The arousal level of consciousness required for working memory performance: An anaesthesia study.

Regarding the stage of arousal level required for working memory to function properly, limited studies have been conducted on changes in working memory performance when the arousal level of consciousness decreases. This study aimed to experimentally clarify the stages of consciousness necessary for optimal working memory function. In this experiment, the sedation levels were changed step-by-step using anaesthesia, and the performance accuracy during the execution of working memory was assessed using a dual-task paradigm. Participants were required to categorize and remember words in a specific target category. Categorization performance was measured across four different sedative phases: before anaesthesia (baseline), and deep, moderate and light stages of sedation. Short-delay recognition tasks were performed under these four sedative stages, followed by long-delay recognition tasks after participants recovered from sedation. The results of the short-delay recognition task showed that the performance was lowest at the deep stage. The performance of the moderate stage was lower than the baseline. In the long-delay recognition task, the performance under moderate sedation was lower than that under baseline and light sedation. In addition, the performance under light sedation was lower than that under baseline. These results suggest that task performance becomes difficult under half sedation and that transferring information to long-term memory is difficult even under one-quarter sedation.

Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent.

Drug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. However, no method has been established to differentiate between the two. In the development of drug-induced steatohepatitis, reactive oxygen species (ROS) is excessively generated in the liver. It has been reported that ROS can be monitored with electron spin resonance (ESR) and dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) by using nitroxyl radicals, which are known to participate in various in vivo redox reactions. The decay/reduction rate, which is an index for monitoring nitroxyl radicals, has been reported to be increased in tissues with excessive ROS levels other than liver, but decreased in methionine choline deficient (MCD) diet-induced steatohepatitis with excess ROS. Therefore, looking to differentiate between drug-induced hepatic steatosis and steatohepatitis, we examined whether the reduction rate decreases in steatohepatitis other than the MCD-diet induced disease and whether the decrease could be detected by MRI. We used STAM™ mice in which hepatic steatosis and steatohepatitis developed sequentially under diabetic conditions. 3-carbamoyl-PROXYL (CmP), one of the nitroxyl radicals, was injected intravenously during the MRI procedure and the reduction rate was calculated. The reduction rate was significantly higher in early steatohepatitis than in hepatic steatosis and the control. Excess ROS in early steatohepatitis was detected by an immunohistochemical marker for ROS. Therefore, it was indicated that the increase or decrease in the reduction rate in steatohepatitis differs depending on the model, and early steatohepatitis could be noninvasively differentiated from hepatic steatosis using CmP in MRI. Since the change in direction of the reduction rate in steatohepatitis in clinical studies could be predicted by confirming the reduction rate in preclinical studies, the present method, which can be used consistently in clinical and preclinical studies, warrants consideration as a candidate monitoring method for differentiating between early drug-induced steatohepatitis and hepatic steatosis in drug development.

Copeptin is associated with microalbuminuria and renal function in the general Japanese population.

An association between copeptin (precursor molecule of arginine vasopressin) and markers for renal function has been reported, but data on the Japanese population has been limited. In this study, we investigated whether elevated copeptin levels are associated with microalbuminuria and renal dysfunction in the general Japanese population. A total of 1,262 participants (842 female and 420 male) were enrolled. Multiple regression analysis was performed to assess the association of copeptin levels (logarithm) with estimated glomerular filtration rate (eGFR) and the urine albumin-to-creatinine ratio (UACR) after adjusting for age, BMI, and lifestyle variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression methods in which chronic kidney disease (CKD) was the dependent variable. The copeptin levels differed significantly with sex, but were not found to be related to age or the span of time from preceding meal to blood sampling. In female participants, copeptin level was negatively correlated with eGFR (beta = -0.100, p-value = 0.006) and positively correlated with UACR (beta = 0.099, p-value = 0.003). In male participants, a negative correlation (beta = -0.140, p-value = 0.008) was observed for eGFR. In both females and males, those with high copeptin levels had more than double the ORs of CKD (OR = 2.1-2.9) adjusted for CKD-related factors. The present study found elevated copeptin levels to be associated with renal function loss in the Japanese population and microalbuminuria in female. Moreover, it was evident that high copeptin levels are associated with CKD. These results suggest that copeptin could be considered a marker of renal function.

Comparison of 1H-magnetic resonance spectroscopy and blood biochemistry as methods for monitoring non-diffuse hepatic steatosis in a rat model.

No method of monitoring drug-induced hepatic steatosis has been established, which is a concern in drug development. Hepatic steatosis is divided into diffuse and non-diffuse forms according to the pattern of fat deposition. Diffuse hepatic steatosis was reported as evaluable by 1H-magnetic resonance spectroscopy (1H-MRS), which is used as an adjunct to the MRI examination. Blood biomarkers for hepatic steatosis have been also actively investigated. However, there are few reports to conduct 1H-MRS or blood test in human or animal non-diffuse hepatic steatosis with reference to histopathology. Therefore, to investigate whether non-diffuse hepatic steatosis can be monitored by 1H-MRS and/or blood samples, we compared histopathology to 1H-MRS and blood biochemistry in a non-diffuse hepatic steatosis rat model. Non-diffuse hepatic steatosis was induced by feeding rats the methionine choline deficient diet (MCDD) for 15 days. The evaluation sites of 1H-MRS and histopathological examination were three hepatic lobes in each animal. The hepatic fat fraction (HFF) and the hepatic fat area ratio (HFAR) were calculated from 1H-MRS spectra and digital histopathological images, respectively. Blood biochemistry analyses included triglycerides, total cholesterol, alanine aminotransferase, and aspartate aminotransferase. A strong correlation was found between HFFs and HFARs in each hepatic lobe (r = 0.78, p < 0.0001) in rats fed the MCDD. On the other hand, no correlation was found between blood biochemistry values and HFARs. This study showed that 1H-MRS parameters correlated with histopathological changes but blood biochemistry parameters didn't, so that it is suggested that 1H-MRS has the potential to be a monitoring method for non-diffuse hepatic steatosis in rats fed the MCDD. Given that 1H-MRS is commonly used in preclinical and clinical studies, 1H-MRS should be considered a candidate method for monitoring drug-induced hepatic steatosis.

Evaluation of in vivo MRI for detecting midodrine-induced arteritis in rats.

There are no specific and sensitive biomarkers for arteritis, and the occurrence of arteritis in nonclinical toxicological studies of a candidate drug makes development of the drug very difficult. However, we showed in a previous study that the high signal intensity region around the artery on magnetic resonance imaging (MRI) could be a candidate biomarker for detection of arteritis. The present study was conducted to clarify the details of midodrine hydrochloride (MH)-induced arteritis lesions and whether arteritis induced by a mechanism other than the vasodilatory effect, which was evaluated in a previous study, could be detected by MRI. MH is a selective peripherally acting alpha-1 adrenergic receptor agonist, known to induce arteritis due to its vasoconstrictor action, but there is not enough information about MH-induced arteritis. Based on the data obtained under multiple dosing conditions, MH was administered subcutaneously to each rat once daily for 2 days at a dose level of 40 mg/kg/day for MRI assessment. The mesenteric arteries were examined using in vivo MRI at 1 day or 7 days after administration of the final dose and examined histopathologically. On the day after the final dose, high signal intensity region around the artery was observed in animals with minimal perivascular lesions confirmed by histopathology and not observed in an animal without histological changes. On the 7th day after the final dose, no abnormality was observed in histopathological examinations and no high signal intensity regions were observed by MRI in any animal. In conclusion, although further investigation is needed to confirm that high signal intensity is a reliable biomarker for humans, it is suggested that high signal intensity around the artery could be a versatile candidate biomarker with high specificity and sensitivity.

Detection of fenoldopam-induced arteritis in rats using ex vivo / in vivo MRI.

A method capable of identifying drug-induced arteritis is highly desirable because no specific and sensitive biomarkers have yet been defined. Although magnetic resonance imaging (MRI) may be used to find a biomarker candidate for drug-induced arteritis, there are no reports on the evaluation of drug-induced arteritis by MRI. The present study was conducted to clarify whether Fenoldopam mesylate (FM)-induced arteritis in rats can be detected by MRI. FM, a dopamine (D1 receptor) agonist, is known to induce arteritis in rats. FM was administered subcutaneously to each rat once daily for 2 days at a dose of 100 mg/kg/day. These arteries were examined with ex vivo high-resolution MRI or postmortem MRI after euthanasia. These arteries were also examined using in vivo MRI on the day after final dosing or 3 days after administration of the final dose. These arteries were examined histopathologically in all experiments. The ex vivo MRI showed low-intensity areas and a high signal intensity region around the artery, and these findings were considered to be erythrocytes infiltrating the arterial wall and perivascular edema, respectively. In the in vivo study, the MRI of the FM-administered group showed a high signal intensity region around the artery. The perivascular edema observed histopathologically was recognized as a high signal intensity region around the artery on the image of MRI. In conclusion, detection of the high signal intensity region around the artery by MRI is considered to be a useful method for identifying arteritis. Although further investigation is needed to be a reliable biomarker, it is suggested that it could be a biomarker candidate.

Benefits of Laparoscopic Surgery for Bleeding Events in Patients with Implantable Left Ventricular Assist Devices during Antithrombotic Therapy.

Hemorrhagic ovarian cysts (HOCs), a common gynecological disease causing intraabdominal bleeding, can be life threatening in patients undergoing antithrombotic therapy, especially those with left ventricular assist device (LVAD) implantation under strong antithrombotic therapy. We encountered three postLVAD implantation cases with intraabdominal bleeding due to suspected HOCs, which required surgery for hemostasis. Such patients are not only at a higher risk of bleeding but also have restrictions in available surgical incision sites to avoid damaging the LVAD driveline located underneath the abdominal wall. Laparoscopic surgery, which can be performed through minute incisions with flexible site selection, may benefit intraabdominal hemorrhage patients with LVADs.

Sleeping Beauty Transposon Mutagenesis Identifies Genes Driving the Initiation and Metastasis of Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is a malignancy, which arises from the uterine smooth muscle. Because of its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, PTEN knockout, KRAS mutant (PTEN KO/KRAS) mice. ULMS quickly developed in SB PTEN KO/KRAS mice, but not in PTEN KO/KRAS mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of ZFP217, was shown to be elevated in human ULMS compared with paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, whereas overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared with primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, whereas overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy. SIGNIFICANCE: An in vivo Sleeping Beauty transposon mutagenesis screen identifies candidate cancer genes that drive initiation and progression of uterine leiomyosarcoma and may serve as therapeutic targets.

Ubiquitin specific peptidase 32 acts as an oncogene in epithelial ovarian cancer by deubiquitylating farnesyl-diphosphate farnesyltransferase 1.

Epithelial ovarian cancer (EOC) is the seventh most common cancer worldwide and the deadliest gynecological malignancy because of its aggressiveness and high recurrence rate. To discover new therapeutic targets for EOC, we combined public EOC microarray datasets with our previous in vivo shRNA screening dataset. The top-ranked gene ubiquitin specific peptidase 32 (USP32), coding a deubiquitinating enzyme, is a component of the ubiquitin proteasome system. Clinically, USP32 is expressed in primary ovarian cancer, especially in metastatic peritoneal tumors, and negatively impacts the survival outcome. USP32 regulates proliferative and epithelial mesenchymal transition capacities that are associated with EOC progression. Proteomic analysis identified farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as a novel substrate of USP32 that is an enzyme in the mevalonate pathway, essentially associated with cell proliferation and stemness. USP32 and FDFT1 expression was higher in tumor spheres than in adherent cells. Inhibition of USP32, FDFT1, or mevalonate pathway considerably suppressed tumor sphere formation, which was restored by adding squalene, a downstream product of FDFT1. These findings suggested that USP32-FDFT1 axis contributes to EOC progression, and could be novel therapeutic targets for EOC treatment.

Corrigendum: An Evolutionarily Threat-Relevant Odor Strengthens Human Fear Memory.

[This corrects the article DOI: 10.3389/fnins.2020.00255.].

An Evolutionarily Threat-Relevant Odor Strengthens Human Fear Memory.

Olfaction is an evolutionary ancient sense, but it remains unclear to what extent it can influence routine human behavior. We examined whether a threat-relevant predator odor (2-methyl-2-thiazoline) would contextually enhance the formation of human fear memory associations. Participants who learned to associate visual stimuli with electric shock in this predator odor context later showed stronger fear responses to the visual stimuli than participants who learned in an aversiveness-matched control odor context. This effect generalized to testing in another odor context, even after extinction training. Results of a separate experiment indicate that a possible biological mechanism for this effect may be increased cortisol levels in a predator odor context. These results suggest that innate olfactory processes can play an important role in human fear learning. Modulatory influences of odor contexts may partly explain the sometimes maladaptive persistence of human fear memory, e.g., in post-traumatic stress disorders.

The Relationships Between Pain-Catastrophizing Subcomponents and Multiple Pain-Related Outcomes in Japanese Outpatients with Chronic Pain: A Cross-Sectional Study.

OBJECTIVES: The present study sought to examine associations between the pain-catastrophizing subcomponents and multiple pain-related outcomes in Japanese individuals with chronic pain. METHODS: A cross-sectional study design was employed with 213 chronic pain outpatients. The participants were recruited from 3 units at a university hospital and from a pain clinic at a municipal hospital. Study measures were used to assess pain catastrophizing, anxiety, depression, pain interference, and pain severity. RESULTS: Path analysis with multiple pain-related outcomes while controlling for age and gender revealed that the Helplessness subcomponent was associated with anxiety, depression, pain interference, and pain severity. The Magnification subcomponent was related to anxiety and depression, and the Rumination subcomponent accounted for the variance of pain interference. DISCUSSION: The present results suggested the important role of helplessness across cultural backgrounds. It also provides guidance on the application of cognitive behavioral techniques for chronic pain management in Japan.

Frequency of mental disorders among chronic pain patients with or without fibromyalgia in Japan.

AIM: To explore the characteristics of psychiatric morbidity in chronic pain patients who present with or without fibromyalgia. METHODS: Patients are referred to our chronic pain clinic from primary medical institutions, as we are a secondary medical institution. Although some patients have chronic pain, they have no clear organic disorder such as rheumatoid arthritis to account for the pain. Among the 367 new patients seen during the period from March 2009 to August 2012, 347 patients underwent psychiatric evaluation in face-to-face interviews with mental health specialists before a physical examination. RESULTS: Of the 347 patients examined, at least one psychiatric diagnosis was made for 94.6%. The average number of DSM-IV-TR diagnoses was 1.46 in the 330 chronic pain patients who had at least one psychiatric diagnosis. The breakdown of the number of psychodiagnoses was one in 60.8%, two in 27.1%, three in 4.9%, and more than three in 2.3% chronic pain patients with or without fibromyalgia. In fibromyalgia patients, the highest relative frequencies were found for somatoform disorders (76%), followed by dysthymic disorder (17%) and major depressive disorder (15%). In patients without fibromyalgia, the highest relative frequencies were found for somatoform disorders (64%), followed by major depressive disorder (15%) and dysthymic disorder (14%). Psychiatric disorders were found in 96.9% of fibromyalgia patients, and in 93.5% of chronic pain patients without fibromyalgia in Japan (no significant difference using chi-square test). CONCLUSION: Results show that chronic pain patients with or without fibromyalgia are extremely likely to be diagnosed with a psychiatric disorder.

Classification and characterisation of brain network changes in chronic back pain: A multicenter study.

Background. Chronic pain is a common, often disabling condition thought to involve a combination of peripheral and central neurobiological factors. However, the extent and nature of changes in the brain is poorly understood. Methods. We investigated brain network architecture using resting-state fMRI data in chronic back pain patients in the UK and Japan (41 patients, 56 controls), as well as open data from USA. We applied machine learning and deep learning (conditional variational autoencoder architecture) methods to explore classification of patients/controls based on network connectivity. We then studied the network topology of the data, and developed a multislice modularity method to look for consensus evidence of modular reorganisation in chronic back pain. Results. Machine learning and deep learning allowed reliable classification of patients in a third, independent open data set with an accuracy of 63%, with 68% in cross validation of all data. We identified robust evidence of network hub disruption in chronic pain, most consistently with respect to clustering coefficient and betweenness centrality. We found a consensus pattern of modular reorganisation involving extensive, bilateral regions of sensorimotor cortex, and characterised primarily by negative reorganisation - a tendency for sensorimotor cortex nodes to be less inclined to form pairwise modular links with other brain nodes. Furthermore, these regions were found to display increased connectivity with the pregenual anterior cingulate cortex, a region known to be involved in endogenous pain control. In contrast, intraparietal sulcus displayed a propensity towards positive modular reorganisation, suggesting that it might have a role in forming modules associated with the chronic pain state. Conclusion. The results provide evidence of consistent and characteristic brain network changes in chronic pain, characterised primarily by extensive reorganisation of the network architecture of the sensorimotor cortex.

Moderate sedation induced by general anaesthetics disrupts audio-spatial feature binding with sustained P3 components in healthy humans.

Feature binding is considered to be the basis for conscious stimulus perception, while anaesthetics exert a gradient effect on the loss of consciousness (LOC). By integrating these two streams of research, the present study assessed the effect of two anaesthetic agents (i.e. propofol and midazolam) on audio-spatial feature binding. We also recorded the electrophysiological activity of the frontal channels. Using pharmacokinetic simulation, we determined the effect-site concentration (Ce) of the anaesthetics at loss of response to verbal command and eyelash reflex. We subsequently adjusted Ce to 75%, 50% and 25% of Ce-LOC to achieve deep, moderate and light sedation, respectively. Behavioural results showed that moderate sedation selectively disrupted feature binding. The frontal channels showed a P3 component (350-600 ms peristimulus period) following the presentation of audio-spatial stimuli at baseline and under moderate and light sedations. Critically, the late event-related potential component (600-1000 ms) returned to the pre-activated level (0-350 ms) at baseline and under light sedation but was sustained under moderate sedation. We propose that audio-spatial feature binding may require the presence of a P3 component and its subsequent and sufficient decline, as under anaesthetic-induced moderate sedation the P3 component was sustained and featured binding was impaired.

Effects of sedation on subjective perception of pain intensity and autonomic nervous responses to pain: A preliminary study.

Rather than relying solely on subjective pain evaluation using means such as the visual analogue scale (VAS), in clinical situations it is possible to observe evoked responses of the autonomic nervous system (ANS) as objective indicators. Few studies, however, have reported these relationships under finely controlled sedation. 16 healthy male participants were administrated in intravenous sedation with either propofol or midazolam randomly. We initially determined, using pharmacokinetic simulation, the effect-site concentration (Ce) of anaesthetic at loss of response to verbal command and eyelash reflex (Ce-LOR). Then subsequently adjusted Ce to 75%, 50%, and 25% of Ce-LOR to achieve deep, moderate, and light sedation. At awake control state and each sedation level, a noxious electrical stimulation was applied three times at the right forearm, an average pain intensity of the three stimuli was rated on a VAS (0-10). Changes in the peripheral perfusion index measured by oximetry were used as an indicator of ANS response. We analyzed the influence of sedation level on VAS and ANS responses compared to the awake control state. While ANS responses were similar in all conditions, VAS was statistically significantly lower in moderate (5.6±0.6, p <0.005) or deep (5.3±0.6, p <0.001) sedation than in the awake state (7.2±0.4). This study revealed that even when the ANS responds similarly to the same stimulation, subjective pain perception is attenuated by sedation. A cerebral mechanism other than that of the brainstem might determine subjective pain intensity.

Effects of a Hypnotic Induction and an Unpleasantness-Focused Analgesia Suggestion on Pain Catastrophizing to an Experimental Heat Stimulus: A Preliminary Study.

Pain catastrophizing is associated with greater levels of pain. While many studies support the efficacy of hypnosis for pain, the effect on pain catastrophizing remains unclear. The present study evaluated the effect of hypnosis on pain catastrophizing using experimental heat stimulation. Twenty-two pain patients engaged in 3 conditions: baseline (no suggestion), hypnotic induction, and hypnotic induction plus analgesia suggestion. Participants with higher baseline pain showed a significant reduction in rumination following hypnotic induction plus analgesia suggestion and significant reductions in pain due to both the hypnotic induction alone and the hypnotic induction plus analgesia suggestion. The findings suggest that unpleasantness-focused hypnotic analgesia reduces pain via its effect on the rumination component of pain catastrophizing.

Go-sha-jinki-Gan (GJG) ameliorates allodynia in chronic constriction injury-model mice via suppression of TNF-α expression in the spinal cord.

BACKGROUND: Alternative medicine is noted for its clinical effect and minimal invasiveness in the treatment of neuropathic pain. Go-sha-jinki-Gan, a traditional Japanese herbal medicine, has been used for meralgia and numbness in elderly patients. However, the exact mechanism of GJG is unclear. This study aimed to investigate the molecular mechanism of the analgesic effect of GJG in a chronic constriction injury model. RESULTS: GJG significantly reduced allodynia and hyperalgesia from the early phase (von Frey test, p<0.0001; cold-plate test, p<0.0001; hot-plate test p»0.011; two-way repeated measures ANOVA). Immunohistochemistry and Western blot analysis revealed that GJG decreased the expression of Iba1 and tumor necrosis factor-a in the spinal cord. Double staining immunohistochemistry showed that most of the tumor necrosis factor-a was co-expressed in Iba1-positive cells at day 3 post-operation. GJG decreased the phosphorylation of p38 in the ipsilateral dorsal horn. Moreover, intrathecal injection of tumor necrosis factor-a opposed the anti-allodynic effect of GJG in the cold-plate test. CONCLUSIONS: Our data suggest that GJG ameliorates allodynia in chronic constriction injury model mice via suppression of tumor necrosis factor-a expression derived from activated microglia. GJG is a promising drug for the treatment of neuropathic pain induced by neuro-inflammation.

Sensory cognitive abnormalities of pain in autism spectrum disorder: a case-control study.

BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) recently included sensory processing abnormalities in the diagnostic criteria for individuals with autism spectrum disorder (ASD). However, there is no standard method for evaluating sensory abnormalities in individuals with ASD. METHODS: Fifteen individuals with ASD and 15 age- and sex-matched controls were enrolled in this study. We compared objective pain sensitivity by measuring the pain detection threshold and pain tolerance to three different stimuli (electricity, heat, and cold). Then, we compared both subjective pain sensitivity, assessed by the visual analog scale (VAS), and quality of pain, assessed by the short-form McGill Pain Questionnaire (SF-MPQ), to determine the maximum tolerable pain intensities of each stimulation. RESULTS: The pain detection threshold and pain tolerance of individuals with ASD were not impaired, indicating that there were no differences in the somatic perception of pain between groups. However, individuals with ASD were hyposensitive to subjective pain intensity compared to controls (VAS; electrical: p = 0.044, cold: p = 0.011, heat: p = 0.042) and hyposensitive to affective aspects of pain sensitivity (SF-MPQ; electrical: p = 0.0071, cold: p = 0.042). CONCLUSIONS: Our results suggest that the cognitive pathways for pain processing are impaired in ASD and, furthermore, that our methodology can be used to assess pain sensitivity in individuals with ASD. Further investigations into sensory abnormalities in individuals with ASD are needed to clarify the pathophysiologic processes that may alter sensory processing in this disorder.

Normative data for Aδ contact heat evoked potentials in adult population: a multicenter study.

There has been a significant increase over recent years in the use of contact heat evoked potentials (CHEPs) for the evaluation of small nerve fiber function. Measuring CHEP amplitude and latency has clinical utility for the diagnosis and assessment of conditions with neuropathic pain. This international multicenter study aimed to provide reference values for CHEPs to stimuli at 5 commonly examined body sites. Contact heat evoked potentials were recorded from 226 subjects (114 females), distributed per age decade between 20 and 79 years. Temperature stimuli were delivered by a thermode (32°C-51°C at a rate of 70°C/s). In phase I of the study, we investigated side-to-side differences and reported the maximum normal side-to-side difference in Aδ CHEP peak latency and amplitude for leg, forearm, and face. In phase II, we obtained normative data for 3 CHEP parameters (N2P2 amplitude, N2 latency, and P2 latency), stratified for gender and age decades from face, upper and lower limbs, and overlying cervical and lumbar spine. In general, larger CHEP amplitudes were associated with higher evoked pain scores. Females had CHEPs of larger amplitude and shorter latency than males. This substantive data set of normative values will facilitate the clinical use of CHEPs as a rapid, noninvasive, and objective technique for the assessment of patients presenting with neuropathic pain.