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Background: Assessment of the nociceptive withdrawal reflex (NWR) is frequently applied to probe the excitability level of the spinal nociceptive circuitry. In humans, the NWR threshold (NWR-T) is often estimated by applying electrical stimulation over the sural nerve at the lateral malleolus. Such stimulation may be associated with substantial pain and discomfort rendering completion of the assessment infeasible., New Method: As an alternative to sural nerve stimulation, NWR-Ts were also estimated by electrical stimulation at the arch of the foot. Failure-rates and test-retest reliability of these two procedures were evaluated. A fully-automated interleaved up-down staircase procedure was used to estimate the NWR-T for both stimulation sites. NWRs were detected from EMG measured over the biceps femoris and tibialis anterior muscles, respectively. A total of three repeated measures were performed in two different sessions to evaluate the test-retest reliability of the two methods using Bland-Altman agreement analysis., Results: The failure rate of NWR-T estimation based on electrical stimulation of the sural nerve (29%) was substantially higher than when the NWR was elicited by stimulation at the arch of the foot (5%)., Comparison With Existing Method: The analysis of test-retest reliability indicated that the two methods for NWR-T estimation were equally reliable for within-session comparisons, but stimulation at the arch of the foot enabled NWR-T estimation with superior between-session reliability, Conclusions: These results support a paradigm shift within NWR-T estimation favoring stimulation at the arch of the foot., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Reasons for Performing Study: To validate a model for investigating the effects of analgesic drugs on mechanical, thermal and electrical stimulation testing., Objectives: To investigate repeatability, sensitivity and specificity of nociceptive tests., Study Design: Randomised experiment with 2 observers in 2 phases., Methods: Mechanical (M), thermal (TL) and electrical (E) stimuli were applied to the dorsal metacarpus (M-left and TL-right) and coronary band of the left thoracic limb (E) and a thoracic thermal stimulus (TT) was applied caudal to the withers in 8 horses (405 ± 43 kg). Stimuli intensities were increased until a clear avoidance response was detected without exceeding 20 N (M), 60°C (TL and TT) and 15 V (E). For each set of tests, 3 real stimuli and one sham stimulus were applied (32 per animal) using a blinded, randomised, crossover design repeated after 6 months. A distribution frequency and, for each stimulus, Chi-square and McNemar tests compared both the proportion of positive responses detected by 2 observers and the 2 study phases. The κ coefficients estimated interobserver agreement in determining endpoints. Sensitivity (384 tests) and specificity (128 tests) were evaluated for each nociceptive stimulus to assess the evaluators' accuracy in detecting real and sham stimuli., Results: Nociceptive thresholds were 3.1 ± 2 N (M), 8.1 ± 3.8 V (E), 51.4 ± 5.5°C (TL) and 55.2 ± 5.3°C (TT). The level of agreement after all tests, M, E, TL and TT, was 90, 100, 84, 98 and 75%, respectively. Sensitivity was 89, 100, 89, 98 and 70% and specificity 92, 97, 88, 91 and 94%, respectively., Conclusions: The high interobserver agreement, sensitivity and specificity suggest that M, E and TL tests are valid for pain studies in horses and are suitable tools for investigating antinociceptive effects of analgesics in horses., (© 2014 EVJ Ltd.)

Objective: Amygdala kindling is a widely used animal model for studying mesial temporal lobe epileptogenesis. In the macaque monkey, electrical amygdala kindling develops slowly and provides an opportunity for investigating ictal perfusion changes during epileptogenesis., Methods: Two rhesus monkeys were electrically kindled through chronically implanted electrodes in the right amygdala over a period of 16 and 17 months. Ictal perfusion single photon emission computed tomography (SPECT) imaging was performed during each of the four predefined clinical stages., Results: Afterdischarge duration increased slowly over 477 days for monkey K and 515 days for monkey S (18 ± 8 s in stage I; 52 ± 13 s in stage IV). During this time, the animals progressed through four clinical stages ranging from interrupting ongoing behavior to bilateral convulsions. Ictal SPECT perfusion imaging showed well-localized but widely distributed regions of hyperperfusion and hypoperfusion, in both cortical and subcortical structures, at every seizure stage. A large portion of the ictal network was involved in the early stages of epileptogenesis and subsequently expanded over time as seizure severity evolved., Significance: Our data indicate that the different mesial temporal lobe seizure types occur within a common network affecting several parts of the brain, and that seizure severity may be determined by seizure-induced epileptogenesis within a bihemispheric network that is implicated from the start of the process., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

This study was designed to investigate the metabosensitive afferent response evoked by electrically induced fatigue (EIF), lactic acid (LA) and potassium chloride (KCl) in three muscle types. We recorded the activity of groups III-IV afferents originating from soleus, gastrocnemius and tibialis anterior muscles. Our data showed a same pattern of response in the three muscles after chemical injections, i.e., a bell curve with maximal discharge rate at 1 mM for LA injections and a linear relationship between KCl concentrations and the afferent discharge rate. Furthermore, a stronger response was recorded after EIF in the gastrocnemius muscle compared to the two other muscles. The change in afferent discharge after 1 mM LA injection was higher for the gastrocnemius muscle compared to the response obtained with the corresponding concentration applied in the two other muscles, whereas changes to KCl injections did not dramatically differ between the three muscles. We conclude that anatomical (mass, phenotype, vascularization, receptor and afferent density…) and functional (flexor vs. extensor) differences between muscles could explain the amplitude of these responses.

Variations of the µ-opioid receptor gene OPRM1 have been shown to modulate pain perception with some evidence pointing towards a modulation of not only physical but also "psychological pain". In line with suggestions of a common neural network involved in the processing of physical pain and negative and distressing stimuli, like social rejection as a psychologically harmful event, we examined the influence of the A118G polymorphism on the neural processing of physical and non-physical pain. Using fMRI, we investigated a sample of 23 females with the more frequent AA genotype, and eight females with the relatively rare but more pain-sensitive AG genotype during electrical stimulation to the dorsum of the non-dominant hand. Non-physical pain was investigated using Cyberball, a virtual ball-tossing game, to induce experiences of non-self-dependent social rejection. A Go/NoGo task with an increased risk of self-dependent erroneous performance was used as a control task to investigate the effects of negative feedback as a more cognitive form of distress. Relative to A118G homozygous A-allele carriers, G-allele carriers showed significantly increased activation of the supplementary motor area/superior frontal gyrus and the precentral gyrus during electrical stimulation. Increased activation of the secondary sensorimotor cortex (SII) was found during social exclusion and during negative feedback. We demonstrate that brain regions particularly related to the somatosensory component of pain processing are modulated by variations in OPRM1. Influences were evident for both physical and psychological pain processing supporting the assumption of shared neural pathways.

Purpose: Modern magnetic resonance imaging scanners with high-performance gradient systems have high maximum gradient strength (Gmax ) and slew rate (Smax ). Peripheral nerve stimulation (PNS) is often a more limiting factor for gradient waveform design than Gmax and Smax . Traditionally, the slew rate is derated globally to adhere to PNS limitations., Methods: In this work, the PNS limitation is already included in the gradient waveform design in the form of a time-varying slew rate, hence shortening the overall gradient duration., Results: Spiral and echo-planar imaging trajectories were designed with a multitude of parameters, and it was demonstrated that trajectory durations from conventional to PNS-optimal design can be shortened by 8 and 3%, respectively., Conclusion: Including PNS-limits in the gradient waveform design can shorten the duration of gradient trajectories, thereby reducing associated artifacts., (© 2014 Wiley Periodicals, Inc.)

Unlabelled: Standards, including IEC 60479-1 and -2, provide current-based ventricular fibrillation thresholds (VFT) for stimuli durations between 0.1 ms and 10 s. It has been established that the amount of electrical charge, not the current calculated by root-mean-square, is most representative of the effects of cardiac stimulation. There are no unified models that present transthoracic charge VFTs for a wide range of stimuli durations. This work proposes a new unified charge model applicable to transthoracic stimuli durations ranging over 1 μs - 300 s. VFTs were compiled from our previous animal work and from other published reports, including from the studies that provided the raw data for IEC 60479-1 and -2. Our study goal was to cover a wide range of stimuli durations, for which reliable data exists. Consistent data were found for stimuli durations covering the range of 1 μs - 300 s where VFTs were expressed as charge. The model predicted a transthoracic charge VFT of 1 mC at 1 μs duration. The charge VFT increased with stimulus duration and reached 10 C at 300 s. Presenting the first charge-based transthoracic VFT model covering stimuli durations over 1 μs - 300 s, we found 3 behavioral regions of charge VFT vs., Duration: For short stimuli durations, 1 μs - 10 ms, VFTs followed a classic Weiss charge strength-duration curve. For long stimuli, longer than 5 s, charge VFTs can be approximated using a 38 mArms constant current model. From 10 ms to 5 s, charge VFTs tracked through a transition zone that could be approximated as a constant charge model Q≈100 mC.

Treatment of partial hearing loss with the combined electrical and acoustical stimulation (EAS) aims at restoring the hearing while preserving the residual hearing. The aim of present study was to establish an in vitro system to study the effects of an electrical field on the auditory hair cells and spiral ganglion cells. Cochlear tissues containing the organ of Corti, spiral limbus and spiral ganglion neurons were dissected from post-natal Wistar rats (p3-p5) and cultured in the micro-channels. Electric current was homogenously applied on the apical, medial and basal parts of explants. Biphasic rectangular pulses were applied continuously over a period of 30 h or 42 h and the explants were fixed and stained to visualize the hair cells and neurites. Application of electrical field for 30 h has not induced significant changes in the number of inner or outer hair cells when compared to the control. However, after 42 h of electric stimulation, the number of hair cells decreased significantly by about 30%. The medial and basal fragments were particularly affected. The number of neurites has not been influenced but significant neuritic beading, consistent with neurodegeneration, was observed after 42 h of electric stimulation. Although performed with immature auditory tissues, our findings hint at the possibility of particular electric current inducing damage or loss of auditory hair cells, which should be considered when designing EAS electrodes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Although nonnoxious, high-frequency electrical stimulation applied segmentally (ie, conventional transcutaneous electrical nerve stimulation [TENS]) has been proposed to modulate pain, the mechanisms underlying analgesia remain poorly understood. To further elucidate how TENS modulates pain, we examined evoked responses to noxious thermal stimuli after the induction of sensitization using capsaicin in healthy volunteers. We hypothesized that sensitization caused by capsaicin application would unmask TENS analgesia, which could not be detected in the absence of sensitization. Forty-nine healthy subjects took part in a series of experiments. The experiments comprised the application of topical capsaicin (.075%) on the left hand in the C6 dermatome, varying the location of TENS (segmental, left C6 dermatome, vs extrasegmental, right shoulder), and assessing rating of perception (numeric rating scale: 0-10) and evoked potentials to noxious contact heat stimuli. The extrasegmental site was included as a control condition because previous studies indicate no analgesic effect to remote conventional TENS. Conventional TENS had no significant effect on rating or sensory evoked potentials in subjects untreated with capsaicin. However, segmental TENS applied in conjunction with capsaicin significantly reduced sensation to noxious thermal stimuli following a 60-minute period of sensitization., Perspective: The study indicates that sensitization with capsaicin unmasks the analgesic effect of conventional TENS on perception of noxious contact heat stimuli. Our findings indicate that TENS may be interacting segmentally to modulate distinct aspects of sensitization, which in turn results in analgesia to thermal stimulation., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Previous research in social neuroscience has consistently shown that empathy for pain recruits brain areas that are also activated during the first-hand experience of pain. This has been interpreted as evidence that empathy relies upon neural processes similar to those underpinning the first-hand experience of emotions. However, whether such overlapping neural activations imply that equivalent neural functions are engaged by empathy and direct emotion experiences remains to be demonstrated. We induced placebo analgesia, a phenomenon specifically modulating the first-hand experience of pain, to test whether this also reduces empathy for pain. Subjective and neural measures of pain and empathy for pain were collected using self-report and event-related potentials (ERPs) while participants underwent painful electrical stimulation or witnessed that another person was undergoing such stimulation. Self-report showed decreased empathy during placebo analgesia, and this was mirrored by reduced amplitudes of the pain-related P2, an ERP component indexing neural computations related to the affective-motivational component of pain. Moreover, these effects were specific for pain, as self-report and ERP measures of control conditions unrelated to pain were not affected by placebo analgesia. Together, the present results suggest that empathy seems to rely on neural processes that are (partially) functionally equivalent to those engaged by first-hand emotion experiences. Moreover, they imply that analgesics may have the unwanted side effect of reducing empathic resonance and concern for others., (Copyright © 2015 the authors 0270-6474/15/358938-10$15.00/0.)

Objectives: Skeletal muscles usually cramp at short lengths, where the tension that can be exerted by muscle fibers is low. Since high tension is an important anabolic stimulus, it is questionable if cramps can induce hypertrophy and strength gains. In the present study we investigated if electrically induced cramps (EIMCs) can elicit these adaptations., Methods: 15 healthy male adults were randomly assigned to an intervention (IG; n=10) and a control group (CG; n=5). The cramp protocol (CP) applied twice a week to one leg of the IG, consisted of 3x6 EIMCs, of 5 s each. Calf muscles of the opposite leg were stimulated equally, but were hindered from cramping by fixating the ankle at 0° plantar flexion (nCP)., Results: After six weeks, the cross sectional area of the triceps surae was similarly increased in both the CP (+9.0±3.4%) and the nCP (+6.8±3.7%). By contrast, force of maximal voluntary contractions, measured at 0° and 30° plantar flexion, increased significantly only in nCP (0°: +8.5±8.8%; 30°: 11.7±13.7%)., Conclusion: The present data indicate that muscle cramps can induce hypertrophy in calf muscles, though lacking high tension as an important anabolic stimulus., Competing Interests: The authors have no conflict of interest.

There is sparse data on the analysis of supplementary motor area in language function using direct cortical stimulation of the supplementary motor area. Here, we report a patient who experienced isolated anomia during stimulation of the anterior supplementary motor area and discuss the role of the supplementary motor area in speech production. The role of the pre-supplementary motor· area in word selection, observed in fMRI studies, can be confirmed by direct cortical stimulation.

Background: We previously observed impaired habituation mechanisms of the conventional blink reflex (BR) in patients with episodic cluster headache (ECH) during the bout, studying only the affected side. Here, we have studied the nociceptive-specific BR (nBR) both on the affected and non-affected sides, and in relation to clinical features., Participants and Methods: We recorded nBR in 18 ECH patients during the bout, and in 18 healthy volunteers (HVs). We compared pain threshold, area, and habituation of the nBR, recorded both for the affected and non-affected sides., Results: In patients, the pain threshold on the affected side was lower than that of the non-affected side (p = 0.009), and lower than in HVs (p = 0.038). Reflex area was decreased on both sides (p < 0.05) compared with HVs, whereas habituation was significantly impaired only on the affected side (p = 0.025 vs. HVs; p = 0.003 vs. non-affected). The habituation slope was positively correlated with the number of days since the onset of the bout and the daily attack frequency., Conclusions: Our data reflect lateralized pathological variations in craniofacial nociception in ECH patients over the course of the cluster period. We hypothesized that this is due to malfunctioning of mechanisms that regulate hypothalamic activity and descending aminergic controls., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

People with Alzheimer's disease (AD) are up to 10 times more likely to develop epilepsy than the age-matched general population. However, given that only a proportion of patients with AD develop epilepsy, it is likely that additional factors may be required for the epilepsy to emerge. This study aimed to better understand the relationship between AD pathology and seizure susceptibility. It also aimed to investigate a "two-hit" hypothesis for seizure susceptibility through amygdala kindling of rodent AD models. Aged AD mice (Tg2576 model) and wild-type (WT) mice underwent electrical amygdala kindling. Compared with WT mice, Tg2576 mice had significantly lower afterdischarge threshold. Significantly fewer stimulations were required for the Tg2576 mice to reach the first class V seizure. Higher death rate was observed with Tg2576 mice in the kindling group. Both sham and kindled Tg2576 animals had increased levels of sprouting in the supragranular layer of the dentate gyrus compared with the WT counterparts. These findings support the "two-hit" hypothesis and represent a potentially novel research model to help better understand the relationship between AD pathology and epilepsy., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

The nociceptive flexion reflex (NFR) is a widely used tool to investigate spinal nociception for scientific and diagnostic purposes, but its clinical use is currently limited due to the painful measurement procedure, especially restricting its applicability for patients suffering from chronic pain disorders. Here we introduce a less painful algorithm to assess the NFR threshold. Application of this new algorithm leads to a reduction of subjective pain ratings by over 30% compared to the standard algorithm. We show that the reflex threshold estimates resulting from application of the new algorithm can be used interchangeably with those of the standard algorithm after adjusting for the constant difference between the algorithms. Furthermore, we show that the new algorithm can be applied at shorter interstimulus intervals than are commonly used with the standard algorithm, since reflex threshold values remain unchanged and no habituation effects occur when reducing the interstimulus interval for the new algorithm down to 3s. Finally we demonstrate the utility of the new algorithm to investigate the modulation of nociception through different states of attention. Taken together, the here presented new algorithm could increase the utility of the NFR for investigation of nociception in subjects who were previously not able to endure the measurement procedure, such as chronic pain patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The beneficial effects of placebo treatments on fear and anxiety (placebo anxiolysis) are well known from clinical practice, and there is strong evidence indicating a contribution of treatment expectations to the efficacy of anxiolytic drugs. Although clinically highly relevant, the neural mechanisms underlying placebo anxiolysis are poorly understood. In two studies in humans, we tested whether the administration of an inactive treatment along with verbal suggestions of anxiolysis can attenuate experimentally induced states of phasic fear and/or sustained anxiety. Phasic fear is the response to a well defined threat and includes attentional focusing on the source of threat and concomitant phasic increases of autonomic arousal, whereas in sustained states of anxiety potential and unclear danger requires vigilant scanning of the environment and elevated tonic arousal levels. Our placebo manipulation consistently reduced vigilance measured in terms of undifferentiated reactivity to salient cues (indexed by subjective ratings, skin conductance responses and EEG event-related potentials) and tonic arousal [indexed by cue-unrelated skin conductance levels and enhanced EEG alpha (8-12 Hz) activity], indicating a downregulation of sustained anxiety rather than phasic fear. We also observed a placebo-dependent sustained increase of frontal midline EEG theta (4-7 Hz) power and frontoposterior theta coupling, suggesting the recruitment of frontally based cognitive control functions. Our results thus support the crucial role of treatment expectations in placebo anxiolysis and provide insight into the underlying neural mechanisms., (Copyright © 2015 the authors 0270-6474/15/357365-09$15.00/0.)

Objective: Brivaracetam (BRV) is a new antiepileptic drug candidate rationally designed for high affinity and selectivity for the synaptic vesicle protein 2A. This study explored anti-ictogenic and antiepileptogenic effects of BRV in rats at different stages of development., Methods: Using a rapid kindling model in P14, P21, P28, and P60 rats, we studied two doses of BRV: 10 and 100 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of BRV 30 min after the injection., Results: BRV 100 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas BRV at 10 mg/kg increased ADT in P60, P28, and P21 rats. BRV also shortens the afterdischarge duration (ADD), achieving statistical significance with 10 and 100 mg/kg at P60 and with 100 mg/kg at P21. At P60, BRV increases the number of stimulations required to achieve a stage 4-5 seizure in a dose-dependent manner. At P28 and P21, BRV increased the number of stimulations required to develop a stage 4-5 seizure in a dose-dependent manner with almost complete elimination of stage 4-5 seizures. In contrast, at P14, BRV had no effect on the number of stage 4-5 seizures. An age-related decrease in blood and brain concentrations of BRV was observed 30 min after injection of BRV 10 mg/kg, whereas with 100 mg/kg there were no significant age-correlated differences in brain and serum BRV concentrations., Significance: BRV exerted dose-dependent anti-ictogenic effects from P60 to P14 independent of brain maturation. BRV also exhibited antiepileptogenic effects at P60, whereas this effect need to be further evaluated at P28 and P21. We did not observe any effect on epileptogenesis at P14 at either dose., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Unlabelled: Neuronal transplantation is a promising experimental treatment approach for intractable epilepsies, but rejection of porcine or human cells in rodent epilepsy models requires adequate immunosuppression to enable long-term survival of xenografts. The commonly used immunosuppressive drug cyclosporine A (CsA) itself was suggested to affect seizure thresholds. However, putative pro- or anticonvulsant effects of CsA have not yet been sufficiently explored in a direct comparison study involving different preparations, dosages, and application routes. We therefore comprehensively investigated the effects of acute versus chronic treatment using different dosages (5mg/kg, 10mg/kg), application routes (i.p., s.c.), and preparations of CsA (pure substance solved in polyethoxylated castor oil and a ready-to-use drug additionally containing ethanol) on acute seizure thresholds in rats in the pentylenetetrazole seizure threshold test and verified the most harmless protocol in the chronic amygdala-kindling model for temporal lobe epilepsy. None of the CsA treatment regimens induced acute changes of seizure thresholds. Chronic CsA treatment also did not robustly change seizure thresholds. As evaluated by whole blood analyses, bioavailability of CsA was significantly higher after i.p. application of the ready-to-use preparation compared to the pure substance and compared to s.c., Application: Observed adverse effects differed between CsA treatment regimens and included reversible diarrhea, lowered body temperature, and tremor, the latter two of which were also induced by vehicle injections containing ethanol and/or polyethoxylated castor oil. Our data suggest that chronic treatment (2 weeks) with 10mg/kg CsA injected i.p. in the ready-to-use preparation is an appropriate protocol for use in neural transplantation in epilepsy research applying the presently used rat models. Transplantation studies in experimental epilepsy research require a careful assessment of putative CsA effects on seizure thresholds in the specific experimental settings to be used., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Attention has been shown to affect the neural processing of pain. However, the exact mechanisms underlying this modulation remain unknown. Here, we used a new method called pain steady-state evoked potentials (PSSEPs) to investigate whether selective spatial attention affects EEG responses to tonic painful stimuli. In general, steady-state evoked potentials reflect changes in the EEG spectrum at a certain frequency that correspond to the frequency of a train of applied stimuli. In this study, high intensity transcutaneous electrical stimulation was delivered to both hands simultaneously with 31 Hz and 37 Hz, respectively. Subject׳s attention was directed to one of the two trains of stimulation in order to detect a small gap that was occasionally interspersed into the stimulus trains. Thereby, they had to ignore the stimulation applied to the other hand. Results show that PSSEPs were induced at 31 Hz and 37 Hz at frontal and central electrodes. PSSEPs occurred contralaterally to the respective hand stimulated with that frequency. Surprisingly, the magnitude of PSSEPs was not modulated by spatial attention towards one of the two stimuli. Our results indicate that attention can hardly be shifted between two simultaneously applied tonic painful stimulations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Acute inflammatory dental pain is a prevalent condition often associated with limited jaw movements. Mustard oil (MO, a small-fiber excitant/inflammatory irritant) application to the rat molar tooth pulp induces increased excitability (i.e., central sensitization) of trigeminal medullary dorsal horn (MDH) nociceptive neurons that can be modulated by MDH application of the astrocytic inhibitor methionine sulfoximine (MSO). The objectives of the study were to determine whether MO application to the rat right maxillary first molar tooth pulp affects left face-M1 excitability manifested as altered intracortical microstimulation thresholds for evoking electromyographic activity in the right anterior digastric (RAD, jaw-opening muscle), and whether MSO application to face-M1 can modulate this MO effect. Under Ketamine general anesthesia, Sprague-Dawley male rats had a microelectrode positioned at a low-threshold (≤30 μA) face-M1 site. Then MO (n = 16) or control solution (n = 16) was applied to the previously exposed tooth pulp, and RAD threshold was monitored for 15 min. MSO (0.1 mM, n = 8) or saline (n = 8) was then applied to the face-M1, and RAD thresholds were monitored every 15 min for 120 min. ANOVA followed by post hoc Bonferroni was used to analyze data (p < 0.05). Within 15 min of MO (but not control) pulp application, RAD thresholds increased significantly (p < 0.001) as compared to baseline. One hour following MSO (but not saline) application to the face-M1, RAD thresholds decreased significantly (p = 0.005) toward baseline. These novel findings suggest that acute inflammatory dental pain is associated with decreased face-M1 excitability that may be dependent on the functional integrity of face-M1 astrocytes and related to mechanisms underlying limited jaw movements in acute orofacial pain conditions.

We aimed to evaluate the effect of painful tooth stimulation on gingival somatosensory sensitivity of healthy volunteers in a randomized, controlled design. Thirteen healthy volunteers (six women, seven men; 28.4 ± 5.0 years) were included for two experimental sessions of electrical tooth stimulation: painful tooth stimulation and tooth stimulation below the sensory threshold (control). Eight of the human subjects participated in a third session without tooth stimulation. In all sessions, the somatosensory sensitivity of the gingiva adjacent to the stimulated tooth was evaluated with a standardized battery of quantitative sensory tests (QST) before, immediately after and 30 min after tooth stimulation. Painful tooth stimulation evoked significant decreases in warmth and heat pain thresholds (P < 0.001) as well as pressure pain thresholds (increased sensitivity) (P = 0.024) and increases in mechanical detection thresholds (decreased sensitivity) (P < 0.050). Similar thermal threshold changes (P < 0.019) but no mechanical changes were found after tooth stimulation below the sensory threshold (P > 0.086). No QST changes were detected in the session without tooth stimulation (P > 0.060). In conclusion, modest increased gingival sensitivity to warmth, painful heat and pressure stimuli as well as desensitization to non-painful mechanical stimulation were demonstrated after tooth stimulation. This suggests involvement of competing heterotopic facilitatory and inhibitory mechanisms. Furthermore, stimulation below the sensory threshold induced similar thermal sensitization suggesting the possibility of activation of axon-reflex-like mechanisms even at intensities below the perception threshold. These findings may have implications for interpretation of somatosensory results in patients with chronic intraoral pain.

Objective: Premenstrual dysphoric disorder (PMDD) is associated with increased pain, but there has been a lack of well-controlled research assessing pain responsivity, sex hormones, and their relationships in this group. This study was designed to address this gap in the literature., Materials and Methods: Healthy, regularly cycling participants (14 PMDD, 14 non-PMDD) attended pain testing sessions during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (order counterbalanced) and salivary estradiol, progesterone, and testosterone were assessed at each testing session. Pain sensitivity was measured from electrocutaneous threshold/tolerance, ischemic threshold/tolerance, sensory and affective ratings of electrocutaneous and ischemic stimuli, and the nociceptive flexion reflex threshold (NFR, a measure of spinal nociception)., Results: Women with PMDD had higher sensory pain ratings of electrocutaneous stimuli and trends for lower ischemic thresholds and higher affective pain ratings of electrocutaneous stimuli. However, there were no group differences observed in NFR threshold. Testosterone levels were also lower during the mid-follicular and ovulatory phases in PMDD. Correlations between pain outcomes and estradiol and testosterone indicated that these hormones are hypoalgesic, with estradiol having a greater hypoalgesic effect within the PMDD group., Discussion: Overall, women with PMDD may have a phase-independent hyperalgesia, with pain amplification likely occurring at the supraspinal level rather than the spinal level, given the lack of group differences in NFR threshold. Because testosterone was hypoalgesic and lower in women with PMDD, and there were strong associations between pain and estradiol in PMDD, sex hormones may play a role in PMDD-related hyperalgesia.

Unlabelled: Recent experimental data show that associative learning processes are involved not only in the acquisition but also in the spreading of pain-related fear. Clinical studies suggest involvement of positive affect in resilience against chronic pain. Surprisingly, the role of positive affect in associative learning in general, and in fear generalization in particular, has received scant attention. In a voluntary movement paradigm, in which one arm movement (reinforced conditioned stimulus [CS+]) was followed by a painful stimulus and another was not (unreinforced conditioned stimulus [CS-]), we tested generalization of fear inhibition in response to 5 novel but related generalization movements (GSs; within-subjects) after either a positive affect induction or a control exercise (Group = between-subjects) in healthy participants (N = 50). The GSs' similarity with the original CS+ movement and CS- movement varied. Fear learning was assessed via verbal ratings. Results indicated that there was an interaction between the increase in positive affect and the linear generalization gradient. Stronger increases in positive affect were associated with steeper generalization curves because of relatively lower pain-unconditioned stimulus expectancy and less fear of stimuli more similar to the CS-. There was no Group by Stimulus interaction. Results thus suggest that positive affect may enhance safety learning through promoting generalization from known safe movements to novel yet related movements. Improved safety learning may be a central mechanism underlying the association between positive affect and increased resilience against chronic pain., Perspective: We investigated the extent to which positive affect influences the generalization (ie, spreading) of pain-related fear inhibition in response to situations similar to the original, pain-eliciting situation. Results suggest that increasing positive affect in the acute pain stage may limit the spreading of pain-related fear, thereby potentially inhibiting transition to chronic pain conditions., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guinea pig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4-aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure., (Copyright © 2015 the authors 0270-6474/15/353048-08$15.00/0.)

The behavioural effects of high-frequency electrical stimulation (HFS) are often similar to the effects of lesions, with the advantage of being reversible. The present study examined the effects of HFS of the nucleus accumbens (NAc), an area that has been shown to be important for sensitization to several psychostimulants, on the development and expression of EtOH sensitization. Male DBA/2 mice received five biweekly injections of EtOH (2.2 g/kg, intraperitoneally) or saline (SAL) immediately before assessments of locomotor activity (LMA). For some of the mice, each EtOH or SAL injection was preceded by 2 h of bilateral NAc HFS, whereas the remaining mice received no stimulation. Seven days after the last injection, LMA was again measured after the mice received a challenge dose of EtOH (1.8 g/kg, intraperitoneally) or SAL, either preceded or not preceded by 2 h of HFS. Mice receiving NAc HFS before EtOH injections during the sensitization period showed progressive increases in LMA that were not different from the LMA scores of EtOH-injected mice which had received no HFS. However, when the latter group was subsequently challenged after receiving HFS, a strong suppression of LMA was observed, in comparison with their own previous LMA scores (-72%) and compared with EtOH-sensitized groups challenged in the absence of HFS (-70%). A separate cohort of mice that were surgically implanted but not stimulated showed a robust EtOH sensitization response that did not differ from that of EtOH-treated mice without electrodes, demonstrating that HFS behavioural effects were not merely a result of the presence of electrodes in the NAc. These results suggest that NAc HFS may have different effects at different stages of the EtOH sensitization process, specifically suppressing expression, but not the development of EtOH sensitization. This pattern of distinct effects of NAc manipulations on different aspects of sensitization is similar to what has been reported for other drugs of abuse, suggesting a commonality of mechanisms. Our findings also suggest that the sensitization may provide a useful paradigm for the investigation of mechanisms of clinical effectiveness of HFS in humans.

Background: Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Understanding the mechanisms of neuron death is key to preventing the neurodegeneration associated with TLE. However, the involvement of neuronal loss to the epileptogenic process has yet to be fully determined. Recent studies have shown that the activation of NLRP1 can generate a functional caspase-1-containing inflammasome in vivo to drive the proinflammatory programmed cell death termed 'pyroptosis', which has a key role in the pathogenesis of neurological disorders. To the best of our knowledge, there are no reported studies that performed detailed identification and validation of NLRP1 inflammasome during the epileptogenic process., Methods: We first compared expression of NLRP1 and caspase-1 in resected hippocampus from patients with intractable mesial temporal lobe epilepsy (mTLE) with that of matched control samples. To further examine whether the activation of NLRP1 inflammasome contributes to neuronal pyroptosis, we employed a nonviral strategy to knock down the expression of NLRP1 and caspase-1 in the amygdala kindling-induced rat model. Proinflammatory cytokines levels and hippocampal neuronal loss were evaluated after 6 weeks of treatment in these NLRP1 or caspase-1 deficiency TLE rats., Results: Western blotting detected upregulated NLRP1 levels and active caspase-1 in mTLE patients in comparison to those levels seen in the controls, suggesting a role for this inflammasome in mTLE. Moreover, we employed direct in vivo infusion of nonviral small interfering RNA to knockdown NLRP1 or caspase-1 in the amygdala kindling-induced rat model, and discovered that these NLRP1 or caspase-1 silencing rats resulted in significantly reduced neuronal pyroptosis., Conclusions: Our data suggest that NLRP1/caspase-1 signaling participates in the seizure-induced degenerative process in humans and in the animal model of TLE and points to the silencing of NLRP1 inflammasome as a promising strategy for TLE therapy.

Emerging evidence implicates the midbrain dopamine system and its interactions with the lateral habenula in processing aversive information and learning to avoid negative outcomes. We examined neural responses to unexpected, aversive events using methods specialized for imaging the midbrain and habenula in humans. Robust activation to aversive relative to neutral events was observed in the habenula and two regions within the ventral midbrain: one located within the ventral tegmental area (VTA) and the other in the substantia nigra (SN). Aversive processing increased functional connectivity between the VTA and the habenula, putamen, and medial prefrontal cortex, whereas the SN exhibited a different pattern of functional connectivity. Our findings provide evidence for a network comprising the VTA and SN, the habenula, and mesocorticolimbic structures that supports processing aversive events in humans., (Copyright © 2015 the authors 0270-6474/15/350198-11$15.00/0.)

Purpose: Neuromuscular electrostimulation (NMES) leads to a spatially fixed, synchronous, and superficial motor unit recruitment, which could induce muscle damage. Therefore, the extent of muscle damage and its spatial occurrence were expected to be heterogeneous across and along the quadriceps femoris (QF) muscles. The aim of the present study was to characterize muscle spatial heterogeneity in QF damage after a single bout of isometric NMES using multimodal magnetic resonance imaging (MRI)., Methods: Twenty-five young healthy males participated in this study. MRI investigations consisted of the assessment of muscle volume, transverse relaxation time (T2), and diffusion tensor imaging (DTI) in muscles positioned near the stimulation electrodes (i.e., vastus lateralis (VL) and vastus medialis (VM)) and muscles located outside the stimulated regions (i.e., vastus intermedius and rectus femoris). These measurements were performed 6 d before, and 2 d and 4 d (D4) after the NMES session., Results: For the muscles placed in direct contact with the stimulation electrodes, volume (VL, +8.5%; VM, +3.8%), T2 (VL, +19.5%; VM, +6.7%) and radial diffusivity (λ3) (VL, + 7.3%; VM, +3.7%) significantly increased at D4. Whereas MRI parameter changes were larger for VL as compared with those for other QF muscles at D4, homogeneous alterations were found along all QF muscles., Conclusions: Isometric NMES induced specific and localized alterations in VL and VM, with heterogeneous damage amplitude among them. Potential effects of unaccustomed intermuscle shear stress during electrically evoked isometric contractions could be a key factor in the spatial occurrence and the extent of damage among QF muscles (especially in VL). The kinetics and extent of MRI changes varied between T2 and diffusion tensor imaging metrics, suggesting the involvement of different physiological processes.

It is well known that ovarian function is regulated by hypothalamic-pituitary-ovarian hormones. However, although several histological studies have described the autonomic innervation of the ovary, the involvement of these autonomic nerves in ovarian function is unclear. Recently, it has been shown that both the superior ovarian nerve (SON) and the ovarian nerve plexus (ONP) induce vasoconstrictor activity by activation of alpha 1-adrenoceptors, whereas the SON, but not the ONP, inhibits ovarian estradiol secretion by activation of alpha 2-adrenoceptors. Furthermore, reflex activation of these ovarian nerves by noxious cutaneous stimulation of the rat hindpaw results in ovarian vasoconstriction and inhibition of estradiol secretion. Thus, in addition to long-term regulation of ovarian function by hormones, ovarian autonomic innervation may be involved in rapid regulation of ovarian function by responding to either internal or external environmental changes.

Withdrawal from long-term dosing with exogenous progesterone precipitates increased anxiety-linked changes in behavior in animal models due to the abrupt decrease in brain concentration of allopregnanolone (ALLO), a neuroactive metabolite of progesterone. We show that a withdrawal-like effect also occurs during the late diestrus phase (LD) of the natural ovarian cycle in rats, when plasma progesterone and ALLO are declining but estrogen secretion maintains a stable low level. This effect at LD was prevented by short-term treatment with low dose fluoxetine. During LD, but not at other stages of the estrous cycle, exposure to anxiogenic stress induced by whole body vibration at 4 Hz for 5 min evoked a significant decrease in tail flick latency (stress-induced hyperalgesia) and a decrease in the number of Fos-positive neurons present in the periaqueductal gray (PAG). The threshold to evoke fear-like behaviors in response to electrical stimulation of the dorsal PAG was lower in the LD phase, indicating an increase in the intrinsic excitability of the PAG circuitry. All these effects were blocked by short-term administration of fluoxetine (2 × 1.75 mg kg(-1) i.p.) during LD. This dosage increased the whole brain concentration of ALLO, as determined using gas chromatography-mass spectrometry, but was without effect on the extracellular concentration of 5-HT in the dorsal PAG, as measured by microdialysis. We suggest that fluoxetine-induced rise in brain ALLO concentration during LD offsets the sharp physiological decline, thus removing the trigger for the development of anxiogenic withdrawal effects., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Background: We have previously shown that hydrogen (H2) inhalation, begun at the start of hyperoxic cardiopulmonary resuscitation, significantly improves brain and cardiac function in a rat model of cardiac arrest. Here, we examine the effectiveness of this therapeutic approach when H2 inhalation is begun on the return of spontaneous circulation (ROSC) under normoxic conditions, either alone or in combination with targeted temperature management (TTM)., Methods and Results: Rats were subjected to 6 minutes of ventricular fibrillation cardiac arrest followed by cardiopulmonary resuscitation. Five minutes after achieving ROSC, post-cardiac arrest rats were randomized into 4 groups: mechanically ventilated with 26% O2 and normothermia (control); mechanically ventilated with 26% O2, 1.3% H2, and normothermia (H2); mechanically ventilated with 26% O2 and TTM (TTM); and mechanically ventilated with 26% O2, 1.3% H2, and TTM (TTM+H2). Animal survival rate at 7 days after ROSC was 38.4% in the control group, 71.4% in the H2 and TTM groups, and 85.7% in the TTM+H2 group. Combined therapy of TTM and H2 inhalation was superior to TTM alone in terms of neurological deficit scores at 24, 48, and 72 hours after ROSC, and motor activity at 7 days after ROSC. Neuronal degeneration and microglial activation in a vulnerable brain region was suppressed by both TTM alone and H2 inhalation alone, with the combined therapy of TTM and H2 inhalation being most effective., Conclusions: H2 inhalation was beneficial when begun after ROSC, even when delivered in the absence of hyperoxia. Combined TTM and H2 inhalation was more effective than TTM alone., (© 2014 American Heart Association, Inc.)

An experimental model of daily episodic pain was developed to investigate peripheral sensitization and cortical reorganization in healthy individuals. Two experiments (A and B) were conducted. Experiments A and B consisted of one and five consecutive days, respectively, in which the participants were subjected to 45 min of intense painful cutaneous electrical stimulation (episodic pain session), using a stimulus paradigm that in animals has been shown to induce long-term potentiation. These electrical stimulations produced a verbal pain rating of approximately 85 on a 0-100 verbal rating scale (VRS). Physiological (blood flow and axon flare reflex), psychophysical (perception threshold and verbal pain ratings) and electrophysiological (128 channels recorded somatosensory evoked potential (SEP)) measurements were recorded. The stimulation evoked a visible axon flare reflex and caused significantly increased cutaneous blood flow around the site of the stimulation. Axon flare reflex and blood flow reached a plateau on day one in all the subjects and no significant changes between the days were observed. The results showed that the effect of the electrical stimulations changed over the five days; pain potentiation was induced on the first day (significant increase in the verbal pain ratings during the 45 min stimulation) but not on any of the subsequent days. After five days of subsequent pain induction, the global field power showed a significant reduction in P2 amplitude in the late stage (200-370 ms, in the central-parietal area). In conclusion, the results suggest that in healthy individuals this model of episodic pain produces a rapid adaptation after day one and that generates significant SEP changes at day five., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18-55 years were randomized to receive gabapentin 900 mg or gabapentin 900 mg+donepezil 5mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800 mg (positive control) for the remaining period. Each treatment period was 14 days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1-13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260 mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800 mg (n=14) significantly reduced the area of allodynia vs placebo (n=14; -12.83 cm(2); 95% confidence interval [CI] -23.14 to -2.53; P=0.015) with supportive results for hyperalgesia (-14.04 cm(2); 95% CI -28.49-0.41; P=0.057), validating the electrical hyperalgesia model. Gabapentin+donepezil (n=30) significantly reduced the area of hyperalgesia vs gabapentin 900 mg (n=30; -11.73 cm(2); 95% CI -21.04 to -2.42; P=0.014), with supportive results for allodynia (-6.62 cm(2); 95% CI -13.29-0.04; P=0.052). The adverse event profile for gabapentin+donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.

Objective: In this study, we consider two localization techniques used in injections of botulinium toxin in children: electrical stimulation and ultrasound. The hypothesis of this work was that injections performed without stimulation would be less painful., Patients and Methods: Monocentric prospective study, with 107 sessions of lower limb injections. Two groups of children were compared: localization by ultrasound only (60 children), detection by stimulation only or by stimulation combined with ultrasound (47 children). Pain assessment was performed by the child or an accompanying party using the Visual Analog Scale (VAS) and by a health care team using the Face, Legs, Activity, Cry, Consolability (FLACC)., Results: A significant difference between the two groups was found in both self-report and by means of the behavioral observational pain scale. Indeed, VAS average and FLACC average were significantly higher with detection by stimulation than with ultrasound alone: 4.5cm±2.54 versus 2.7cm±2.27; P<0.001 for VAS scale and 3.7±2.1 versus 2.7±2.3; P<0.05 for FLACC scale., Conclusion: When compared to ultrasound detection, localization by electrostimulation appears to increase the overall pain caused during injections of botulinum toxin in children., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Events that threaten tissue integrity including noxious stimulation activate central noradrenergic circuits, particularly locus coeruleus and its projections. Recent advances in theory hold that an adaptive, defensive shift in brain activity takes place in response to threat. In principle, this shift may accentuate the autonomic and central biomarkers of the perception of painful events and the experience of pain itself. We have examined the effects of an alpha-2 agonist on pupil dilation responses, skin conductance responses, near field somatosensory evoked potentials and pain reports in normal volunteers undergoing repeated trials of painful fingertip stimulation delivered at low, medium and high intensities. In a double-blinded study, 114 healthy male and female volunteers underwent repeated noxious stimulation under baseline, placebo and active drug conditions where the active drug was the alpha-2 agonist tizanidine 4 mg. In contrast to baseline and placebo conditions, tizanidine 4 mg significantly reduced the magnitudes of the mean pupil dilation response, the mean skin conductance response, the mean near field somatosensory evoked potential peak-to-peak amplitude and the mean pain intensity rating. Stimulus intensity significantly altered all three biomarkers and the pain report in a graded fashion. There were no sex differences. These findings support the hypotheses that painful events activate central noradrenergic circuits, and that these circuits play a role in the autonomic and central arousal associated with pain., (© The Author(s) 2014.)

Temporal lobe epilepsy (TLE) often becomes refractory, and patients with TLE show a high incidence of psychiatric symptoms, including anxiety and depression. Therefore, it is necessary to identify molecules that were previously unknown to contribute to epilepsy and its associated disorders. We previously found that the sialyltransferase ST3Gal IV is up-regulated within the neural circuits through which amygdala-kindling stimulation propagates epileptic seizures. In contrast, this study demonstrated that kindling stimulation failed to evoke epileptic seizures in ST3Gal IV-deficient mice. Furthermore, approximately 80% of these mice failed to show tonic-clonic seizures with stimulation, whereas all littermate wild-type mice showed tonic-clonic seizures. This indicates that the loss of ST3Gal IV does not cause TLE in mice. Meanwhile, ST3Gal IV-deficient mice exhibited decreased acclimation in the open field test, increased immobility in the forced swim test, enhanced freezing during delay auditory fear conditioning, and sleep disturbances. Thus, the loss of ST3Gal IV modulates anxiety-related behaviors. These findings indicate that ST3Gal IV is a key molecule in the mechanisms underlying anxiety - a side effect of TLE - and may therefore also be an effective target for treating epilepsy, acting through the same circuits., (© 2014 International Society for Neurochemistry.)

Introduction: Renal sympathetic nerve (RSN) activity plays a key role in systemic sympathetic hyperactivity. Previous studies have shown that cardiac sympathetic hyperactivity, especially the left stellate ganglion (LSG), contributes to the pathogenesis of ventricular arrhythmias (VAs) after acute myocardial infarction (AMI)., Methods and Results: Twenty-eight dogs received 3 hours of continuous left-sided electrical stimulation of RSN (LRS; Group-1, n = 9), sham RSN stimulation (Group-2, n = 9), or LSG ablation plus 3 hours of LRS (Group-3, n = 10) were included. AMI was induced by ligating the proximal left anterior descending coronary artery. LRS was performed using electrical stimulation on the adventitia of left renal artery at the voltage increasing the systolic blood pressure (BP) by 10%. BP, heart rate variability (HRV), serum norepinephrine (NE) level, and LSG function were measured at baseline and the end of each hour of LRS. C-fos and nerve growth factor (NGF) protein expressed in the LSG were examined in Group-1 and Group-2. Compared with baseline, 3 hours of LRS induced a significant increase in BP, sympathetic indices of HRV, serum NE level, and LSG function. The incidence of VAs in Group-1 was significantly higher than other groups. The expression of c-fos and NGF protein in the LSG was significantly higher in Group-1 than Group-2., Conclusion: Three hours of LRS induces both systemic and cardiac sympathetic hyperactivity and increases the incidence of ischemia-induced VAs., (© 2014 Wiley Periodicals, Inc.)

Within the Pavlovian conditioning framework, extinction is a procedure in which, after conditioning, the conditioned stimulus (CS) is repeatedly presented without the unconditioned stimulus (US). During this procedure the conditioned response (CR) is gradually attenuated. It has been suggested that extinction during the early stages of ontogeny is a qualitatively different process from extinction in adulthood: during infancy, extinction may result in erasure of the memory, while during adulthood extinction involves new learning. This conclusion was supported by studies showing that renewal, reinstatement or spontaneous recovery procedures were not effective during infancy for recovering the CR once it had been extinguished. These studies used the freezing response as the only behavioral index, although some recent evidence indicates that the absence of freezing after conditioning or after extinction does not necessarily imply a deficit in memory, and that other behavioral indexes may be more sensitive to detecting conditioning effects. The goal of the present study was to analyze extinction in preweanling rats by examining the possibility of the spontaneous recovery of a conditioned fear response, measured through a different set of mutually-exclusive behaviors that constitute an exhaustive ethogram, and including control groups (Experiment 1: US-Only and CS-Only; Experiment 2: US-Only, CS-Only and Unpaired) in order to examine whether non-associative learning may explain quantitative or qualitative changes in the frequency of specific responses during extinction or recovery. Extinction produced changes in the expression of freezing, grooming and exploration, and the clearest evidence of spontaneous recovery came from the analysis of freezing behavior. The pattern of behavior observed during extinction is compatible with theoretical approaches which consider different dynamic behavioral systems, and it also fit in well with a molar approach to the analysis of behavior, which considers that extinction involves a transition from one allocation of time among behaviors to another allocation, rather than a loss of strength in any particular discrete response. These results have implications for the study of extinction during infancy, since they are compatible with the hypothesis that the original memory survives extinction, and highlight the importance of control conditions for detecting this effect during this ontogenetic period., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Peripheral nerve catheters (PNC) play an important role in postoperative pain treatment following major extremity surgery. There are several trials reported in the literature which investigated the efficacy and safety of ultrasound (US) and nerve stimulator (NS) guided PNC placement; however, most of these trials were only small and focused mainly on anesthesiologist-related indicators of block success (e.g. block onset time and procedure time) but not primarily on patient-related outcome data including postoperative pain during movement., Aim: This retrospective analysis compared the analgesic efficacy and safety of US versus NS guided peripheral nerve catheters (PNC) for postoperative pain therapy in a large cohort of patients., Material and Methods: Data of patients (June 2006-December 2010) treated with US (nus = 368 June 2008-December 2010) and NS (nns = 574, June 2006-May 2008) guided PNC were systematically analyzed. Apart from demographic data, postoperative pain scores [numeric rating scale (NRS): 0-10] on each treatment day, the number of patients with need for additional opioids, cumulative local anesthetic consumption and catheter-related complications were compared., Results: On the day of surgery patients treated with US-guided PNC reported lower NRS at rest (p = 0.034) and during movement (p < 0.001). Additionally, the number of patients requiring additional opioids on the day of surgery was lower in the US group (absolute difference 12.4 %, p = 0.001). Furthermore, the number of multiple puncture attempts (absolute difference 5.6 %, p < 0.001) and failed catheter placements (absolute difference 3.4 %, p = 0.06) were lower in the US group. There were no patients in both groups with long-lasting neurological impairment., Conclusion: This database analysis demonstrated that patients treated with US-guided PNC reported significantly lower postoperative pain scores and the number of patients requiring additional opioids was significantly lower on the day of surgery. The numbers of multiple punctures and failed catheter placements were reduced in the US group, which might be seen as an advantage of US-guided regional anaesthesia.

Touch perception on the fingers and hand is essential for fine motor control, contributes to our sense of self, allows for effective communication, and aids in our fundamental perception of the world. Despite increasingly sophisticated mechatronics, prosthetic devices still do not directly convey sensation back to their wearers. We show that implanted peripheral nerve interfaces in two human subjects with upper limb amputation provided stable, natural touch sensation in their hands for more than 1 year. Electrical stimulation using implanted peripheral nerve cuff electrodes that did not penetrate the nerve produced touch perceptions at many locations on the phantom hand with repeatable, stable responses in the two subjects for 16 and 24 months. Patterned stimulation intensity produced a sensation that the subjects described as natural and without "tingling," or paresthesia. Different patterns produced different types of sensory perception at the same location on the phantom hand. The two subjects reported tactile perceptions they described as natural tapping, constant pressure, light moving touch, and vibration. Changing average stimulation intensity controlled the size of the percept area; changing stimulation frequency controlled sensation strength. Artificial touch sensation improved the subjects' ability to control grasping strength of the prosthesis and enabled them to better manipulate delicate objects. Thus, electrical stimulation through peripheral nerve electrodes produced long-term sensory restoration after limb loss., (Copyright © 2014, American Association for the Advancement of Science.)

Introduction: The purpose of this study was to propose a method that allows extraction of the current muscle state under electrically induced fatigue., Methods: The triceps surae muscle of 5 subjects paralyzed by spinal cord injury was fatigued by intermittent electrical stimulation (5 × 5 trains at 30 Hz). Classical fatigue indices representing muscle contractile properties [peak twitch (Pt) and half-relaxation time (HRT)] were assessed before and after each 5-train series and were used to identify 2 relevant parameters (Fm , Ur ) of a previously developed mathematical model using the Sigma-Point Kalman Filter., Results: Pt declined significantly during the protocol, whereas HRT remained unchanged. Identification of the model parameters with experimental data yielded a model-based fatigue assessment that gave a more stable evaluation of fatigue than classical parameters., Conclusions: This work reinforces clinical research by providing a tool that clinicians can use to monitor fatigue development during stimulation., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Electronic control devices (ECDs) are weapons used to incapacitate violent subjects. Subjects have died suddenly after ECD application, but because cardiac dysrhythmias have been inconsistently observed during ECD application in animals, the cause for death is uncertain., Objectives: The objective was to identify the factors contributing to cardiac stimulation during ECD application detected by transesophageal echocardiography., Methods: Four Yorkshire pigs were anesthetized, paralyzed with vecuronium, and restrained in a supine position. A GE 6T echo probe was placed in the esophagus to directly visualize left ventricular function. M-mode echocardiography was used to estimate heart rate. Two dart locations, chest and abdomen, were assessed. ECD applications were delivered from one of five commercially available devices (Taser X26, Singer S200 AT, Taser M26, Taser X3, and Taser C2) in random order to each pig, four times in each orientation., Results: Cardiac stimulation, characterized by multiple PVCs or the sudden increase in ventricular contraction rate during application, did not occur with abdominal dart location. With chest dart application in small pigs, cardiac stimulation occurred with all ECDs except with the Taser X3 (p < 0.0001). In large pigs, cardiac stimulation occurred only during chest application of the S200 AT (chest vs. abdomen: 207 beats/min, vs. 91 beats/min, p < 0.0001)., Conclusion: Cardiac stimulation occurs during ECD application in pigs, and is dependent upon subject size, dart orientation, and ECD. The Taser X3 did not result in cardiac stimulation in small or large pigs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Defining optimal parameters for stimulation is a critical step in the development of noninvasive neuromodulation techniques. Transcranial pulsed current stimulation (tPCS) is emerging as another option in the field of neuromodulation; however, little is known about its mechanistic effects on electrical brain activity and how it can modulate its oscillatory patterns. The aim of this study was to identify the current intensity needed to exert an effect on quantitative electroencephalogram (qEEG) measurements. Forty healthy volunteers were randomized to receive a single session of sham or active stimulation at 0.2, 1, or 2 mA current intensity with a random frequency with an oscillatory pulsed range between 1 and 5 Hz. We conducted an exploratory frequency domain analysis to detect changes in absolute power for theta, alpha, and beta frequency bands and also interhemispheric coherence for alpha, theta, and four different sub-bands. Cognitive and nonspecific adverse effects were also recorded. Our results showed that both 1 and 2 mA can modulate interhemispheric coherence at the fronto-temporal areas for the theta band as compared with sham, while 2 mA also increased the low-beta and high-beta interhemispheric coherence at the same anatomical location. There were no group differences for adverse effects and participants could not guess correctly whether they received active versus sham stimulation. On the basis of our results, we conclude that tPCS is associated with an intensity-dependent facilitatory effect on interhemispheric connectivity. These results can guide future tPCS applications and will define its role as a neuromodulatory technique in the field.

Background: Strength training and neuromuscular electrical stimulation (NMES) are effective training modalities for improving muscle function, exercise performance and health status in individuals with COPD. The aim of the present study was to analyze the metabolic load of these training modalities at baseline, half-way, and at the end of an eight-week interdisciplinary pulmonary rehabilitation program in a subgroup of individuals with COPD of the DICES trial., Methods: Of 24 individuals with COPD (FEV1: 34 ± 2% predicted, men: 58%, age: 66 (61-68) years), peak oxygen uptake (VO2), peak minute ventilation (VE), heart rate, oxygen saturation and symptom scores were assessed during HF-NMES (75 Hz), LF-NMES (15 Hz) and strength training at three moments during their pulmonary rehabilitation program., Results: Intervention-related peak VO2 did not change over time during HF-NMES, LF-NMES or strength training. Intervention-related peak VE did not change over time during strength training or LF-NMES and increased slightly, but significantly over time during HF-NMES. Peak VO2 and VE were significantly higher during strength training compared to HF-NMES or LF-NMES. Oxygen saturation significantly decreased after the first measurements during HF-NMES and strength training group to baseline, while no significant changes in oxygen saturation were observed during the other measurements. Heart rate significantly increased compared to baseline in all groups at all moments and was significantly higher after strength training compared to HF-NMES or LF-NMES. Median end scores (points) for dyspnea, fatigue and muscle pain ranged from 1 to 3, from 0.5 to 2 and from 0 to 6 after HF-NMES, from 2 to 3, from 2 to 5 and from 0 to 9 after LF-NMES and from 2 to 5, from 1.5 to 4 and from 0 to 28 after strength training respectively., Conclusions: To conclude, the metabolic load and symptom scores remain acceptable low over time with increasing training loads during HF-NMES, LF-NMES or strength training., Trial Registration: NTR2322.

About 25% of patients with epilepsy are refractory to treatment, so that new, more effective antiepileptic drugs (AEDs) are urgently needed. Animal models that simulate the clinical situation with individuals responding and not responding to treatment are important to determine mechanisms of AED resistance and develop novel more effective treatments. We have previously developed and characterized such a model in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. In this model, prolonged treatment of epileptic rats with phenobarbital (PB) results in two subgroups, PB responders and PB nonresponders. When PB nonresponders were treated in previous experiments with phenytoin (PHT), 83% of the PB-resistant rats were also resistant to PHT. In the present study we examined if rats with PB resistant seizures are also resistant to lamotrigine (LTG), using continuous EEG/video recording of spontaneous seizures over 10 consecutive weeks. For this purpose, a new group of epileptic rats was produced and selected by treatment with PB into responders and nonresponders. As in previous studies, PB nonresponders had a significantly higher seizure frequency before onset of treatment. During subsequent treatment with LTG, all PB nonresponders and 60% of the PB responders exhibited >75% reduction of seizure frequency and were therefore considered as LTG responders. Plasma levels of LTG did not differ significantly between responders and nonresponders. The data of this pilot study indicate that LTG is more effective than PHT to suppress seizures in PB nonresponders in this model, but that not all PB responders also respond to LTG. Overall, our data provide further evidence that AED studies in post-SE TLE models are useful in determining and comparing AED efficacy and investigating predictors and mechanisms of pharmacoresistance., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Low-frequency stimulation (LFS) is a potential therapy utilized in patients who do not achieve satisfactory control of seizures with pharmacological treatments. Here, we investigated the interaction between anticonvulsant effects of LFS and phenobarbital (a commonly used medicine) on amygdala-kindled seizures in rats. Animals were kindled by electrical stimulation of basolateral amygdala in a rapid manner (12 stimulations/day). Fully kindled animals randomly received one of the three treatment choices: phenobarbital (1, 2, 3, 4 and 8 mg/kg; i.p.; 30 min before kindling stimulation), LFS (one or 4 packages contained 100 or 200 monophasic square wave pulses, 0.1-ms pulse duration at 1 Hz, immediately before kindling stimulation) or a combination of both (phenobarbital at 3 mg/kg and LFS). Phenobarbital alone at the doses of 1, 2 and 3 mg/kg had no significant effect on the main seizure parameters. LFS application always produced anticonvulsant effects unless applied with the pattern of one package of 100 pulses, which is considered as non-effective. All the seizure parameters were significantly reduced when phenobarbital (3 mg/kg) was administered prior to the application of the non-effective pattern of LFS. Phenobarbital (3 mg/kg) also increased the anticonvulsant actions of the effective LFS pattern. Our results provide an evidence of a positive cumulative anticonvulsant effect of LFS and phenobarbital, suggesting a potential combination therapy at sub-threshold dosages of phenobarbital and LFS to achieve a satisfactory clinical effect.

Unlabelled: Sex differences in pain perception are still poorly understood, but they may be related to the way the brains of men and women respond to the affective dimensions of pain. Using a matched pain intensity paradigm, where pain intensity was kept constant across participants but pain unpleasantness was left free to vary among participants, we studied the relationship between pain unpleasantness and pain-evoked brain activity in healthy men and women separately. Experimental pain was provoked using transcutaneous electrical stimulation of the sural nerve while pain-related brain activity was measured using somatosensory-evoked brain potentials with source localization. Cardiac responses to pain were also measured using electrocardiac recordings. Results revealed that subjective pain unpleasantness was strongly associated with increased perigenual anterior cingulate cortex activity in women, whereas it was strongly associated with decreased ventromedial prefrontal cortex activity in men. Only ventromedial prefrontal cortex deactivations in men were additionally associated with increased autonomic cardiac arousal. These results suggest that in order to deal with pain's objectionable properties, men preferentially deactivate prefrontal suppression regions, leading to the mobilization of threat-control circuits, whereas women recruit well-known emotion-processing areas of the brain., Perspective: This article presents neuroimaging findings demonstrating that subjective pain unpleasantness ratings are associated with different pain-evoked brain responses in men and women, which has potentially important implications regarding sex differences in the risk of developing chronic pain., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that is involved in modulation of diverse physiological processes. The role of this receptor in epilepsy has not been studied well. Therefore, we investigated the role of central TRPV1 receptors on the development of pentylenetetrazole (PTZ) and amygdala-induced kindling in rats. Male Wistar rats received subconvulsive dose of PTZ intraperitoneally, every other day. TRPV1 receptor agonist, OLDA and its antagonist, AMG-9810 were injected intracerebroventricularly 30 min prior to PTZ administration. In electrical kindling, stimulating and recording electrodes were implanted in the right amygdala of male rats. After kindling, the effect of TRPV1 receptor agonist or antagonist on afterdischarge duration (ADD), latency to the onset of bilateral forelimb clonuses (S4L) and duration of loss of equilibrium (stage 5 seizures, S5D) were measured. The results demonstrated that, OLDA at the doses of 0.01, 0.1 and 1 μg/rat, significantly accelerated the incidence of all seizure stages, increased S5D and decreased S4L in the PTZ model of kindling. Also, in amygdala kindling, S5D and ADD were significantly reduced following the administration of AMG-9810. In contrast, OLDA significantly aggravated the indices of seizure in both models of epileptic seizure. This study demonstrated that central TRPV1 receptors may be involved in the development of electrical and PTZ-induced kindling.