Neuropharmacological basis of rTMS-induced analgesia: The role of endogenous opioids

We investigated the role of endogenous opioid systems in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). We compared the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation before and after naloxone or placebo treatment, in a randomized, double-blind crossover design, in healthy volunteers. Three groups of 12 volunteers were selected at random and given active stimulation (frequency 10 Hz, at 80% motor threshold intensity, 1500 pulses per session) of the right M1, active stimulation of the right DLPFC, or sham stimulation, during two experimental sessions 2 weeks apart. Cold pain thresholds and the intensity of pain induced by a series of fixed-temperature cold stimuli (5, 10, and 15 degrees C) were used to evaluate the analgesic effects of rTMS. Measurements were made at the left thenar eminence, before and 1 hour after the intravenous injection of naloxone (bolus of 0.1 mg/kg followed by a continuous infusion of 0.1 mg/kg/h until the end of rTMS) or placebo (saline). Naloxone injection significantly decreased the analgesic effects of M1 stimulation, but did not change the effects of rTMS of the DLPFC or sham rTMS. This study demonstrates, for the first time, the involvement of endogenous opioid systems in rTMS-induced analgesia. The differential effects of naloxone on M1 and DLPFC stimulation suggest that the analgesic effects induced by the stimulation of these 2 cortical sites are mediated by different mechanisms. (C) 2010 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.

Auditory results from cochlear implants in elderly people

According to data from the Brazilian Institute of Geography and Statistics, the elderly population grew 47.8% in the last decade in Brazil. A portion of this population has severe and/or profound hearing loss and do not benefit from conventional hearing aids. Thus, the use of cochlear implant is required. Aim: To analyze the benefits of cochlear implants in the elderly based on the comparison of primary auditory thresholds before and after the operation, discrimination of sentences in speech and in talking on the telephone. Methodology: Retrospective cohort study, analyzing medical records from patients aged over 60 years, users of cochlear implant for at least 1 year. Results: Fourteen medical records were analyzed. Mean age of patients was 63.07 years. The mean pure tone thresholds between 500Hz, 1kHz, 2kHz and 4kHz before the implantation was 113dBHL. None of the patients, before operation, could discriminate sentences in open sets and only 3 scored 17% in closed sets sentence recognition. After one year of implantation, the mean sound field thresholds reached 34dBHL, and open set sentences recognition of 93.57%, while 71% of the patients had become able to have a conversation on the telephone. Conclusion: The elderly users of cochlear implant showed important outcomes, with significant improvement in understanding in the open set and in using the telephone.

International study of temperature, heat and urban mortality: the `ISOTHURM` project

Background This study describes heat- and cold-related mortality in 12 urban populations in low- and middle-income countries, thereby extending knowledge of how diverse populations, in non-OECD countries, respond to temperature extremes. Methods The cities were: Delhi, Monterrey, Mexico City, Chiang Mai, Bangkok, Salvador, So Paulo, Santiago, Cape Town, Ljubljana, Bucharest and Sofia. For each city, daily mortality was examined in relation to ambient temperature using autoregressive Poisson models (2- to 5-year series) adjusted for season, relative humidity, air pollution, day of week and public holidays. Results Most cities showed a U-shaped temperature-mortality relationship, with clear evidence of increasing death rates at colder temperatures in all cities except Ljubljana, Salvador and Delhi and with increasing heat in all cities except Chiang Mai and Cape Town. Estimates of the temperature threshold below which cold-related mortality began to increase ranged from 15 degrees C to 29 degrees C; the threshold for heat-related deaths ranged from 16 degrees C to 31C. Heat thresholds were generally higher in cities with warmer climates, while cold thresholds were unrelated to climate. Conclusions Urban populations, in diverse geographic settings, experience increases in mortality due to both high and low temperatures. The effects of heat and cold vary depending on climate and non-climate factors such as the population disease profile and age structure. Although such populations will undergo some adaptation to increasing temperatures, many are likely to have substantial vulnerability to climate change. Additional research is needed to elucidate vulnerability within populations.

Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers

We investigated the analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in two models of experimental pain in healthy volunteers. Two studies were carried out in parallel in two groups of 26 paid healthy volunteers. The effects of active or sham rTMS (frequency, 10 Hz; intensity, 80% resting motor threshold) applied to the right M1 or DLPFC were compared in a double-blind randomized cross-over design. In the first series of experiments, we analyzed the effects of rTMS on thermal (heat and cold) detection and pain thresholds measured on both hands and the left foot, by standardized quantitative sensory testing methods. In the second series of experiments, we measured the effects of M1 or DLPFC rTMS on the threshold and recruitment curves of the RIII nociceptive reflex evoked by ipsilateral electrical stimulation of the sural nerve and recorded on the biceps femoris of both lower limbs. In both studies, measurements were taken before and up to 60 min after the end of rTMS. Active rTMS of both M1 and DLPFC significantly increased the thermal pain thresholds, measured for both hands and the left foot, this effect being most marked for cold pain. These effects, which lasted at least 1 h after rTMS, were selective because they were not associated with changes in non-painful thermal sensations. By contrast, the second study showed that rTMS of M1 or DLPFC had no significant effect on the threshold or recruitment curve of the nociceptive flexion RIII reflex. Our findings demonstrate that unilateral rTMS of M1 or DLPFC induces diffuse and selective analgesic effects in healthy volunteers. The lack of effect on the RIII reflex suggests that such analgesic effects may not depend on the activation of descending inhibitory systems. (C) 2009 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Temporomandibular disorders and cutaneous allodynia are associated in individuals with migraine

The objective of this study was to estimate and contrast the occurrence of ictal and interictal cutaneous allodynia (CA) in individuals with migraine with and without temporomandibular disorders (TMD). Both TMD and CA are common in migraine and may be associated with migraine transformation from episodic into a chronic form. Herein we hypothesize that TMD contributes to the development of CA and to more severe headaches. In a clinic-based sample of individuals with episodic migraine, the presence of TMD was assessed using the research diagnostic criteria for myofascial or mixed (myofascial and arthralgic) TMD. Ictal CA was quantified using the validated Allodynia Symptom Checklist (ASC-12). The ASC-12 measures CA over the preceding month by asking 12 questions about the frequency of allodynia symptoms during headaches. Interictal CA was assessed in the domains of heat, cold and mechanical static allodynia using quantitative sensory testing. Our sample consists of 55 individuals; 40 (73%) had TMD (23 with myofascial TMD and 17 with the mixed type). CA of any severity (as assessed by ASC-12) occurred in 40% of those without TMD (reference group), 86.9% of those with myofascial TMD (P = 0.041, RR = 3.2, 95% CI = 1.5-7.0) and in 82.3% of those with mixed TMD (P = 0.02, RR = 2.5, 95% CI = 1.2-5.3). Individuals with TMD were more likely to have moderate or severe CA associated with their headaches. Interictally (quantitative sensory testing), thresholds for heat and mechanical nociception were significantly lower in individuals with TMD. Cold nociceptive thresholds were not significantly different in migraine patients with and without TMD. TMDs were also associated with change in extra-cephalic pain thresholds. In logistical regression, TMD remained associated with CA after adjusting for aura, gender and age. TMD and CA are associated in individuals with migraine.

Effects of hyperbaric oxygen treatment on auditory hair cells after acute noise damage

Acute acoustic trauma (AAT) is a sudden sensorineural hearing loss caused by exposure of the hearing organ to acoustic overstimulation, typically an intense sound impulse, hyperbaric oxygen therapy (HOT), which favors repair of the microcirculation, can be potentially used to treat it. Hence, this study aimed to assess the effects of HOT on guinea pigs exposed to acoustic trauma. Fifteen guinea pigs were exposed to noise in the 4-kHz range with intensity of 110 dB sound level pressure for 72 h. They were assessed by brainstem auditory evoked potential (BAEP) and by distortion product otoacoustic emission (DPOAE) before and after exposure and after HOT at 2.0 absolute atmospheres for 1 h. The cochleae were then analyzed using scanning electron microscopy (SEM). There was a statistically significant difference in the signal-to-noise ratio of the DPOAE amplitudes for the 1- to 4-kHz frequencies and the SEM findings revealed damaged outer hair cells (OHC) after exposure to noise, with recovery after HOT (p = 0.0159), which did not occur on thresholds and amplitudes to BAEP (p = 0.1593). The electrophysiological BAEP data did not demonstrate effectiveness of HOT against AAT damage. However, there was improvement of the anatomical pattern of damage detected by SEM, with a significant reduction of the number of injured cochlear OHC and their functionality detected by DPOAE.

Impact of depressive symptoms on visceral sensitivity among patients with different subtypes of irritable Bowel syndrome

The etiology of irritable bowel syndrome (IBS) is complex and multifaceted. Psychosocial factors play a role in such a process. Several reports suggest that IBS patients have increased psychopathology scores as compared with population controls. The influence of depressive symptoms on rectal sensitivity thresholds vary across different studies. The influence of predominant bowel habits on rectal sensitivity thresholds as determined by barostat-based investigations is not well established. The present report aimed to investigate the influence of depressive symptoms on rectal sensitivity in different subtypes of IBS patients (diarrhea/constipation-predominant vs. alternating subtypes). Depressive symptoms correlated well with first pain sensitivity threshold in alternating patients (n = 8; [rho] = -0.77; p = 0.02) but not in diarrhea/constipation predominant symptoms (n = 11; [rho] = -0.44; p = 0.27). These data suggest that depressive symptoms might impact pain thresholds differently according to the subtype of IBS.

5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: Role of dorsal raphe nucleus

Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 mu g/0.2 mu L) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also Suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception. (C) 2009 Elsevier Inc. All rights reserved.

Serotonergic neurotransmission in the dorsal raphe nucleus recruits in situ 5-HT2A/2C receptors to modulate the post-ictal antinociception

The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and humans. The aim of this study was to assess the involvement of the dorsal raphe nucleus (DRN) in the post-ictal antinociception. The second aim was to study the role of serotonergic intrinsic mechanisms of the DRN in this hypo-algesic phenomenon. Pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl- influx antagonist, was peripherally used to induce tonic-clonic seizures in Wistar rats. The nociceptive threshold was measured by the tail-flick test. Neurochemical lesions of the DRN, performed with microinjection of ibotenic acid (1.0 mu g/0.2 mu L), caused a significant decrease of tonic-clonic seizure-induced antinociception, suggesting the involvement of this nucleus in this antinociceptive Process. Microinjections of methysergide (1.0 and 5.0 mu g/0.2 mu L), a non-selective serotonergic receptor antagonist, into DRN caused a significant decrease in the post-ictal antinociception in seizing animals, compared to controls, in all post-ictal periods Presently studied. These findings were corroborated by microinjections of ketanserin (at 1.0 and 5.0 mu g/0.2 mu L) into DRN. Ketanserin is an antagonist with large affinity for 5-HT2A/2C serotonergic receptors, which, in this Case, Caused a significant decrease in the tail-flick latencies in seizing animals, compared to controls after the first 20 min following tonic-clonic convulsive reactions. These results indicate that serotonergic neurotransmission of the DRN neuronal clusters is involved in the organization of the post-ictal hypo-algesia. The 5-HT2A/2C receptors of DRN neurons seem to be critically involved in the increase of nociceptive thresholds following tonic-clonic seizures. (c) 2008 Elsevier Inc, All rights reserved.

GABA(A) receptor blockade in dorsomedial and ventromedial nuclei of the hypothalamus evokes panic-like elaborated defensive behaviour followed by innate fear-induced antinociception

Dysfunction in the hypothalamic GABAergic system has been implicated in panic syndrome in humans. Furthermore, several studies have implicated the hypothalamus in the elaboration of pain modulation. Panic-prone states are able to be experimentally induced in laboratory animals to study this phenomenon. The aim of the present work was to investigate the involvement of medial hypothalamic nuclei in the organization of panic-like behaviour and the innate fear-induced oscillations of nociceptive thresholds. The blockade of GABA(A) receptors in the neuronal substrates of the ventromedial. or dorsomedial hypothalamus was followed by elaborated defensive panic-like reactions. Moreover, innate fear-induced antinociception was consistently elicited after the escape behaviour. The escape responses organized by the dorsomedial and ventromedial hypothalamic nuclei were characteristically more elaborated, and a remarkable exploratory behaviour was recorded during GABA(A) receptor blockade in the medial hypothalamus. The motor characteristic of the elaborated defensive escape behaviour and the patterns of defensive alertness and defensive immobility induced by microinjection of the bicuculline either into the dorsomedial. or into the ventromedial hypothalamus were very similar. This was followed by the same pattern of innate fear-induced antinociceptive response that lasted approximately 40 min after the elaborated defensive escape reaction in both cases. These findings suggest that dysfunction of the GABA-mediated neuronal system in the medial hypothalamus causes panic-like responses in laboratory animals, and that the elaborated escape behaviour organized in both dorsomedial and ventromedial hypothalamic nuclei are followed by significant innate-fear-induced antinociception. Our findings indicate that the GABA(A) receptor of dorsomedial and ventromedial hypothalamic nuclei are critically involved in the modulation of panic-like behaviour. (C) 2009 Elsevier B.V. All rights reserved.

Assessment of two central auditory tests in elderly patients without hearing complaints

Speech understanding disorders in the elderly may be due to peripheral or central auditory dysfunctions. Asymmetry of results in dichotic testing increases with age, and may reflect on a lack of inter-hemisphere transmission and cognitive decline. Aim: To investigate auditory processing of aged people with no hearing complaints. Study design: clinical prospective. Materials and Methods: Twenty-two voluntary individuals, aged between 55 and 75 years, were evaluated. They reported no hearing complaints and had maximal auditory thresholds of 40 dB HL until 4 KHz, 80% of minimal speech recognition scores and peripheral symmetry between the ears. We used two kinds of tests: speech in noise and dichotic alternated dissyllables (SSW). Results were compared between males and females, right and left ears and between age groups. Results: There were no significant differences between genders, in both tests. Their Left ears showed worse results, in the competitive condition of SSW. Individuals aged 65 or older had poorer performances than those aged 55 to 64. Conclusion: Central auditory tests showed worse performance with aging. The employment of a dichotic test in the auditory evaluation setting in the elderly may help in the early identification of degenerative processes, which are common among these patients.

GLOBAL POSTURAL REEDUCATION AND STATIC STRETCHING EXERCISES IN THE TREATMENT OF MYOGENIC TEMPOROMANDIBULAR DISORDERS: A RANDOMIZED STUDY

Objective: The purpose of this study was to compare 2 different interventions, global postural reeducation (GPR) and static stretching exercises (SS), in the treatment of women with temporomandibular disorders (TMDs). Methods: A total of 28 subjects with TMDs were randomized into 2 treatment groups: GPR, where therapy involved muscle global chain stretching, or SS, with conventional static stretching; but only 24 completed the study. Eight treatment sessions lasting 40 minutes each (weekly) were performed. Assessments were conducted at baseline, immediately after treatment end, and 2 months later. Measurements included pain intensity at the temporomandibular joint, headache, cervicalgia, teeth clenching, ear symptoms, restricted sleep, and difficulties for mastication, using a visual analogue scale. In addition, electromyographic activity and pain thresholds were measured at the masseter, anterior temporalis, stemocleidomastoid, and upper trapezius muscles. Two-way analysis of variance with Tukey post hoc test was used for between-group comparisons. Significance level was .05. Results: Comparing the pain assessments using the visual analogue scale, no significant differences were seen with the exception of severity of headaches at treatment end (GPR, 3.92 +/- 2.98 cm; SS, 1.64 +/- 1.66 cm; P < .024). In addition, no significant differences were seen for pain thresholds and for electromyographic activity (P > .05). Conclusions: For the subjects in this study, both GPR and SS were similarly effective for the treatment of TMDs with muscular component. They equally reduced pain intensity, increased pain thresholds, and decreased electromyographic activity. (J Manipulative Physiol Ther 2010;33:500-507)

Auditory Neuropathy/Auditory Dyssynchrony in children with Cochlear Implants

The electrical stimulation generated by the Cochlear Implant (CI) may improve the neural synchrony and hence contribute to the development of auditory skills in patients with Auditory Neuropathy / Auditory Dyssynchrony (AN/AD). Aim: Prospective cohort cross-sectional study to evaluate the auditory performance and the characteristics of the electrically evoked compound action potential (ECAP) in 18 children with AN/AD and cochlear implants. Material and methods: The auditory perception was evaluated by sound field thresholds and speech perception tests. To evaluate ECAP`s characteristics, the threshold and amplitude of neural response were evaluated at 80Hz and 35Hz. Results: No significant statistical difference was found concerning the development of auditory skills. The ECAP`s characteristics differences at 80 and 35Hz stimulation rate were also not statistically significant. Conclusion: The CI was seen as an efficient resource to develop auditory skills in 94% of the AN/AD patients studied. The auditory perception benefits and the possibility to measure ECAP showed that the electrical stimulation could compensate for the neural dyssynchrony caused by the AN/AD. However, a unique clinical procedure cannot be proposed at this point. Therefore, a careful and complete evaluation of each AN/AD patient before recommending a Cochlear Implant is advised. Clinical Trials: NCT01023932

Auditory steady state response in pediatric audiology

The main issue regarding pediatric audiology diagnosis is determining procedures to configure reliable results which can be used to predict frequency-specific hearing thresholds. Aim: To investigate the correlation between auditory steady-state response (ASSR) with other tests in children with sensorineural hearing loss. Methods: Prospective cross-sectional contemporary cohort study. Twenty-three children (ages 1 to 7; mean, 3 years old) were submitted to ASSR, behavioral audiometry, click audiometry brain stem response (ABR), tone burst ABR, and predicting hearing level from the acoustic reflex. Results: the correlation between behavioral thresholds and ASSR was (0.70- 0.93), for the ABR tone burst it was (0.73 -0.93), for the ABR click it was (0.83-0.89) only at 2k and 4 kHz. The match between the ASSR and the hearing threshold prediction rule was considered moderate. Conclusion: there was a significant correlation between the ASSR and audiometry, as well as between ABR click (2k and 4 kHz) and for the ABR tone burst. The acoustic reflex can be used to add information to diagnosis in children.

The impact of stress and anxiety on the pressure pain threshold of myofascial pain patients

The purpose of this study was to evaluate the influence of stress and anxiety on the pressure pain threshold (PPT) of masticatory muscles and on the subjective pain report. Forty-five women, students, with mean age of 19.75 years, were divided into two groups: group 1:29 presenting with masticatory myofascial pain (MFP), according to the Research Diagnostic Criteria for Temporomandibular Disorders and group 2: 16 asymptomatic controls. An electronic algometer registered the pain thresholds on four different occasions throughout the academic year. To measure levels of stress, anxiety and pain, the Beck Anxiety Inventory, Lipp Stress Symptoms Inventory and Visual Analog Scale (VAS) were used. Three-way anova and Tukey`s tests were used to verify differences in PPT between groups, times and sites. Levels of anxiety and VAS were compared using Mann-Whitney test, while Friedman`s test was used for the within-groups comparison at different times (T1 to T4). The chi-squared and Cochran tests were performed to compare groups for the proportion of subjects with stress (alpha = 0.05). Differences in PPT recordings between time (P = 0.001) and sites (P < 0.001) were detected. Higher levels of anxiety and lower PPT figures were detected at T2 (academic examination) (P = 0.001). There was no difference between groups for anxiety and stress at any time (P > 0.05). The MFP group also has shown significant increase of VAS at the time of academic examination (P < 0.001). External stressors such as academic examinations have a potential impact on masticatory muscle tenderness, regardless of the presence of a previous condition such as masticatory myofascial pain.