正常人运动皮质的功能连接网络及其小世界性

目的 利用静息态fMRI观察运动皮质的功能连接网络及其小世界性.方法 对90名健康成年志愿者行静息态fMRI数据采集,分别以双侧M1区为种子点获得全脑正性及负性功能连接脑图.以这些区域作为节点,计算其平均聚类系数Cp和平均最短路径长度Lp、全脑随机网络属性Crand和Lrana;按照公式γ=Cp/C怕nd＞1和λ=Lp/Lrand≈1分别计算γ及λ值,以验证其小世界网络属性.结果 静息态以M1区为种子点的正激活区域主要包括双侧初级运动皮质、运动前区及辅助运动区;负激活区域包括双侧额上回、楔前叶、缘上回、角回、双侧颞上回及小脑后叶.在矩阵稀疏度0.1≤Sparsity＜0.5范围内,这些区域的小世界属性符合γ=Cp/Crand＞1及λ=Lp/Lrand≈1.结论 运动皮质的正性连接主要集中在运动系统内,负性连接与脑的默认网络类似,运动皮质功能网络具有小世界性.     

Deep pain thresholds in the distal limbs of healthy human subjects.

Pressure pain thresholds (PPTs) in distal limbs have been under-investigated despite their potential clinical importance. Therefore, we compared PPTs over nail bed, bony prominences, and muscle in distal parts of upper and lower limbs. We investigated 12 healthy subjects using three handheld devices: a spring-loaded, analogue pressure threshold meter (PTM) with two operating ranges, and an electronic Algometer. PPTs were determined with three series of ascending stimulus intensities with a ramp of about 50 kPa/s. PPTs were normally distributed in logarithmic space. PPTs over different tissues varied significantly (ANOVA, p<0.001): mean thresholds and 95% confidence intervals were 615 kPa (266-1424 kPa) over the nail bed, 581 kPa (271-1245 kPa) over bony prominences, and 520 kPa (246-1100 kPa) over muscles. PPTs on the foot were higher than on the hand (ANOVA, p<0.01), except over muscles. PPTs were significantly lower with the Algometer than with PTMs (ANOVA, p<0.01); again these differences were least when testing over muscle. There was no significant right-left difference (ANOVA, p=0.33). In spite of considerable variability across subjects, reproducibility within subjects was high (correlation coefficients>0.90). For within-subject comparisons, threshold elevations beyond 33-43% would be abnormal (95% confidence intervals), whereas only deviations from the group mean by at least a factor of two would be abnormal with respect to absolute normative values. PPTs over distal muscles were comparable to published values on proximal limb and trunk muscles. These findings suggest that pressure pain testing over distal muscles may be a sensitive test for deep pain sensitivity and that the simple and less expensive devices are sufficient for testing this tissue type. Intra-individual site-to-site comparisons will be more sensitive than absolute normative values.     

Effects of TENS frequency, intensity and stimulation site parameter manipulation on pressure pain thresholds in healthy human subjects

This study evaluated the effects of varying frequency, intensity and stimulation site, of transcutaneous electrical nerve stimulation (TENS) in an experimental model of pain. In a double-blind design 240 volunteers were randomised to one of six experimental TENS groups, a sham TENS or control (n=30 per group; gender balanced). Two TENS frequencies (110 or 4 Hz) and two intensities (strong but comfortable or highest tolerable) at a fixed pulse duration (200 micros) were applied at three sites relative to the measurement site (segmentally, extrasegmentally or a combination of these), for 30 min. Pressure pain thresholds (PPT) were measured using a pressure algometer, in the first dorsal interosseous muscle, every 10 min, during stimulation and for a further 30 min. The high frequency, high intensity segmental, and combined stimulation groups, showed rapid onset and significant hypoalgesic effects. This effect was sustained for 20 min post-stimulation in the high frequency segmental group. All other TENS intervention groups showed hypoalgesic responses similar to the sham TENS group, and none of these groups reached a clinically significant hypoalgesic level. CONCLUSIONS: The role of TENS frequency, intensity and site are pivotal to achieving optimal hypoalgesic effects, during and after stimulation. Clinical applications of these parameter combinations require further investigations.     

Changes in pain perception and descending inhibitory controls start at middle age in healthy adults

OBJECTIVES: Previous studies have shown a reduction of diffuse noxious inhibitory controls (DNICs) in elderly adults compared with younger adults. Unfortunately, little is known regarding the developmental course of DNIC deficits and so it is still unclear whether middle-aged adults also show a DNIC deficit. The aims of the present study were to better characterize the developmental time course of the change in DNIC response by adding a middle-aged group. The role of expectations was also investigated. METHODS: The pain thresholds (PTs) of 20 young, 20 middle-aged, and 20 healthy elderly volunteers were assessed before and during a cold pressor task (water at 7 degrees C). Acute nociceptive stimuli were administered using a thermode and consisted of a range of painless and painful heat pulses. RESULTS: Analyses showed that thermal PTs increase by middle age but that the DNIC-induced increase in PT dampens progressively with advancing age. DNIC response was negatively correlated with advancing age, however, expectations regarding DNIC efficacy did not vary with age. This suggests that age-related changes in the size of the DNIC response are not best explained by an age-related change in expectation. DISCUSSION: The findings tell us that changes in pain perception and endogenous pain modulation arrive earlier than previously suggested. Studies on aging and pain should include a middle-aged group when comparing pain measures across the adult lifespan.     

Reliability of cephalic thermal thresholds in healthy subjects

Reproducibility and normal variation of cephalic warm and cold detection thresholds were investigated in three healthy subject groups. The face, the mastoid process, and the hands were studied. No significant intra-observer test-retest difference ( n =20) was found. Good reliability (intra-class correlation coefficient [ICC]>0.4) was found for 13 of 14 measurements. A small significant inter-observer difference ( n =20) was found for cold thresholds. Good reliability (ICC>0.4) was observed for both cold and warm thresholds in most of the test locations (6 of 8). In general, the largest variability was found in the mastoid and frontal lateral regions. Thermal thresholds varied with investigation site in 56 controls (ANOVA, p <0.0005). No significant gender differences were found for cephalic warm and cold thresholds. Most cold thresholds (4 of 5) but also some warm thresholds (2 of 5) increased with age at the cephalic sites. Our results reveal the frontal medial, the maxillar medial, and lateral regions as the most reliable cephalic test locations. The mastoid region may also be useful for investigating the upper cervical small-fiber function.     

Segmental and plurisegmental modulation of pressure pain thresholds during static muscle contractions in healthy individuals.

The purpose of this study was to assess possible segmental (uni- and/or bilateral) and plurisegmental changes in pressure pain thresholds (PPTs) during static muscle contractions. Twenty-four healthy subjects (12 female, 12 male) performed a standardised isometric contraction with the dominant m. quadriceps femoris (MQF) and m. infraspinatus (MI), respectively. PPTs were assessed using pressure algometry at the contracting muscle, at the contralateral (resting) muscle and at a distant resting muscle (MI during contraction of MQF and vice versa). The PPT assessments were performed before, during and 30min. following each contraction. The contractions were held until exhaustion or for a maximum of 10 PPT assessments/muscle. During contraction of MQF PPTs increased compared to baseline at the middle ( p<0.001) and the end (p<0.001) of the contraction period at all assessed sites alike. During contraction of MI PPTs increased compared to baseline at the middle (p<0.001) and the end (p<0.007) of the contraction period at all sites. The increase was more pronounced at the contracting muscle compared to the contralateral (p<0.002; p<0.01) and the distant (p<0.002; p<0.002) site. No statistically significant difference was seen in PPTs between the latter two. Following the contractions PPTs returned to baseline. Submaximal isometric contraction of MQF and MI gave rise to a statistically significant increase in PPTs at the contracting muscle, the resting homologous contralateral muscle and at the distant resting muscle indicating that generalised pain inhibitory mechanisms were activated. Contraction of MI, but not of MQF, gave rise to an additional activation of unilateral segmental antinociceptive effects.     

Sensory stimulation (TENS): effects of parameter manipulation on mechanical pain thresholds in healthy human subjects

Transcutaneous electrical nerve stimulation (TENS) is a popular form of electrostimulation. Despite an extensive research base, there remains no consensus regarding the parameter selection required to achieve maximal hypoalgesic effects. The aim of this double blind, sham-controlled study was to investigate the relative hypoalgesic effects of different TENS parameters (frequency, intensity and stimulation site) upon experimentally induced mechanical pain. Two hundred and forty participants were recruited in order to provide statistical analysis with 80% power at alpha = 0.05. Subjects were randomised to one of the six TENS groups, a control, and a sham TENS group (n = 30, 15 males, 15 females, per group). TENS groups differed in their combinations of stimulation; frequency (4 or 110 Hz), intensity ('to tolerance' or 'strong but comfortable') and stimulation site (segmental--over the distribution of the radial nerve or, extrasegmental--over acupuncture point 'gall bladder 34', or a combination of both segmental and extrasegmental). Pulse duration was fixed at 200 micros. Stimulation was delivered for 30 min and subjects were then monitored for a further 30 min. Mechanical pain threshold (MPT) was measured using a pressure algometer and taken from the first dorsal interosseous muscle of the dominant hand, ipsilateral to the stimulation site. MPT measures were taken, at baseline, and at 10-min intervals for 60 min. Difference scores were analysed using repeated measures and one-way ANOVA and relevant post hoc tests. Low frequency, high intensity, extrasegmental stimulation produced a rapid onset hypoalgesic effect, which increased during the stimulation period (P < 0.0005 control and sham) and was sustained for 30 min post-stimulation (P < 0.0005(control), P = 0.024(sham)). Whilst high frequency, 'strong but comfortable' intensity, segmental stimulation produced comparable hypoalgesic levels during stimulation, this effect was not sustained post-stimulation. Stimulation at a combination of the two sites did not produce any greater hypoalgesic effects. These results may have implications for the clinical use of sensory stimulation.     

Morphine blocks descending pain inhibitory controls in humans.

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In 9 subjects in the present study, a 2 min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the second min of the conditioning period, showing a 80% inhibition of the RIII reflex which gradually recovered to its baseline value 7 min after the end of the conditioning period. Such inhibitory effects were completely blocked 15-26 min after administration of a low dose of morphine hydrochloride (0.05 mg/kg, i.v.). The lifting of the inhibitions was compatible with an action at the opioid receptors since the inhibitions were re-observed 5-16 min after naloxone injection (0.006 mg/kg, i.v.). During all the experimental sessions, heart and respiratory rates remained stable at their control levels. Since it has been shown previously that such a dose of morphine could not have a direct effect within the spinal cord (Willer 1985), it is concluded that this opiate blocks, in a naloxone-reversible fashion, those bulbo-spinal controls which are triggered by heterotopic nociceptive events. Possible implications for hypoalgesia based on the principles of counter-irritation are discussed.     

Changes to somatosensory detection and pain thresholds following high frequency repetitive TMS of the motor cortex in individuals suffering from chronic pain

Research has shown that transcranial magnetic stimulation (TMS) results in a transient reduction in the experience of chronic pain. The present research aimed to investigate whether a single session of high frequency TMS is able to change the sensory thresholds of individuals suffering from chronic pain. Detection and pain thresholds for cold and heat sensations were measured before and after 20Hz repetitive TMS (rTMS) administered over the motor cortex. A significant decrease in temperature for cold detection and pain thresholds and a significant increase in temperature for heat pain thresholds were evident following a single session of rTMS. In contrast, no change in detection and pain thresholds was obtained following sham rTMS. The finding that rTMS can have a direct effect on sensory thresholds in individuals suffering from chronic pain has implications for the therapeutic use of rTMS in the relief of chronic pain.     

Effects of diflunisal on cutaneous sensory and pain thresholds

The analgesic activity of diflunisal was evaluated through the measurement of cutaneous sensory and pain thresholds after electrical stimulation. Twelve healthy volunteers were examined at baseline and five hourly intervals after oral administration of 500 mg and 1 gm of diflunisal. The results showed that the sensory threshold was not modified by diflunisal, but that the pain threshold was significantly increased two and three hours after 500 mg of diflunisal and one, two, and three hours after 1 gm of diflunisal. At two hours the pain threshold was significantly higher after 1 gm than after 500 mg of diflunisal. It is concluded that diflunisal produces an actual increase of the pain threshold in healthy human subjects and that the amplitude, latency, and duration of its effect are dose related.     

Effect of ketamine on endogenous pain modulation in healthy volunteers

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40 mg per 70 kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P < 0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC.     

Tactile and pain thresholds in the intra- and extra-oral regions of symptom-free subjects

The aim of the present study was to evaluate the tactile detection threshold (TDT), the filament-prick pain detection threshold (FPT), the pressure pain threshold (PPT), and the pressure pain tolerance detection threshold (PTOL) at multiple measuring points in the orofacial region of normal subjects. Sixteen males and 16 females (age range from 20 to 41 years) participated. The TDT and the FPT were measured on the cheek skin overlying the central part of the masseter muscles (MM), on the maxillary gingiva, and at the tip of the tongue, using Semmes-Weinstein monofilaments. The PPT and PTOL were measured at the central part of the MM, using a pressure algometer. The pain intensity during the FPT, PPT and the PTOL measurements was assessed on a numeric rating scale (NRS). The tongue tip had the lowest value in TDT and FPT compared to the other sites. Females showed a significantly lower TDT and FPT at the cheek skin than males. Further, measurements of PPT and PTOL confirmed the previously reported higher thresholds in males. In contrast, while the intra-oral threshold measurements revealed no gender differences, a significantly higher pain perception as evaluated using NRS, was seen in the males. A strong correlation was found between the pain responses at the same measuring site (FPT, PPT, and PTOL over the MM). In addition, the TDT and the pain responses were also correlated positively.     

Age-related differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults

Despite decades of research, hundreds of studies, and a number of recent reviews, the effects of aging on the experience of pain remain poorly understood. Many prior investigators have reported increases in persistent pain conditions and diminished tolerance for certain types of laboratory-induced pain among the elderly. While explanations for these effects often propose senescent decrements in endogenous analgesic systems as a possible contributory mechanism, almost no direct empirical evidence for this hypothesis has yet emerged in human studies. The present investigation was designed to evaluate the existence and nature of these putative age-related differences in endogenous pain inhibition. Groups of healthy younger (n=45, mean age=21.6 years, range=18-25) and older (n=48, mean age=63.1 years, range=55-67) adults participated in a controlled, two-session laboratory assessment of diffuse noxious inhibitory controls (DNIC), a measure of endogenous pain inhibition. In this study, we examined age differences in the effects of concurrent cold pain on ratings of heterotopically presented repetitive noxious thermal stimuli. Interestingly, older adults demonstrated facilitation rather than inhibition of thermal pain during concurrent noxious cold stimulation while younger adults demonstrated some expected DNIC effects (i.e. a reduction in thermal pain ratings during heterotopic stimulation with noxious cold). Collectively, the findings of the present study suggest age-associated decrements in at least one form of endogenous analgesic response. If replicated, such findings of reduced pain-modulatory capacity in the elderly may partially explain age-related differences in the prevalence, severity, and impact of chronic pain.     

The influence of menstrual phases on pain modulation in healthy women

This study investigated if conditioned pain modulation (CPM) varies across the menstrual cycle in healthy, normally menstruating women and investigated correlations between sex hormone levels and CPM across the menstrual cycle. Thirty-six normally menstruating women were tested during 3 phases of the menstrual cycle: early follicular, ovulatory, and midluteal, confirmed by hormone determinations. Mechanical pressure (test stimulus) was applied to the masseter muscle and the induced pain assessed before, during, and after immersion of the hand into ice water (conditioning stimulus) to activate CPM or tepid water (control). Conditioning pain, ie, pain in the hand during CPM/control experiment, and tolerance time were also measured. Test pain intensity was suppressed during CPM in all phases (P < .001), but with more effective suppression during the ovulatry than during the early follicular phase (P < .05). There were no changes in test pain intensity during the control experiment and no significant differences in conditioning pain, or tolerance time between phases. In conclusion, our results showed more effective pain modulation in the ovulatory phase of the menstrual cycle, when estradiol levels are high and progesterone levels are low, than in the early follicular phase when both these hormones are low. PERSPECTIVE: Deficient pain modulation is believed to be an important pathogenic factor in many chronic pain conditions that affect women. This article shows that sex hormones modulate conditioned pain modulation, because pain inhibition was more effective in the ovulatory phase of the menstrual cycle than in the early follicular phase.     

Comparison of pain and dyspnea perceptual responses in healthy subjects

Dyspnea and pain have a number of similarities. Recent brain imaging experiments showed that similar cortical regions are activated by the perceptions of dyspnea and pain. We tested the hypothesis that an individual’s pain sensitivity might parallel the individual’s dyspnea sensitivity. Studies were carried out in 52 young healthy subjects. Each subject experienced experimentally induced pain and dyspnea. Pain was induced by a cold-pressor test and dyspnea was induced by breathholding while the unpleasant experience of pain and dyspnea was assessed by using a Visual Analogue Scale (VAS). The times from the start of cold stimulation and breathholding to the onset of uncomfortable sensation (pain threshold time and the period of no respiratory sensation, respectively) and to the limit of tolerance (pain endurance time and total breathholding time, respectively) were also measured. In response to cold pain stimulation, a behavioral dichotomy (pain-tolerant and pain-sensitive) was observed. The period of no respiratory sensation was significantly shorter in the PS (pain-sensitive) group than in the PT (pain-tolerant) group (16.9 ± 3.8 vs. 19.6 ± 5.3 s: P < 0.05), whereas no significant difference in the total breathholding time was found between the PT and PS groups. A significant correlation was observed between the pain threshold time and the period of no respiratory sensation in both the PT and PS groups. However, no significant association was observed between pain and dyspnea tolerance in both groups. In conclusion, an individual’s pain threshold is correlated to the individual’s dyspnea threshold, but the individual’s pain tolerance is not consistently correlated to the individual’s dyspnea tolerance.     

The reproducibility of cephalic pain pressure thresholds in control subjects and headache patients

Pain pressure thresholds (PPT) were measured at 13 cephalic points bilaterally in 30 headache patients (10 with tension-type headache, l0 with migraine and 10 with cervicogenic headache) and 10 control subjects on three different days. During the sessions, the subjects reported their pain intensity on the right and left sides of the head on a visual analogue scale (VAS). The variability between days was estimated as a coefficient of repeatability (CR=2 standard deviations of intraindividual differences). The mean CR across all 13 locations was larger in headache patients (2.0 kg/cm²) than in controls (1.68 kg/cm²). Variability (CR) was larger in headache patients as compared to control subjects for 11 of the 13 points (p=0.02). Reliability was better in controls (intraclass correlation coefficients (ICC) ranging from 0.55 to 0.85) than in headache patients (ICC ranging from 0.43 to 0.78). A moderate negative association between PPT and pain intensity was demonstrated. The intraindividual PPT difference (PPT on the most painful occasions-PPT on the least painful occasions) was negative at 12 of 13 cephalic points (p=0.003, across-location mean difference: −0.20 kg/cm²). The PPT differed significantly from one day to the next. A part of this variation was presumably related to the circumstances around the procedure; thresholds were lower when the subjects came directly to algometry without any preceding medical examination at all 13 points (p=0.0002). These results have implications for the planning of future algometer studies. The sample size that is required in studies of headache patients is greater than that in studies of healthy subjects, especially when patients suffer from pain during the PPT session. Particular attention should be paid to circumstances (e.g. preceding medical investigations) around the algometry procedure in order to reduce variability.     

Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone

The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP-induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region-of-interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone.     

GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM). Dose-response analysis of nociception and neurological deficits

We have examined the effects of muscimol and bicuculline microinjected in the rostral ventromedial medulla (RVM) on motor function and on nociception in three pain tests. In Exp. 1 microinjection of muscimol (6.25-400 ng in 1 microl) in the RVM dose-dependently decreased pain threshold of rats and the ED(50) for muscimol was the same in both the hot plate and tail immersion pain tests. In the hot plate test, but not in the tail immersion test, paw withdrawal latencies increased again with high doses of muscimol (75-400 ng). High doses also produced catalepsy. Exp. 2 examined the effects of muscimol (50 ng) and bicuculline (50 ng) over a range of formalin concentrations (0.25-4%) in the formalin test. Muscimol increased responsiveness to formalin and reduced the slope of the formalin dose-response relation. Bicuculline decreased responses to formalin and reduced the slope of the formalin dose-response relation. It is suggested that RVM cells with inhibitory projections to the dorsal horn are not subject to strong GABAergic influence under mild noxious stimulation. RVM cells are thus active, and spinal dorsal horn relay neurons are inhibited. On the other hand, intense noxious peripheral stimulation may stimulate the release of GABA onto RVM cells, which in turn shuts off descending inhibitory fibers to allow transmission of nociceptor input through the dorsal horn.