Noradrenaline increases hyperalgesia to heat in skin sensitized by capsaicin

Neurophysiological and behavioural observations in animals suggest that sympathetic neural activity and noradrenaline have an excitatory effect on nociceptor discharge in inflamed skin. To determine whether noradrenaline influences pain sensations in humans, heat hyperalgesia in forearm skin sensitized by topical application of 0.6% capsaicin was measured at sites of noradrenaline or saline ionophoresis in 10 healthy subjects. At control sites and sites of saline ionophoresis heat hyperalgesia decreased over the course of the experiment as inflammation subsided. In contrast, heat hyperalgesia persisted at sites of noradrenaline ionophoresis. These findings are consistent with neurophysiological observations that noradrenaline and sympathetic neural stimulation increase nociceptor discharge in inflamed skin, and suggest that sympathetic neural activity might increase pain associated with skin damage.     

α1‐Adrenoceptors augment thermal hyperalgesia in mildly burnt skin

The effect of the α₁‐adrenoceptor agonist phenylephrine on sensitivity to heat was investigated at three sites of mild burn injury in the cutaneous forearm of 19 healthy participants. Two of the sites were pre‐treated with the α₁‐antagonist terazosin, to determine whether the effect of phenylephrine was mediated by α₁‐adrenoceptors. Terazosin was administered before the burn injury at one site, and after the burn injury at the other site. In another 15 participants, the nociceptive effect of the α₂‐adrenoceptor agonist clonidine was investigated with and without prior treatment with the α₂‐antagonist rauwolscine. Drugs were introduced into the skin by iontophoresis, and burns were induced by heating the skin to 48°C for 2min. Heat pain thresholds to a temperature ramp (0.5°C/s), and heat pain ratings to a thermal stimulus (45°C, 7s), were determined before and after the administration of each drug. Thermal hyperalgesia provoked by phenylephrine was inhibited by terazosin administered after the burn injury, but not by terazosin administered before the burn injury. However, neither α₂‐adrenoceptor stimulation nor blockade affected sensitivity to heat in the mildly burnt skin. These findings suggest that stimulation of cutaneous α₁‐adrenoceptors increased the excitability of heat‐sensitized nociceptive afferents. As terazosin was more effective when administered in burnt skin, an inflammatory response induced by the burn injury may have facilitated access of adrenergic agents to α₁‐adrenoceptors.     

电刺激在痛觉功能磁共振成像研究中的应用

目的探讨直流脉冲电刺激在痛觉功能磁共振成像（fMRI）研究中的应用与价值。方法采用Medtronic全功能肌电图／诱发电位仪对10名健康右利手志愿者分别施加1倍痛阈、2倍痛阈、3倍痛阈三个不同强度的电刺激任务，同期采用GE1．5T超导型磁共振扫描系统进行全脑fMRI扫描，应用功能性神经图像分析（AFNI）软件包对原始数据进行后处理以获得脑功能图像。结果10名受试者的痛阈测定结果为1．17～2．12mA，平均痛阈强度为1．75mA。实验中所有受试者均顺利完成了各刺激任务，无受试者中途退出实验，数据处理后获得较为理想的脑功能激活图。结论电刺激对于诱发痛觉的强度、频率等各项参数能够达到精确量化，是一种较为理想的刺激方式，在痛觉的fMRI研究中具有重要的价值。     

Spinal cord stimulation in adolescents with complex regional pain syndrome type I (CRPS‐I)

Complex regional pain syndrome type I (CRPS‐I) is not uncommon in children, particularly in adolescent girls. Most often, the condition involves a foot and is characterized by spontaneous pain, tactile allodynia and dysautonomic signs. There is usually a history of a minor, local trauma but sometimes no reasonable cause can be identified, and there are no signs of persistent tissue injury giving rise to ongoing nociception. Common analgesics are generally of no benefit, and the standard treatment includes sociopsychological support, physiotherapy, tricyclic antidepressants and antiepileptic drugs, sympathetic blocks (SB), and cognitive‐behavioural therapy. For a minority of patients who prove to be resistant to such therapies, spinal cord stimulation (SCS) may be tried. The present study comprises seven girls, 11–14 years of age, presenting with severe, incapacitating and therapy‐resistant CRPS‐I, who were subjected to SCS. In two of them, percutaneous electrode implantation had to be performed in general anaesthesia. Trial stimulation was performed in all, but one. In two cases, it was not possible to produce paraesthesias that entirely covered the pain area. A pain relieving effect of SCS was usually not reported until after 1–2 weeks of trial stimulation. After another 2–6 weeks, pain alleviation was complete in five of the seven patients, one to eight years after the intervention. In one case, a local infection necessitated the removal of the electrode; nevertheless a few days of trial stimulation produced substantial pain relief that still persists. In four patients, the SCS use was gradually diminished and eventually the device could be removed. The favourable outcome in all seven cases with no or minor remaining symptoms and without severe recurrences illustrates that SCS may also be an efficient treatment in paediatric cases with exceptionally therapy resistant forms of CRPS I.     

Long-term depression of spinal nociception and pain in man: Influence of varying stimulation parameters

Electrical low-frequency stimulation (LFS) of spinal afferents induces long-term depression (LTD) of nociceptive processing in rodents. LTD and its parameters in man are largely unknown. This study addresses the hypothesis that LTD of spinal nociception and pain in man depends on LFS frequency (0.5, 1, 2 Hz), number of electrical pulses (300, 600, 1200), intensity (relating to pain threshold I_P: 1 × I_P, 2 × I_P, 4 × I_P), and on LFS repetition. One hundred and twenty electrophysiological and psychophysical experiments were performed in 29 healthy volunteers. Painful electrical test stimulation (0.125 Hz) and conditioning LFS were applied to right hand dorsum by a concentric electrode. Somatosensory evoked cortical potentials (SEP) were recorded and volunteers rated stimulus intensity. LFS with 0.5, 1, and 2 Hz induced significant reduction of SEP and pain ratings as compared to Control group. Effect on SEP amplitude after 1 Hz LFS preponderated that of 2 Hz stimulation. LTD of SEP and pain perception was induced by noxious LFS with 300–1200 pulses. SEP suppression augmented with increasing number of pulses. LFS with intensities 2 × I_P and 4 × I_P evoked sustained depression of SEP and pain perception in comparison to Control and 1 × I_P LFS. Established LTD after single LFS was amplified by an additional second LFS. Hence this study provides electrophysiological and psychophysical evidence for LTD of spinal nociceptive processing and pain perception in man and indicates appropriate LFS parameters 1 Hz, 1200 pulses and 4 × I_P for future studies on human LTD.     

Long-term skin temperature measurements - a practical diagnostic tool in complex regional pain syndrome

Despite the development of the IASP criteria, diagnosing complex regional pain syndrome (CRPS) remains a challenge because all symptoms vary interindividually, including the vascular abnormalities. Previous studies showed that skin temperature asymmetries between the affected and contralateral extremity around 2 degrees C are useful for diagnosing CRPS. However, they were either assessed only at one single point in time or during specific investigations including controlled thermoregulatory modulation of sympathetic activity which limits their practicability. The present study evaluated long-term skin temperature changes under everyday circumstances in 22 patients with CRPS, 18 patients with limb pain of other origin and 23 healthy controls. The asymmetries in skin temperature and oscillation number (Q Oscill), the percentage of assessed time with a-synchron temperature changes on both body sides and the determination coefficient of the individual regression (r2 id) were compared between the groups. Patients with CRPS differed significantly from healthy controls in nearly all parameters. Minor differences between both patient groups were found regarding the percentage of assessed time with side difference >2 degrees C (DeltaT2). However, both patient groups differed significantly in parameters characterizing the skin temperature dynamics. A sum score (2 *Q Oscill +r2 id +DeltaT2) allowed diagnosing CRPS with a specificity of 67% vs. patients with other painful diseases and 79% vs. healthy controls (sensitivity: 73%, respectively, 94%) and reflected the severity of the dysfunction in CRPS better than the mean skin temperature side differences alone. The applied skin temperature analysis can be easily applied in the clinical settings and serves as a further facet in the difficult diagnosis of CRPS.     

Viscero‐somatic reflexes in referred pain areas evoked by capsaicin stimulation of the human gut

The interaction between visceral pain and the sympathetic nervous system is only sparsely investigated in quantitative human studies. Referred visceral pain can be evoked experimentally by application of substances such as capsaicin (the pungent substance of chilli pepper) to the gut. The aim of the present study was to induce referred visceral pain from the small and large intestine in 32 volunteers via the stomal opening in patients with ileo‐ or colostomy and quantify the viscero‐somatic reflex responses in these referred pain areas by thermography and laser doppler flowmetry. Capsaicin evoked pain and referred pain areas in all subjects. In the referred pain area, the temperature increased by approximately 0.6°C (P<0.001) and the blood flow by approximately 35AU (P<0.001). Saline was used in a control experiment, and no temperature and blood flow changes were found. The present quantitative human study of viscero‐somatic reflexes showed dramatic sympathetic responses in the referred pain areas after experimentally induced gut pain.     

Middle short gyrus of the insula implicated in pain processing

Different lines of evidence have suggested an involvement of the insular cortex in pain processing. Direct electrical stimulation (ES) of the human insular cortex during surgical procedure sometimes induces painful sensations and painful stimuli induce activation of the insular cortex as shown by functional neuroimaging. Invasive evaluation of epileptic patients by deep brain stereotactically implanted electrodes provides an opportunity to analyze responses induced by ES of the insular cortex in awake and fully conscious patients. For this study, we included 25 patients suffering from drug refractory focal epilepsy with at least one electrode stereotactically implanted in the insular cortex using an oblique approach (transfrontal or transparietal). Out of the 83 responses induced by insular ES, eight (9.6%) were reported by five patients as painful sensations. Four were restricted to the cephalic region and four were felt on the ipsilateral or bilateral upper limbs, the shoulders and the trunk (pinprick sensations). The eight stimulation sites were anatomically localized via image fusion between pre-implantation 3D MRI and post-implantation 3D CT scans revealing the electrode contacts. All sites inducing painful sensations were restricted to the upper portion of the middle short gyrus of the insula. The findings of this study suggest that middle short gyrus is involved in the processing of pain-producing stimuli.     

Long‐term depression of pain‐related cerebral activation in healthy man: An fMRI study

Electrical low‐frequency stimulation (LFS) of cutaneous afferents reliably induces long‐term depression (LTD) of nociception and pain in man. In this study LFS effects on cerebral activation were investigated by functional magnetic resonance imaging (fMRI). In 17 healthy volunteers, nociceptive fibers of right hand dorsum were electrically stimulated via a concentric electrode. Test stimulation sessions consisted of three alternating stimulation periods and rest periods. They were performed before (Pre) and after (Post) conditioning LFS (1200 stimuli, 1 Hz) or 20 min break (Control). Volunteers rated sensory and affective pain perception. Before LFS, test stimulation produced activation in bilateral primary and secondary somatosensory cortex (S1, S2), insula, anterior cingulate cortex (ACC), superior temporal cortex (STG), prefrontal cortex and right inferior parietal lobule (IPL). After LFS, exclusively right IPL was activated. Contrast between Pre and Post LFS indicated significant activity decrease in bilateral S1, S2, and ACC and right insula, IPL, and STG. Pre Control and Pre LFS were not different. Activity in Control experiments remained unchanged. Sensory and affective pain rating solely decreased after LFS. Subsequent regression analysis showed significant correlation between pain relief and increased activity after LFS in ACC, anterior insula, striatum, frontal and temporal cortex. The study revealed LTD of pain‐related cerebral activation, involving sensory, affective, cognitive, and attentional processes. Positive correlation between pain relief and increased brain activation after LFS may indicate involvement of endogenous pain control mechanisms in LTD. These experiments may help to judge the potency of LTD for future chronic pain treatment.     

Adult attachment and reports of pain in experimentally‐induced pain

Attachment theory has been proposed as a framework for understanding the development of chronic pain, with evidence supporting the overrepresentation of insecure attachment styles in chronic pain populations and links between insecure attachment and factors known to impact one's ability to cope with pain. The present study sought to extend two earlier studies exploring the relationships between adult attachment and communication of an acute pain experience, in anticipation of providing insight into individual differences in vulnerability in development of chronic pain. It was hypothesised that: (a) fearful attachment would be associated with perceptions of the pain as less intense, and (b) anxious attachment would be associated with lower pain thresholds. A convenience sample of 82 healthy adults completed self‐report measures of attachment, neuroticism, and negative affect prior to taking part in a coldpressor pain inducement task. Results demonstrated that fearful attachment was associated with lower levels of pain intensity throughout the coldpressor task. In addition, dismissing attachment was also associated with less intense pain, as well as increased coldpressor endurance (tolerance) in the presence of a known assessor. These associations were retained after controlling for measures of neuroticism, negative affect, age, and social desirability. The results of this study are consistent with the proposition that fearful and dismissing individuals tend to mask their underlying distress caused by the pain experience, potentially leading to difficulties coping with pain over time.     

Ultraviolet‐B induced inflammation of human skin: Characterisation and comparison with traditional models of hyperlagesia

The effect on human skin of over‐exposure to solar ultraviolet radiation (UVR) has been well described. The erythema produced is commonly referred to as ‘sunburn’. Recently UVR induced inflammation has been utilised as a human model of sub‐acute pain. Our aim was to characterise the sensory phenotype of UVB inflammation in human volunteers. We delivered UVB to small areas of volar forearm skin in healthy volunteers and found that the degree of inflammation and concomitant increase in sensitivity to cutaneous stimuli were UVB dose and time dependant. We directly compared UVB induced inflammation and the more established thermal burn and topical capsaicin pain models. UVB inflammation produced precisely demarcated erythematous lesions without secondary flare. Both thermal burns and topical capsaicin produced large areas of flare, indistinguishable in character from the primary lesions. Moreover, UVB inflammation induced large reductions in mechanical pain threshold restricted to the primary lesion site, whereas the more established inflammatory pain models produced not only primary hypersensitivity but also significant areas of secondary mechanical hypersensitivity. Taken together these findings suggest that UVB inflammation, at least using moderate doses produces sensory changes primarily by sensitising peripheral pain processing in the relative absence of alterations in central pain processing.     

Autonomic pain responses during sleep: A study of heart rate variability

The autonomic nervous system (ANS) reacts to nociceptive stimulation during sleep, but whether this reaction is contingent to cortical arousal, and whether one of the autonomic arms (sympathetic/parasympathetic) predominates over the other remains unknown. We assessed ANS reactivity to nociceptive stimulation during all sleep stages through heart rate variability, and correlated the results with the presence of cortical arousal measured in concomitant 32‐channel EEG. Fourteen healthy volunteers underwent whole‐night polysomnography during which nociceptive laser stimuli were applied over the hand. RR intervals (RR) and spectral analysis by wavelet transform were performed to assess parasympathetic (HF^WV) and sympathetic (LF^WV and LF^WV/HF^WV ratio) reactivity. During all sleep stages, RR significantly decreased in reaction to nociceptive stimulations, reaching a level similar to that of wakefulness, at the 3rd beat post‐stimulus and returning to baseline after seven beats. This RR decrease was associated with an increase in sympathetic LF^WV and LF^WV/HF^WV ratio without any parasympathetic HF^WV change. Albeit RR decrease existed even in the absence of arousals, it was significantly higher when an arousal followed the noxious stimulus. These results suggest that the sympathetic‐dependent cardiac activation induced by nociceptive stimuli is modulated by a sleep dependent phenomenon related to cortical activation and not by sleep itself, since it reaches a same intensity whatever the state of vigilance.     

fMRI of pain processing in the brain: a within-animal comparative study of BOLD vs. CBV and noxious electrical vs. noxious mechanical stimulation in rat

This study aims to identify fMRI signatures of nociceptive processing in whole brain of anesthetized rats during noxious electrical stimulation (NES) and noxious mechanical stimulation (NMS) of paw. Activation patterns for NES were mapped with blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) fMRI, respectively, to investigate the spatially-dependent hemodynamic responses during nociception processing. A systematic evaluation of fMRI responses to varying frequencies of electrical stimulus was carried out to optimize the NES protocol. Both BOLD and CBV fMRI showed widespread activations, but with different spatial characteristics. While BOLD and CBV showed well-localized activations in ipsilateral dorsal column nucleus, contralateral primary somatosensory cortex (S1), and bilateral caudate putamen (CPu), CBV fMRI showed additional bilateral activations in the regions of pons, midbrain and thalamus compared to BOLD fMRI. CBV fMRI that offers higher sensitivity compared to BOLD was then used to compare the nociception processing during NES and NMS in the same animal. The activations in most regions were similar. In the medulla, however, NES induced a robust activation in the ipsilateral dorsal column nucleus while NMS showed no activation. This study demonstrates that (1) the hemodynamic response to nociception is spatial-dependent; (2) the widespread activations during nociception in CBV fMRI are similar to what have been observed in ¹⁴C-2-deoxyglucose (2DG) autoradiography and PET; (3) the bilateral activations in the brain originate from the divergence of neural responses at supraspinal level; and (4) the similarity of activation patterns suggests that nociceptive processing in rats is similar during NES and NMS.     

Depletion of capsaicin sensitive afferents prevents lamina‐dependent increases in spinal N‐methyl‐d‐aspartate receptor subunit 1 expression and phosphorylation associated with thermal hyperalgesia in neuropathic rats

Phosphorylation of the N‐methyl‐d ‐aspartate (NMDA) receptor NR1 subunit (pNR1) in the spinal cord is associated with increased neuronal responsiveness, which underlies the process of central sensitization. Because of the importance of NR1 in central sensitization, the first goal of this study was to examine both time‐ and lamina‐dependent changes in spinal NR1 and pNR1 expression in a chronic constriction injury (CCI) model of neuropathic pain. Increased excitability of capsaicin sensitive primary afferents (CSPAs), which express TRPV1 receptors, also contributes to central sensitization. Thus, we next examined whether the depletion of CSPAs with resiniferatoxin (RTX) modified the change of spinal NR1 and pNR1 expression induced by CCI. Experimental rats were euthanized at 1, 3, 7, 14, and 28 days post‐CCI surgery and spinal cords processed for NR1 or pNR1 immunostaining. The number of NR1 or pNR1‐immunoreactive neurons was significantly increased in all lamina (I–VI) of the ipsilateral L4/L5 dorsal horn from 1 or 7 days post‐CCI, respectively. Pretreatment with RTX (0.3mg/kg, s.c. in the scruff of the neck or intraplantar) 2 days prior to CCI completely prevented induction of thermal hyperalgesia, but not mechanical allodynia in neuropathic rats. Interestingly, RTX treatment significantly attenuated the CCI‐induced upregulation of NR1 and pNR1 in spinal laminae I–II and V–VI, but not laminae III–IV as compared with that of vehicle‐treated CCI rats. These findings demonstrate that the increased expression of NR1 and pNR1 in spinal laminae I–II and V–VI is dependent on activation of CSPAs, which ultimately contribute to the development of thermal hyperalgesia in neuropathic rats.     

Reversal of neuropathic pain by HSV-1-mediated decrease of noradrenaline in a pain facilitatory area of the brain

Descending modulation of nociceptive transmission depends on the release of noradrenaline at the spinal cord. The role of noradrenaline in the control of nociceptive transmission at the supraspinal pain control system remains understudied. As chronic pain is associated with enhanced descending facilitation of nociceptive transmission, we sought to determine the role of noradrenaline in pain facilitation from the brain during neuropathic pain. We determined the action of the noradrenergic input to the dorsal reticular nucleus (DRt), a unique pain facilitatory area, using the spared nerve injury model. Injections of the α1-adrenoreceptor agonist phenylephrine into the DRt induced hyperalgesia and allodynia, indicating that α1-adrenoreceptors enhance the facilitatory action of the nucleus. This led us to reduce noradrenaline release at the DRt using a viral vector derived from the Herpes Simplex virus type 1 (HSV-1) which carried the tyrosine hydroxylase (TH) transgene in antisense orientation. The reduction of noradrenaline release, confirmed by microdialysis experiments, induced a long-lasting attenuation of pain responses, which was reverted by the local administration of phenylephrine. The present study indicates that the noradrenergic modulation of a pronociceptive area at the supraspinal pain control system accounts for pain facilitation, through the activation of α1-adrenoreceptors. The study also shows that sustained effects on chronic pain can be achieved by decreasing the release of noradrenaline in a pain facilitatory centre of the brain using gene transfer.     

The effects of skin‐to‐skin contact during acute pain in preterm newborns

Background and purpose: Several promising non‐pharmacological interventions have been developed to reduce acute pain in preterm infants including skin‐to‐skin contact between a mother and her infant. However, variability in physiological outcomes of existing studies on skin‐to‐skin makes it difficult to determine treatment effects of this naturalistic approach for the preterm infant. The aim of this study was to test the efficacy of mother and infant skin‐to‐skin contact during heel prick in premature infants. Method: Fifty nine stable preterm infants (born at least 30 weeks gestational age) who were undergoing routine heel lance were randomly assigned to either 15min of skin‐to‐skin contact before, during and following heel prick (n=31, treatment group), or to regular care (n=28, control group). Throughout the heel lance procedure, all infants were assessed for change in facial action (NFCS), behavioral state, crying, and heart rate. Results: Statistically significant differences were noted between the treatment and control groups during the puncture, heel squeeze and the post phases of heel prick. Infants who received skin‐to‐skin contact were more likely to show lower NFCS scores throughout the procedure. Both groups of infants cried and showed increased heart rate during puncture and heel squeeze although changes in these measures were less for the treated infants. Conclusions: Skin‐to‐skin contact promoted reduction in behavioral measures and less physiological increase during procedure. It is recommended that skin‐to‐skin contact be used as a non‐pharmacologic intervention to relieve acute pain in stable premature infants born 30 weeks gestational age or older.     

血氧水平依赖功能磁共振成像技术分析正常成人痛觉相关皮层中枢的分布及量化特征

目的 应用血氧水平依赖功能磁共振成像(BOLD-fMRI)技术,分析正常成人痛觉相关皮层中枢的分布及量化特征.方法 选取10名正常成人志愿者,测定其痛阈并给予利手和非利手腕部2倍痛阈的电刺激,同时进行脑功能BOLD-fMRI扫描,应用SPM5进行后处理获得脑功能图像和数据,对脑激活区进行定位并测定其体积、强度.结果 刺激利手时激活对侧Brodmann Area(BA)3、1、2区7例,BA40区5例,BA5、7区3例,BA9、10、11区3例,BA6、8区2例,激活同侧BA5、7区2例,BA9、10、11区2例,BA6、8区3例;刺激非利手时激活对侧BA3、1、2区7例,BA40区6例,BA5、7区3例,BA9、10、11区2例,BA6、8区1例,激活同侧BA5、7区3例,BA9、10、11区1例,BA6、8区2例.3例在刺激两侧时BA3、1、2区和BA5、7区均没有激活,刺激利手时激活对侧BA40区2例、BA6区2例、前额叶皮质1例,刺激非利手时激活对侧BA40区2例、BA6区1例、前额叶皮质1例.结论 痛觉刺激可同时激活一般躯体感觉中枢、缘上回、辅助运动区、边缘系统等相关的皮层中枢,从而引发情绪、认知和内脏系统以及躲避反应等一系列相关活动.     

Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: diffuse noxious inhibitory controls in the trigeminal nerve territory.

The purpose of this study was to determine whether the late component of somatosensory evoked potentials (SEP) induced by electrical tooth stimulation and pain intensity are inhibited by heterotopic ischemic stimulation. The tourniquet pressure with 50 mmHg greater than the individual's systolic pressure was applied to the left upper arm for 10 min as ischemic conditioning stimulation. The late component of SEP and visual analogue scale (VAS) were recorded at 4 times and both were significantly decreased when ischemic conditioning stimulation was applied. The maximum reductions in SEP amplitude and the VAS value were 26.1% and 21.2%, respectively, during ischemic conditioning stimulation. After-effect was observed 5 min after removal of the conditioning stimulation. The present study revealed that heterotopic ischemic stimulation attenuated the late component of SEP induced by electrical tooth stimulation, triggering diffuse noxious inhibitory controls (DNIC) and after-effects in the trigeminal nerve territory. It was also suggested that the DNIC effect differs, depending on the intensity, kind, and quality of the test and conditioning stimuli.     

Electric muscle stimulation of the quadriceps in the treatment of patellofemoral pain

OBJECTIVE: To compare a commercially available electric muscle stimulation regimen with a novel form of stimulation for the rehabilitation of the quadriceps muscle, in patients with patellofemoral pain syndrome. DESIGN: Double-blinded randomized trial with a parallel control group and stratified randomization. SETTING: Home-based rehabilitation program assessed in research center. PARTICIPANTS: Eighty patients (47 women, 33 men) with patellofemoral pain syndrome. INTERVENTIONS: One group (EMPI) received 1 uniform constant frequency component of 35Hz. The other (EXPER) group received an experimental form of stimulation that contained 5 simultaneously delivered frequency components of 125, 83, 50, 2.5, and 2Hz. Stimulation was applied to the quadriceps muscles of the affected leg for 1 hour daily for 6 weeks, a total of 42 treatments. MAIN OUTCOME MEASURES: Lower-limb isometric and isokinetic torque, quadriceps fatigue, knee flexion, patellar pain, a step test, quadriceps cross-sectional area, and Kujala patellofemoral score for pain before and after treatment. RESULTS: Seventy-four patients (43 women, 31 men) completed the trial. Patients in both groups showed significant improvements in all outcomes (P<.05). No significant differences existed between the 2 stimulators in any outcome (P>.05) except for quadriceps cross-sectional area (P=.023). CONCLUSIONS: One form of stimulation was just as efficacious as the other in improving subjective and objective measures.     

Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex

The question whether pain encoding in the human insula shows some somatotopic organization is still pending. We studied 142 patients undergoing depth stereotactic EEG (SEEG) exploration of the insular cortex for pre-surgical evaluation of epilepsy. 472 insular electrical stimulations were delivered, of which only 49 (10.5%) elicited a painful sensation in 38 patients (27%). Most sites where low intensity electric stimulation produced pain, without after-discharge or concomitant visually detectable change in EEG activity outside the insula, were located in the posterior two thirds of the insula. Pain was located in a body area restricted to face, upper limb or lower limb for 27 stimulations (55%) and affected more than one of these regions for all others. The insular cortex being oriented parallel to the medial sagittal plane we found no significant difference between body segment representations in the medio-lateral axis. Conversely a somatotopic organization of sites where stimulation produced pain was observed along the rostro-caudal and vertical axis of the insula, showing a face representation rostral to those of upper and lower limbs, with an upper limb representation located above that of the lower limb. These data suggest that, in spite of large and often bilateral receptive fields, pain representation shows some degree of somatotopic organization in the human insula.