Correlation between PainDETECT Questionnaire and Quantitative Sensory Testing for the Detection of Neuropathic Pain in Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that is often severely painful due to nociceptive mechanisms (i.e., stimulation of cutaneous nociceptors). However, patient-reported pain character suggests that neuropathy may also drive HS pain in a subset of patients. Quantitative sensory testing (QST) can help identify neuropathic pain by testing for heightened and paradoxical pain responses in patients, but it is less feasible for routine clinical use compared with brief questionnaires. We therefore tested the suitability of a standardized neuropathic questionnaire (PainDETECT; PD-Q) for use as a surrogate clinical measure by directly comparing it with QST-identified neuropathic pain in HS. METHODS: This observational, cross-sectional study included 22 adults with painful HS lesions who completed the PD-Q and underwent QST. A receiver operating characteristic curve was generated and Cohen's Kappa, sensitivity, and specificity were examined at three scoring thresholds. RESULTS: Of the 22 participants, 14 (64%) exhibited dynamic mechanical allodynia and/or paradoxical thermal sensations in QST, which are characteristically found in neuropathic pain. According to the PD-Q, 8 participants (36%) were unlikely, 8 (36%) were possible, and 6 (27%) were likely to have neuropathic pain. A PD-Q Score indicating possible or likely neuropathic pain (i.e., ≥13) demonstrated 82% agreement with QST-determined neuropathic pain (Cohen's Kappa = 0.61 [p = 0.004]; sensitivity = 86%; specificity = 75%). CONCLUSION: The PD-Q demonstrates moderate agreement with QST in screening for neuropathic pain in HS and may be a helpful clinical tool.

Quantitative Sensory Testing to Characterize Sensory Changes in Hidradenitis Suppurativa Skin Lesions.

Importance: Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. Objective: To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. Design, Setting, and Participants: This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Exposure: Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Main Outcomes and Measures: Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. Results: This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). Conclusions and Relevance: The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.

Characterization of visual processing in temporomandibular disorders using functional magnetic resonance imaging.

BACKGROUND AND PURPOSE: Many patients with chronic pain report hypersensitivity not only to noxious stimuli, but also to other modalities including innocuous touch, sound, and light, possibly due to differences in the processing of these stimuli. The goal of this study was to characterize functional connectivity (FC) differences between subjects with temporomandibular disorders (TMD) and pain-free controls during a visual functional magnetic resonance imaging (fMRI) task that included an unpleasant, strobing visual stimulus. We hypothesized the TMD cohort would exhibit maladaptations in brain networks consistent with multisensory hypersensitivities observed in TMD patients. METHODS: This pilot study included 16 subjects, 10 with TMD and 6 pain-free controls. Clinical pain was characterized using self-reported questionnaires. Visual task-based fMRI data were collected on a 3T MR scanner and used to determine differences in FC via group independent component analysis. RESULTS: Compared to controls, subjects with TMD exhibited abnormally increased FC between the default mode network and lateral prefrontal areas involved in attention and executive function, and impaired FC between the frontoparietal network and higher order visual processing areas. CONCLUSIONS: The results indicate maladaptation of brain functional networks, likely due to deficits in multisensory integration, default mode network function, and visual attention and engendered by chronic pain mechanisms.

Topology of pain networks in patients with temporomandibular disorder and pain-free controls with and without concurrent experimental pain: A pilot study.

Temporomandibular disorders (TMD) involve chronic pain in the masticatory muscles and jaw joints, but the mechanisms underlying the pain are heterogenous and vary across individuals. In some cases, structural, functional, and metabolic changes in the brain may underlie the condition. In the present study, we evaluated the functional connectivity between 86 regions of interest (ROIs), which were chosen based on previously reported neuroimaging studies of pain and differences in brain morphology identified in an initial surface-based morphometry analysis. Our main objectives were to investigate the topology of the network formed by these ROIs and how it differs between individuals with TMD and chronic pain (n = 16) and pain-free control participants (n = 12). In addition to a true resting state functional connectivity scan, we also measured functional connectivity during a 6-min application of a noxious cuff stimulus applied to the left leg. Our principal finding is individuals with TMD exhibit more suprathreshold correlations (higher nodal degree) among all ROIs but fewer "hub" nodes (i.e., decreased betweenness centrality) across conditions and across all pain pathways. These results suggest is this pain-related network of nodes may be "over-wired" in individuals with TMD and chronic pain compared to controls, both at rest and during experimental pain.

Are Outcomes of Temporomandibular Joint Arthroscopy Influenced by Central Sensitization?

PURPOSE: A proportion of subjects with internal derangements of the temporomandibular joint (TMJ) may have a central sensitization disorder that may affect pain perception after surgery. This study aims to estimate the association between fibromyalgianess (FMness) score, a summed score of the Widespread Pain Index (WPI) and Symptom Severity Sore (SSS), and outcomes following TMJ arthroscopy. METHODS: A retrospective cohort study including individuals who received arthroscopy for TMJ internal derangement at Michigan Medicine between 2011 and 2020 was performed. A predictor variable, FMness score, was assigned via the sum of WPI and SSS. Univariate and bivariate analyses were performed. Linear-mixed effects models were used to analyze 6 different outcomes, each in their own model: pain, jaw functional limitation scale (JFLS), JFLS-mobility domain, pain-related disability, comfortable maximum interincisal opening, and active maximum interincisal opening. Covariance structure was selected based on null model fit separately for each outcome. RESULTS: Thirty-one subjects were included in the study sample. Twenty-eight subjects were female. Average age was 45.9 years. Bivariate analysis demonstrated that subject's FMness score was not correlated with pain (b = 0.03 [-0.10, 0.17] P = .59) or JFLS score (b = 1.00 [-.80, 2.81] P = .27). However, subject's FMness score was significant for predicting JFLS-mobility domain score (b = .61, [0.05, 1.18] P = .04). CONCLUSION: A greater extent of central sensitization was associated with lower comfortable mouth opening after surgery, greater limitations in opening wide enough to eat various foods (higher JFLS-mobility scores), and higher pain-related disability. Future studies with larger sample sizes and reconstructive TMJ operations such as total TMJ arthroplasty may help clarify the impact of SSS and WPI scores on outcomes of TMJ surgery.

Prediction of Differential Pharmacologic Response in Chronic Pain Using Functional Neuroimaging Biomarkers and a Support Vector Machine Algorithm: An Exploratory Study.

OBJECTIVE: There is increasing demand for prediction of chronic pain treatment outcomes using machine-learning models, in order to improve suboptimal pain management. In this exploratory study, we used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM. METHODS: FM patients participated in 2 separate double-blind, placebo-controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin. RESULTS: Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies. CONCLUSION: Our findings indicate that brain functional connectivity patterns used in a machine-learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.

Stimulation of zona incerta selectively modulates pain in humans.

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.

Impact of Fibromyalgia Phenotype in Temporomandibular Disorders.

BACKGROUND: Mounting evidence suggests that central nervous system amplification, similar to that seen in fibromyalgia (FM), contributes to the pain experience in a subset of patients with temporomandibular disorders (TMD). METHODS: In this prospective observational study, patients with TMD completed the 2011 FM survey questionnaire, a surrogate measure of "centralized" pain. The influence of centralized pain on TMD pain, dysfunction, and disability was assessed dichotomously by determining the incidence of FM-positive cases in the sample and by using FM survey scores as a continuous measure of "fibromyalgia-ness" ("FM-ness"). RESULTS: The patients meeting criteria for FM diagnosis (17 of 89) had significantly more disease burden on numerous measures. FM-ness was positively associated with pain at rest, negative mood, tenderness to palpation, perceived jaw functional limitation, and pain-related disability, and it was negatively associated with comfortable pain-free jaw opening. The impact of FM-ness on perceived jaw functional limitation and disability was mediated by levels of spontaneous, ongoing pain in the orofacial region. Importantly, this pattern of findings was still present even in those not meeting the criteria for FM diagnosis. CONCLUSION: Together, these results imply that higher FM-ness increases TMD patient burden by amplifying spontaneous pain and further hampering painless jaw function, even in patients who do not meet criteria for FM diagnosis. These results are highly relevant for the clinical management of TMD, as they imply that targeting the central nervous system in the treatment of patients with TMD with evidence of pain centralization may help ameliorate both pain and jaw dysfunction.

Applications of sensory and physiological measurement in oral-facial dental pain.

Dentists regularly employ a variety of self-report and sensory techniques to aid in the diagnosis and treatment of tooth-related disease. Many of these techniques leverage principles borrowed from psychophysics, the quantitative measurement of the relationship between stimuli and evoked sensations, which falls under the larger umbrella of quantitative sensory testing (QST). However, most clinicians fail to meet the bar for what could be considered quantitative sensory testing, and instead focus on qualitative and dichotomous "yes/no" aspects of sensory experience. With our current subjective measurements for pain assessments, diagnosis and treatment of dental pain in young children and individuals (any age) with severe cognitive impairment rely extensively on third-party observations. Consequently, the limitation of inadequate pain diagnosis can lead to poor pain management. In this review, it discusses mechanisms that underlie acute and chronic dental pain. It details the measurement of somatosensory responses and pulpal blood flow as objective measures of tooth health and pain. It proposes that bridging these varied methodologies will significantly improve diagnosis and treatment of orofacial pain and pathology. It concludes that improving the precision of sensory measurements could yield important improvements in diagnostic challenges in pulpal pathology for noncommunicative and cognitively impaired individuals.

Sensory sensitivity and symptom severity represent unique dimensions of chronic pain: a MAPP Research Network study.

Chronic overlapping pain conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This "centralized pain" phenotype has been described using a large and diverse set of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here, we used 3 cohorts, including patients with urologic chronic pelvic pain syndrome, a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified 2 general factors in all 3 cohorts, one characterized by a broad increased sensitivity to internal somatic sensations,environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity, and one characterized by constitutional symptoms-Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the urologic chronic pelvic pain syndrome cohort found the same 2-factor structure at month 6 and 1 year, suggesting that the 2-factor structure is reproducible over time. In secondary analyses, we found that Generalized Sensory Sensitivity particularly is associated with the presence of comorbid COPCs, whereas SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent an important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.

Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation.

Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. The present cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls (HC; n = 14) and FM patients (n = 15), and to probe for differences that could explain the pain-facilitative CPM that was observed in our patient sample. Voxel-based morphometry identified a cluster encompassing the periaqueductal gray (PAG) that contained significantly less gray matter volume in FM patients. Higher resting connectivity between this cluster and cortical pain processing regions was associated with more efficient inhibitory CPM in both groups, whereas PAG connectivity with the dorsal pons was associated with greater CPM inhibition only in HC. Greater PAG connectivity to the caudal pons/rostral medulla, which was pain-inhibitory in HC, was associated with pain facilitation in FM patients. PERSPECTIVE: These findings indicate that variation in the strength of the PAG resting functional connectivity can explain some of the normal variability in CPM. In addition, pain-facilitative CPM observed in FM patients likely involves attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system.

Relationships between brain metabolite levels, functional connectivity, and negative mood in urologic chronic pelvic pain syndrome patients compared to controls: A MAPP research network study.

Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (1H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p = 0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p = 0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.

Somatic Awareness and Tender Points in a Community Sample.

Somatic awareness (SA) refers to heightened sensitivity to a variety of physical sensations and symptoms. Few attempts have been made to dissociate the relationship of SA and affective symptoms with pain outcomes. We used a validated measure of mood and anxiety symptoms that includes questions related to SA to predict the number of tender points found on physical examination in a large cross-sectional community sample (the Midlife in the United States [MIDUS] Biomarker study). General distress, positive affect, and SA, which were all significantly associated with tender point number in bivariate analyses, were used as predictors of the number of tender points in a multivariate negative binomial regression model. In this model a greater number of tender points was associated with higher levels of SA (P = .02) but not general distress (P = .13) or positive affect (P = .50). Follow-up mediation analyses indicated that the relationship between general distress and tender points was partially mediated by levels of SA. Our primary finding was that SA is strongly related to the number of tender points in a community sample. Mechanisms linking SA to the spatial distribution of pain sensitivity should be investigated further. PERSPECTIVE: This article presents an analysis of 3 overlapping psychological constructs and their relationship to widespread pain sensitivity on palpation. The findings suggest that SA is most strongly related to the spatial distribution of pain sensitivity and that further assessing it may improve our understanding of the relationship between psychological factors and pain.

Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study.

Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P < 0.001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.

Discordant Dry Eye Disease (An American Ophthalmological Society Thesis).

PURPOSE: To improve understanding of dry eye disease and highlight a subgroup of patients who have a component of central sensitization and neuropathic pain contributing to their condition. METHODS: Prospective, cross-sectional, IRB-approved study comparing isolated dry eye disease (n=48) to fibromyalgia (positive control; n=23) and healthy (negative control; n=26) individuals with ocular surface examination, corneal confocal microscopy, quantitative sensory testing, and self-reported ocular symptoms and systemic associations. A subset of patients also underwent skin biopsy and/or brain neuroimaging. Dry eye patients were split into concordant (ie, those with dry eyes on examination) and discordant (ie, those with dry eye symptoms but normal examination) subgroups for further analysis. We hypothesized that on the systemic measures included, concordant patients would resemble healthy controls, whereas discordant patients would show evidence of centralized mechanisms similar to fibromyalgia. RESULTS: Schirmer test and Ocular Surface Disease Index (OSDI) scores indicated significant decreases in tear production (Schirmer: healthy, 18.5±8.2 mm; dry, 11.2±5.4 mm; fibromyalgia, 14.4±7.5; P<.001) and increases in self-reported dry eye symptoms (OSDI: healthy, 1.9±3.0; dry, 20.3±17.7; fibromyalgia, 20.3±17.1; P<.001) in the dry eye and fibromyalgia patients, compared to controls. The discordant subgroup had decreased corneal nerve density and decreased visual quality-of-life scores, similar to patients with fibromyalgia. Concordant patients were more similar to healthy controls on these measures. CONCLUSIONS: Individuals with discordant dry eye may have a central pathophysiologic mechanism leading to their eye pain symptoms, which could be an important factor to consider in treatment of chronic idiopathic dry eye.

Coolness both underlies and protects against the painfulness of the thermal grill illusion.

We investigated the contributions of warm and cool signals in generating the thermal grill illusion (TGI), a phenomenon in which interlaced warm and cool bars generate an experience of burning, and under some conditions painful, heat. Each subject underwent 3 runs, 2 of which tested the effects of preadapting subjects to the grill's warm or cool bars (while the interlaced bars were thermally neutral) on the subsequent intensity of the illusion. In a control run, all bars were neutral during the adaptation phase. Thermal visual analogue scale ratings during the warm and cool adaptation periods revealed significant and equivalent adaptation to the 2 temperatures. Adaptation to the grill's cool bars significantly reduced pain and perceived thermal intensity of the TGI, compared to the control condition, while adaptation to the grill's warm bars had little effect. These results suggest that the cool stimulus triggers the pain signals that produce the illusion. The inability of warm adaptation to attenuate the TGI is at odds with theories suggesting that the illusion depends upon a simple addition of warm and cool signals. While the grill's cool bars are necessary for the TGI's painfulness, we also observed that the more often a participant reported feeling coolness or coldness, the less pain he or she experienced from the TGI. These results are consistent with research showing that cool temperatures generate activity in both thermoreceptive-specific, pain-inhibitory neurons and nociceptive dorsal horn neurons.

Is touch gating due to sensory or cognitive interference?

Touch gating, the attenuation of tactile sensitivity in the presence of pain, is a well-documented phenomenon, but its mechanism is unknown. The ability of pain to capture attention suggests that touch gating may be an example of distraction, but the fact that pain raises tactile but not auditory thresholds argues that touch gating is a form of somatosensory interaction. Therefore, the present study was carried out to determine whether touch gating is the result of sensory or cognitive interference. Touch gating was repeatedly produced by delivering a colocalized painful heat stimulus (45°C) during forced-choice measurements of vibration threshold on the palm. Noxious heat significantly increased thresholds compared with those measured at normal skin temperature, and this interference did not decline over the course of an extended series of experiments during which pain intensity significantly habituated. Touch gating was thus related to the constant physical intensity, rather than to the changing subjective intensity, of the noxious stimulus. For comparison, a form of unambiguously cognitive interference, the Stroop effect, was also measured repeatedly; it declined significantly across sessions, unlike touch gating interference. Finally, touch gating was not correlated with measures of participants' distractibility, fear of pain, hypervigilance, or anxiety, variables previously found to influence pain on a cognitive level. Taken together, the results suggest that touch gating is a robust, stimulus-locked form of sensory interaction, rather than a transitory result of distraction or other cognitive processes.

The Drosophila protein kinase LK6 is regulated by ERK and phosphorylates the eukaryotic initiation factor eIF4E in vivo.

In Drosophila cells, phosphorylation of eIF4E (eukaryotic initiation factor 4E) is required for growth and development. In Drosophila melanogaster, LK6 is the closest homologue of mammalian Mnk1 and Mnk2 [MAPK (mitogen-activated protein kinase) signal-integrating kinases 1 and 2 respectively] that phosphorylate mammalian eIF4E. Mnk1 is activated by both mitogen- and stress-activated signalling pathways [ERK (extracellular-signal-regulated kinase) and p38 MAPK], whereas Mnk2 contains a MAPK-binding motif that is selective for ERKs. LK6 possesses a binding motif similar to that in Mnk2. In the present study, we show that LK6 can phosphorylate eIF4E at the physiological site. LK6 activity is increased by the ERK signalling pathway and not by the stress-activated p38 MAPK signalling pathway. Consistent with this, LK6 binds ERK in mammalian cells, and this requires an intact binding motif. LK6 can bind to eIF4G in mammalian cells, and expression of LK6 increases the phosphorylation of the endogenous eIF4E. In Drosophila S2 Schneider cells, LK6 binds the ERK homologue Rolled, but not the p38 MAPK homologue. LK6 phosphorylates Drosophila eIF4E in vitro. The phosphorylation of endogenous eIF4E in Drosophila cells is increased by activation of the ERK pathway but not by arsenite, an activator of p38 MAPK. RNA interference directed against LK6 significantly decreases eIF4E phosphorylation in Drosophila cells. These results show that LK6 binds to ERK and is activated by ERK signalling and it is responsible for phosphorylating eIF4E in Drosophila.