibration models are established with enhanced nonlinear techniques based (i) on a new piece-wise linear version of PLS by employing fuzzy rules for local partitioning the latent variable space and (ii) on extensions of support vector regression variants (𝜖-PLSSVR and ν-PLSSVR), for overcoming high computation times in high-dimensional problems and time-intensive and inappropriate settings of the kernel parameters. Furthermore, we introduce a new model selection scheme based on bagged ensembles in order to improve robustness and thus predictive quality of the final models. The approaches are tested on real-world calibration data sets for wort and beer mix beverages, and successfully compared to linear methods, showing a clear out-performance in most cases and being able to meet the model quality requirements defined by the experts at the beer company. Figure Workflow for calibration of non-Linear model ensembles from FT-MIR spectra in beer production .

Cerebral Networks Linked to Itch-related Sensations Induced by Histamine and Capsaicin.

This functional magnetic resonance imaging (fMRI) study explored the central nervous processing of itch induced by histamine and capsaicin, delivered via inactivated cowhage spicules, and the influence of low-dose naltrexone. Scratch bouts were delivered at regular intervals after spicule insertion in order temporarily to suppress the itch. At the end of each trial the subjects rated their itch and scratch-related sensations. Stepwise multiple regression analyses were employed for identifying cerebral networks contributing to the intensities of "itching", "burning", "stinging", "pricking" and "itch relief by scratching". In the capsaicin experiments a network for "burning" was identified, which included the posterior insula, caudate and putamen. In the histamine experiments networks for "itching" and "itch relief" were found, which included operculum, hippocampus and amygdala. Naltrexone generally reduced fMRI activation and the correlations between fMRI signal and ratings. Furthermore, scratching was significantly less pleasant under naltrexone.

Gender differences in itch and pain-related sensations provoked by histamine, cowhage and capsaicin.

Cowhage, capsaicin and histamine, all applied via spicules, were used to induce itch and pain-related sensations in 15 male and 15 female subjects. Sensory qualities were assessed by questionnaire; intensities and time courses of the "itching" and "burning" sensation were measured alternately, but continuously on a VAS. In addition, axon reflexes were assessed. Only histamine and capsaicin produced a clear axon reflex flare (histamine > capsaicin, male = female). The 3 types of spicules caused mixed burning and itching sensations with different time courses. In the beginning burning prevailed, in the following minutes histamine induced mostly itching, capsaicin predominantly burning, cowhage both sensory components equally. Female subjects experienced more pain-related sensations (questionnaire), and their ratings leaned more toward burning than those of males. These findings indicate that the mixed itching and burning sensations are differentially processed by both genders. No indications were found for gender specific differential processing in the primary afferents as reflected by nearly identical flare responses.

Separating fusion from rivalry.

Visual fusion is the process in which differing but compatible binocular information is transformed into a unified percept. Even though this is at the basis of binocular vision, the underlying neural processes are, as yet, poorly understood. In our study we therefore aimed to investigate neural correlates of visual fusion. To this end, we presented binocularly compatible, fusible (BF), and incompatible, rivaling (BR) stimuli, as well as an intermediate stimulus type containing both binocularly fusible and monocular, incompatible elements (BFR). Comparing BFR stimuli with BF and BR stimuli, respectively, we were able to disentangle brain responses associated with either visual fusion or rivalry. By means of functional magnetic resonance imaging, we measured brain responses to these stimulus classes in the visual cortex, and investigated them in detail at various retinal eccentricities. Compared with BF stimuli, the response to BFR stimuli was elevated in visual cortical areas V1 and V2, but not in V3 and V4 - implying that the response to monocular stimulus features decreased from V1 to V4. Compared to BR stimuli, the response to BFR stimuli decreased with increasing eccentricity, specifically within V3 and V4. Taken together, it seems that although the processing of exclusively monocular information decreases from V1 to V4, the processing of binocularly fused information increases from earlier to later visual areas. Our findings suggest the presence of an inhibitory neural mechanism which, depending on the presence of fusion, acts differently on the processing of monocular information.

Effect of low-level laser therapy on blood flow and oxygen- hemoglobin saturation of the foot skin in healthy subjects: a pilot study.

BACKGROUND AND AIMS: This study on healthy test subjects intends to show whether one-off Low-Level Laser Therapy (LLLT) has an instant effect on the perfusion or the oxygenation of the skin tissue. These possible instant effects may have an influence on the accelerated wound healing which is often observed after application of LLLT, in addition to the usual postulated effects of LLLT which occur with a time delay normally. STUDY DESIGN/MATERIALS AND METHODS: The study was carried out double-blind and placebo-controlled in two batches of testing. The test subjects received one-off LLLT on a defined area of the arch of the foot. Simultaneously a placebo treatment was carried out on the corresponding contralateral area. In the first batch of tests, the blood flow was measured immediately before and after treatment using thermography and LDI. In the second batch of tests, the blood flow and the oxygen saturation were determined immediately before and after the treatment using an O2C device. RESULTS: No evidence that the LLLT has a significant instant effect on the circulation or the oxygen saturation could be found. CONCLUSION: No immediate effect of an LLLT on the perfusion or oxygenation situation is to be expected with physiologically normal starting conditions. An additional investigation should be carried out in which either the radiation dose is varied or the starting conditions are pathological (e.g. chronic wounds) in order to rule out immediate effects on circulation or oxygen saturation as the cause of the improved wound healing which is often observed.

CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study.

BACKGROUND: It has recently been shown that electrical stimulation of sensory afferents within the outer auditory canal may facilitate a transcutaneous form of central nervous system stimulation. Functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) effects in limbic and temporal structures have been detected in two independent studies. In the present study, we investigated BOLD fMRI effects in response to transcutaneous electrical stimulation of two different zones in the left outer auditory canal. It is hypothesized that different central nervous system (CNS) activation patterns might help to localize and specifically stimulate auricular cutaneous vagal afferents. METHODOLOGY: 16 healthy subjects aged between 20 and 37 years were divided into two groups. 8 subjects were stimulated in the anterior wall, the other 8 persons received transcutaneous vagus nervous stimulation (tVNS) at the posterior side of their left outer auditory canal. For sham control, both groups were also stimulated in an alternating manner on their corresponding ear lobe, which is generally known to be free of cutaneous vagal innervation. Functional MR data from the cortex and brain stem level were collected and a group analysis was performed. RESULTS: In most cortical areas, BOLD changes were in the opposite direction when comparing anterior vs. posterior stimulation of the left auditory canal. The only exception was in the insular cortex, where both stimulation types evoked positive BOLD changes. Prominent decreases of the BOLD signals were detected in the parahippocampal gyrus, posterior cingulate cortex and right thalamus (pulvinar) following anterior stimulation. In subcortical areas at brain stem level, a stronger BOLD decrease as compared with sham stimulation was found in the locus coeruleus and the solitary tract only during stimulation of the anterior part of the auditory canal. CONCLUSIONS: The results of the study are in line with previous fMRI studies showing robust BOLD signal decreases in limbic structures and the brain stem during electrical stimulation of the left anterior auditory canal. BOLD signal decreases in the area of the nuclei of the vagus nerve may indicate an effective stimulation of vagal afferences. In contrast, stimulation at the posterior wall seems to lead to unspecific changes of the BOLD signal within the solitary tract, which is a key relay station of vagal neurotransmission. The results of the study show promise for a specific novel method of cranial nerve stimulation and provide a basis for further developments and applications of non-invasive transcutaneous vagus stimulation in psychiatric patients.

Central projection of pain arising from delayed onset muscle soreness (DOMS) in human subjects.

Delayed onset muscle soreness (DOMS) is a subacute pain state arising 24-48 hours after a bout of unaccustomed eccentric muscle contractions. Functional magnetic resonance imaging (fMRI) was used to examine the patterns of cortical activation arising during DOMS-related pain in the quadriceps muscle of healthy volunteers evoked by either voluntary contraction or physical stimulation. The painful movement or physical stimulation of the DOMS-affected thigh disclosed widespread activation in the primary somatosensory and motor (S1, M1) cortices, stretching far beyond the corresponding areas somatotopically related to contraction or physical stimulation of the thigh; activation also included a large area within the cingulate cortex encompassing posteroanterior regions and the cingulate motor area. Pain-related activations were also found in premotor (M2) areas, bilateral in the insular cortex and the thalamic nuclei. In contrast, movement of a DOMS-affected limb led also to activation in the ipsilateral anterior cerebellum, while DOMS-related pain evoked by physical stimulation devoid of limb movement did not.

Differences and similarities on neuronal activities of people being happily and unhappily in love: a functional magnetic resonance imaging study.

BACKGROUND: Brain activity was studied in grief following frustrated love compared to romantic love, and it was hypothesized that unhappy lovers compared to happy lovers would have decreased brain activity in regions specific to emotional and reward circuits, such as frontal brain areas, anterior cingulate cortex (ACC), bilateral insula or posterior cingulate cortex (PCC). METHODS: Twelve volunteers intensely in love and 12 volunteers recently separated from their romantic partners were scanned performing 3 runs of functional magnetic resonance imaging acquisition. Subjects viewed partner pictures versus erotic pictures during the first run of the scanning process, autobiographical pictures versus neutral pictures during the second and autobiographical texts versus neutral texts during the third run. The Passionate Love Scale (PLS) and the Beck Depression Inventory (BDI) were additionally recorded. RESULTS: Decreased brain activity in unhappy lovers compared to happy lovers occurred in frontal areas, ACC and PCC and bilateral insula. Unhappy lovers also revealed clinical depressive symptoms in the BDI. CONCLUSION: Unhappy lovers compared to happy lovers exhibited clinical depressive symptoms and reduced blood oxygen level dependency changes in a brain network which has been described as being involved in major depression. This might be a cue for the close relationship between grief and depression.

Bilateral brainstem activation by thermal stimulation of the face in healthy volunteers.

Contralateral sensory deficits in Wallenberg's lateral medullary syndrome suggest bilateral processing of trigeminal afferent input in the human brainstem. On the basis of experiments in rodents and clinical data, the present study addresses the hypothesis of bilateral projection of facial nociceptive input onto the spinal trigeminal nucleus (STN) in healthy humans. Nociceptive processing in the brainstem was investigated by functional magnetic resonance imaging (fMRI) in 18 healthy volunteers. Heat stimuli (39, 43, 46 degrees C) were applied by a Peltier type thermode to the left forehead (V1) and the left mental region (V3). Analyses of fMRI data were performed with SPM2 and BrainVoyager software. A region-of-interest approach analyzed local activation in the STN. Heat evoked significant bilateral activation in the STN (P < 0.01, T > 2.8). Contralateral activation was more frequent during stimulation of the V1 than of the V3 region. Whereas activation by V1 stimulation was located in caudal STN, V3 stimulation induced activity in more rostral parts of the STN. Functional MRI data in humans suggest bilateral brainstem activation when heat is applied to the face. Contralateral brainstem activity is more pronounced by stimulation of V1 as compared to V3. The results indicate similar nociceptive processing in humans and rodents and may explain clinical findings.

Cerebral representation of the relief of itch by scratching.

Cerebral processing of itch-scratching cycles was studied with functional magnetic resonance imaging (fMRI) in healthy volunteers. The back of the hand was repetitively scratched in the absence and presence of itch induced by histamine applied close to the scratched site. Blood-oxygenation-level-dependent (BOLD) effects were assessed in predefined cortical and subcortical brain regions of interest. Scratch-related activation clusters were found in cortical and subcortical areas which had been associated before with pain processing, namely S1, S2, parietal association cortex, motor and premotor cortex, anterior and posterior insula, anterior and medial cingulum, lateral and medial frontal areas, ipsilateral cerebellum and contralateral putamen. Cortical activations were generally stronger in the contralateral hemisphere. General linear model (GLM) analysis and GLM contrast analysis revealed stronger activations during itch-related trials in the motor and premotor cortex, in lateral frontal fields of both sides, and in a left medial frontal cluster. Subcortically, stronger activation during itch-related scratching trials was found in the contralateral putamen and in the ipsilateral cerebellum. Time course analysis showed significantly higher BOLD levels during the last 3-6 s before the start of scratching when the itch intensity was strongest. This effect was found in frontal areas, in the putamen, and in the somatosensory projection areas. During the scratching, no significant differences were found between itch and control conditions with the exception of the putamen, which showed stronger activations during itch-related scratch bouts. We interpret these itch-related activations anticipating the scratching as possible cerebral correlates of the itch processing and the craving for scratch.

Impact of scratching on itch and sympathetic reflexes induced by cowhage (Mucuna pruriens) and histamine.

Cowhage and histamine, both applied via spicules, were used to induce itch. The quality and intensity of the sensations, axon reflex flare, sympathetic skin vasoconstrictions and the interference of scratching with itch processing were studied. Axon reflex flare reactions were measured by laser Doppler imaging and reflex vasoconstrictions in the finger were recorded by laser Doppler flowmetry. Magnitude of itch sensations was assessed on an electronic visual analogue scale while the skin was intermittently scratched proximal to the application site. The quality of itch was assessed with a questionnaire. Only histamine produced an axon reflex flare. Histamine itch increased faster, but recovered more slowly after scratching, by which it was more effectively suppressed. Cowhage induced a sharper itch sensation and stronger vasoconstrictor reflexes. These findings support the notion that both agents activate different pathways. The differences in sympathetic reflex induction and in the modulation by scratching indicate differential central nervous processing.

Experimental tooth pain elevates substance P and matrix metalloproteinase-8 levels in human gingival crevice fluid.

OBJECTIVE: Tooth pain can induce a neurogenic inflammatory reaction in gingiva in association with local elevations of matrix metalloproteinase (MMP)-8, which is considered the major tissue destructive protease in gingival crevice fluid (GCF). The pro-inflammatory neuropeptides released by sensory nerves coordinate the activities of the immuno-effector cells and may influence the secretion of MMP-8. With this background, we studied whether experimental tooth pain can trigger changes in GCF levels of the neuropeptide substance P (SP) and MMP-8. MATERIAL AND METHODS: The GCF SP levels of stimulated and non-stimulated teeth were analyzed for SP using a competitive enzyme immunoassay (EIA). The GCF MMP-8 levels were determined by quantitative immunofluorometric assay (IFMA). RESULTS: Painful stimulation of the upper central incisor caused significant elevations in GCF SP and MMP-8 levels of the stimulated tooth. At the same time, the GCF SP and MMP-8 levels of non-stimulated control teeth were unchanged. CONCLUSIONS: These data indicate that experimental tooth pain can induce local elevations of SP and MMP-8 levels in GCF simultaneously. This supports the possibility of a local neurogenic spread of inflammatory reactions from intrapulpal to surrounding periodontal tissues.

The influence of simultaneous ratings on cortical BOLD effects during painful and non-painful stimulation.

This fMRI study investigates the influence of a rating procedure on BOLD signals in common pain-activated cortical brain regions. Painful and non-painful mechanical impact stimuli were applied to the left hand of healthy volunteers. Subjects performed ratings of the perceived intensity during every second stimulation period by operating a visual analogue scale with the right hand. During every other stimulus period the subjects rested passively. Pain and touch stimuli were found to activate the same cortical areas previously defined as the "cortical pain matrix". General Linear Models were used to calculate contrasts between cortical activations during the "rating" and "non-rating" paradigm. In most brain regions activation following pain and touch was stronger during "rating" compared to "non-rating" conditions. Only the responses in the S1 projection field of the stimulated hand following pain were not influenced by the rating procedure. Furthermore, activations in the right and left posterior insular cortex and in the left superior frontal gyrus showed an opposite pattern, namely a stronger BOLD signal during "non-rating". We concluded: (1) Cortical areas regularly activated by painful stimuli may also be activated by touch stimulation. (2) Enhancement of the BOLD contrast by a rating procedure is probably an effect of closer stimulus evaluation and attention focussing. (3) In contrast to most other cortical regions, the posterior insular cortex, which is crucial for the integration of interoceptive afferent input, shows stronger responses in the absence of ratings, which points to a unique role of this region in the processing of somato-visceral information.

Itch induced by a novel method leads to limbic deactivations a functional MRI study.

Functional brain imaging studies on itch usually use histamine as a stimulus and, in consequence, have to cope with the highly variable time course of this particular itch sensation. In this study, we describe a novel method of histamine application. To provoke itch, a mixture of histamine and codeine was applied through intradermally positioned microdialysis fiber. The itch was terminated by lidocaine application through the same fiber. During one fMRI session, this procedure was repeated four times in four different microdialysis fibers, including one placebo control. Itch ratings of the subjects were correlated with blood-oxygen-level-dependent (BOLD) effects. In a subsequent experiment performed in the same fMRI session, heat pain was provoked in the right forearm with a Peltier thermode. During both experiments, activation clusters were found in brain areas that have been described previously to be frequently activated in response to painful stimuli. This includes prefrontal areas, supplementary motor areas (SMA), premotor cortex, anterior insula, anterior midcingulate cortex, S1, S2, thalamus, basal ganglia, and cerebellum. In general, itch stimulation entailed more activation clusters, in particular on the contralateral brain side. Only on itch, but not on heat pain, negative BOLD signals were found in the subgenual anterior cingulate cortex and the amygdala. The latter results may be associated with the itch induced urge to scratch. Amygdala deactivation may be related to the preparation of scratching by aiming to dissolve the otherwise aversive effects of the noxious scratch stimuli. These negative BOLD effects may also be attributed to the stressful character of itch stimulation.

Brain activation during input from mechanoinsensitive versus polymodal C-nociceptors.

C-nociceptors mediating cutaneous pain in humans can be distinguished in mechano-heat-responsive units (CMH) and mechano-insensitive units (CMi). However, if sensitized in damaged tissue, CMi play an important role in inflammatory pain. CMi differ from CMH by higher electrical thresholds and by mediating the axon reflex. Using these properties, we established two stimulation paradigms: (1) transcutaneous stimulation (TCS) of low current density below the CMi threshold and (2) intracutaneous stimulation (ICS) of high current density that excites CMi. This was proven by the quantification of the axon-reflex flare. Applying these stimulation paradigms during functional magnetic resonance imaging, we investigated whether nociceptor stimulation that recruits CMi leads to different cerebral activation than stimuli that do not recruit CMi. Brain activation by CMi was inferred by subtraction. Both stimuli recruited multiple afferents other than CMi, and we expected a common network of regions involved in different aspects of pain perception and motor nocifensive reactions in both stimuli. ICS that additionally recruited CMi should activate regions with low acuity that are involved in pain memory and emotional attribution. Besides a common network of pain in both stimuli, TCS activated the supplementary motor area, motor thalamic nuclei, the ipsilateral insula, and the medial cingulate cortex. These regions contribute to a pain processing loop that coordinates the nocifensive motor reaction. CMi nociceptor activation did not cause relevant activation in this loop and does not seem to play a role in withdrawal. The posterior cingulate cortex was selectively activated by ICS and is apparently important for the processing of inflammatory pain.