Relationship between Motor Corticospinal System, Endogenous Pain Modulation Mechanisms and Clinical Symptoms in Patients with Knee Osteoarthritis: New Perspectives on an Old Disease.

Knee osteoarthritis (OA) is a painful condition characterized by joint and bone changes. A growing number of studies suggest that these changes only partially explain the pain experienced by individuals with OA. The purpose of the current study was to evaluate if corticospinal and bulbospinal projection measurements were interrelated in patients with knee OA, and to explore the relationship between these neurophysiological measures and temporal summation (excitatory mechanisms of pain) on one hand, and clinical symptoms on the other. Twenty-eight (28) patients with knee OA were recruited. Corticospinal projections were measured using transcranial magnetic stimulation, while bulbospinal projections were evaluated with a conditioned pain modulation (CPM) protocol using a counter-irritation paradigm. Validated questionnaires were used to document clinical and psychological manifestations. All participants suffered from moderate to severe pain. There was a positive association between corticospinal excitability and the effectiveness of the CPM (rs = 0.67, p = 0.01, n = 13). There was also a positive relationship between pain intensity and corticospinal excitability (rs = 0.45, p = 0.03, n = 23), and between pain intensity and temporal summation (rs = 0.58, p = 0.01, n = 18). The results of this study highlight some of the central nervous system changes that could be involved in knee OA and underline the importance of interindividual variability to better understand and explain the semiology and pathophysiology of knee OA.

Sex-Related Effects of Adrenergic Drugs on Conditioned Pain Modulation: A Randomized Controlled Cross-Over Double-Blind Trial.

Objective: Endogenous pain inhibition can be investigated using conditioned pain modulation (CPM). CPM efficacy has been reported to be influenced by various factors, such as gender and cardiovascular (autonomic) activity. The aim of this study is to describe the effect of pharmacological manipulations of autonomic activity on CPM efficacy. Methods: Thirty healthy participants were enrolled to assess CPM efficacy in 4 experimental sessions. The first session consisted of the determination of baseline CPM effectiveness. The three following sessions were performed in a randomized order and consisted of the injection of (1) esmolol, (2) ephedrine, or (3) placebo, before the conditioning stimulus. Pain intensity induced by using a contact heat stimulation thermode was compared before and after a cold-pressure conditioning stimulus to evaluate CPM effectiveness. Results: Our results show that inhibiting sympathetic nervous activity with esmolol did not have a significant effect on CPM. Conversely, enhancing sympathetic nervous activity with ephedrine increased CPM effectiveness in healthy women but decreased it in men. Conclusions: Increasing sympathetic activity with adrenergic agonists, such as ephedrine, could improve CPM effectiveness in women. It will be interesting to verify if the same results are present in patients suffering from chronic pain and if adrenergic agonists could have better therapeutic effects in women showing reduced CPM effectiveness.

Relieving Chronic Musculoskeletal Pain in Older Adults Using Transcranial Direct Current Stimulation: Effects on Pain Intensity, Quality, and Pain-Related Outcomes.

Introduction: Chronic pain is a significant health problem and is particularly prevalent amongst the elderly. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has been proposed to reduce chronic pain. The aim of this study was to evaluate and compare the efficacy of active and sham tDCS in reducing pain in older individuals living with chronic musculoskeletal pain. Materials and Methods: Twenty-four older individuals (mean age: 68 ± 7 years) suffering from chronic musculoskeletal pain were randomized to receive either anodal tDCS over the contralateral motor cortex (2 mA, 20 min; n = 12) or sham tDCS (20 min; n = 12) for five consecutive days. Pain logbooks were used to measure pain intensity. Questionnaires (McGill Pain Questionnaire, Brief Pain Inventory, Beck Depression Inventory [BDI], Beck Anxiety Inventory, Pain Catastrophizing Scale [PCS], and Margolis Pain Drawing and Scoring System [MPDSS]) were also used to assess pain in its globality. Results: Analysis of pain logbooks revealed that active tDCS led to a reduction in daily average pain intensity (all p ≤ 0.04), while sham tDCS did not produce any change (p = 0.15). Between-group comparisons for change in pain intensity reduction between active and sham tDCS showed a trend during treatment (p = 0.08) which was significant at the follow-up period (p = 0.02). Active tDCS also improved scores of all questionnaires (all p ≤ 0.02), while sham tDCS only reduced MPDSS scores (p = 0.04). Between-group comparisons for the pain-related outcomes showed significant differences for BDI et PCS after the last tDCS session. Conclusions: These results suggest that anodal tDCS applied over the primary motor cortex is an effective modality to decrease pain in older individuals. tDCS can also improve other key outcomes, such as physical and emotional functioning, and catastrophic thinking.

Decreased Initial Peak Pain Sensation with Aging: A Psychophysical Study.

BACKGROUND AND PURPOSE: Aging is associated with an impairment of diverse physiological functions, including nociception. For example, older adults in comparison to young adults, show an overall increase in pain thresholds, reflecting a decline in pain sensitivity and changes in the nociceptive pathways. These results are, however, debated as they were not always replicated depending on the stimulus modality, duration, and location. The aim of the current study was to determine how the temporal evolution of pain intensity during a continuous tonic heat pain test is influenced by aging. More specifically, we wanted to 1) assess the effect of age on initial peak and late-phase pain and 2) determine whether potential age effects depend on the stimulation site. PARTICIPANTS AND METHODS: 13 young adults (average of 27.9 years old) and 13 older adults (average of 67.5 years old) participated in this study. Experimental heat pain was evoked on an appendicular (forearm) and axial (lower-back) body region, using a thermode (2-minute stimulation at a constant, individually-adjusted temperature). During the nociceptive stimulation, participants used a computerized visual analogue scale to continuously rate their pain. RESULTS: We show that initial peak (0-30 seconds) pain sensation was significantly lower in older adults compared to young adults, while late-phase (30-120 seconds) pain sensation was similar across the two age groups. These results hold true for both stimulation sites, suggesting the existence of an age effect on both appendicular and axial body regions. CONCLUSION: The lower magnitude of initial peak pain observed in older adults, which affects both appendicular and axial body regions, could reflect generalized peripheral or central alterations of the nociceptive system in older adults. These alterations in older adults could have significant clinical impacts, such as an increased vulnerability to injury or an underestimation of the severity of their pain condition.

Combining Transcranial Direct Current Stimulation and Transcutaneous Electrical Nerve Stimulation to Relieve Persistent Pain in a Patient Suffering from Complex Regional Pain Syndrome: A Case Report.

PURPOSE: Complex regional pain syndrome (CRPS) is a rare neuropathic pain condition characterized by sensory, motor and autonomic alterations. Previous investigations have shown that transcranial direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) can alleviate pain in various populations, and that a combination of these treatments could provide greater hypoalgesic effects. In the present case report, we describe the effect of tDCS and TENS treatment on pain intensity and unpleasantness in a patient suffering from chronic CRPS. RESULTS: The patient was a 37-year-old woman, suffering from left lower limb CRPS (type I) for more than 5 years. Despite medication (pregabalin, tapentadol, duloxetine), rehabilitation treatments (sensorimotor retraining, graded motor imagery) and spinal cord stimulation (SCS), the participant reported moderate to severe pain. Treatments of tDCS alone (performed with SCS turned off during tDCS application, 1 session/day, for 5 consecutive days) did not significantly decrease pain. Combining tDCS with TENS (SCS temporarily turned off during tDCS, 1 session/day, for 5 consecutive days) slightly reduced pain intensity and unpleasantness. DISCUSSION: Our results suggest that combining tDCS and TENS could be a therapeutic strategy worth investigating further to relieve pain in chronic CRPS patients. Future studies should examine the efficacy of combined tDCS and TENS treatments in CRPS patients, and other chronic pain conditions, with special attention to the cumulative and long-term effects and its effect on function and quality of life.

Perturbing the activity of the superior temporal gyrus during pain encoding prevents the exaggeration of pain memories: A virtual lesion study using single-pulse transcranial magnetic stimulation.

BACKGROUND: Past studies have shown that pain memories are often inaccurate, a phenomenon known as mnemonic pain bias. Pain memories are thought to play an important role on how future pain is felt. Recent evidence from our laboratory suggests that individuals who exaggerate past pain display increased superior temporal gyrus (STG) activity during the encoding of experimental painful stimulations, suggesting that this brain structure plays an important role in pain memories. OBJECTIVE: /hypothesis. To determine whether a virtual lesion paradigm, targeting the STG during pain encoding, can affect long-lasting pain memories. We hypothesized that interfering with the activity of the STG would attenuate mnemonic bias. METHODS: Randomized double-blind study with two parallel groups. Participants received either sham (n = 21) or real (n = 21) transcranial magnetic stimulation (TMS - virtual lesion paradigm) over the STG during pain encoding (milliseconds after the administration of a painful stimuli). Pain intensity and unpleasantness were evaluated using a visual analog scale (VAS; 0 to 10) immediately after the painful event, and at recall, 2 months later. The mnemonic pain bias (calculated by subtracting the pain scores obtained at recall from the pain score obtained during encoding) was compared between the two groups for both pain intensity and unpleasantness. RESULTS: Participants in both groups did not differ in terms of age and gender (real TMS = 27 years ±â€¯9, 43% female; sham TMS = 25 years ±â€¯4, 49% female; p > 0.64). The mnemonic bias related to pain intensity was similar in both groups (p = 0.83). However, the mnemonic bias related to pain unpleasantness was lower in the real TMS group (p = 0.04). CONCLUSIONS: Our results provide the first evidence that the STG, is causally involved in the formation of biased memories of pain unpleasantness.

Transcranial Magnetic Stimulation Measures in the Elderly: Reliability, Smallest Detectable Change and the Potential Influence of Lifestyle Habits.

Background: Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to evaluate cortical function and corticospinal pathway in normal and pathological aging. Yet, the metrologic properties of TMS-related measurements is still limited in the aging population. Objectives: The aim of this cross-sectional study was to document the reliability and smallest detectable change of TMS measurements among community-dwelling seniors. A secondary objective was to test if TMS measurements differ between elders based on lifestyle, medical and socio-demographic factors. Methods: Motor evoked potentials (MEPs) elicited by single-pulse TMS were recorded in the first dorsal interosseous (FDI) in 26 elderly individuals (mean age = 70 ± 3.8 years). Resting motor threshold (rMT), MEP amplitudes and contralateral silent period (cSP) were measured on two separate occasions (1-week interval), and the standard error of the measurement (SEMeas), intraclass correlation coefficient (ICC), and smallest detectable change in an individual (SDCindv) were calculated. Lifestyle, medical and socio-demographic factors were collected using questionnaires. TMS-related outcomes were compared using independent sample t-test based on the presence of chronic health diseases, chronic medication intake, obesity, history of smoking, physical activity levels, gender, and level of education. Results: rMT and cSP measures were the most reliable outcomes, with the lowest SEMeas and highest ICCs, whereas MEP amplitude-related measures were less reliable. SDCindv levels were generally high, even for rMT (7.29 %MSO) and cSP (43.16-50.84 ms) measures. Although not systematically significant, results pointed toward a higher corticospinal excitability in elderly individuals who were regularly active, who had no chronic medical conditions and who did not take any medication. Conclusion: Even though SDCindv levels were relatively high, these results show that rMT and cSP are the most reliable outcomes to investigate age-related changes in the corticomotor system and suggest that the influence of factors such as lifestyle habits and medications on TMS measures should be investigated further.

Transcutaneous electrical nerve stimulation and placebo analgesia: is the effect the same for young and older individuals?

PURPOSE: Placebo analgesia refers to a perceived reduction in pain intensity following the administration of a simulated or otherwise medically ineffective treatment. Previous studies have shown that many factors can influence the magnitude of placebo analgesia. However, few investigations have examined the effect of age on placebo analgesia, and none have done it in the context of electrotherapeutic interventions. The objective of this study is to compare the placebo response induced by sham transcutaneous electrical nerve stimulation (TENS) between young and older individuals, using an experimental heat-pain paradigm. PATIENTS AND METHODS: Twenty-two young (21-39 years) and 22 older (58-76 years) healthy adults participated in this comparative study. Experimental heat pain was evoked with a thermode (2-min stimulation at a constant individually adjusted temperature) applied on the lumbar region. Participants were asked to evaluate the intensity of their pain using a computerized visual analog scale. Experimental pain was induced before and after an unconditioned placebo intervention (placebo TENS) applied for 25 min. RESULTS: In young individuals, no significant pain reductions were noted, whereas in older individuals, a statistically significant pain reduction was observed after the placebo stimulation (P<0.01). Between-group analyses revealed that placebo analgesia was greater in older individuals (40% pain reduction) compared with young individuals (15% pain reduction) (P<0.05). However, sham TENS increased heat-pain thresholds in the young group (P<0.01), but not in the older group (P=0.43). CONCLUSION: Our results indicate that placebo analgesia is influenced by age, with older individuals showing larger placebo analgesia than young adults. Although these results should be confirmed in clinical pain populations, the current observations bear potentially important consequences for the design of future placebo-controlled trials and for healthcare professionals working with elderly patients.

Evidence of motor system reorganization in complex regional pain syndrome type 1: A case report.

BACKGROUND: Central nervous system reorganization, particularly in networks devoted to somatosensation, is thought to be a significant feature of complex regional pain syndrome (CRPS). AIMS: In the present case report, we evaluated the corticomotor system of a woman suffering from CRPS, as she started and completed her rehabilitation, in order to explore whether CRPS could also be linked to changes in motor networks. METHODS: The patient, a 58-year-old woman, was diagnosed with right-hand CRPS. Transcranial magnetic stimulation measures, reflecting the strength of the corticospinal projections, were evaluated before, during, and after an 8-week graded motor imagery (GMI) program. RESULTS: Before treatment, the patient reported significant pain and disability, and the strength of the corticospinal projections of the first dorsal interosseous of the affected hand was reduced compared to the healthy, unaffected hand. Pain and disability decreased as the patient completed the GMI program. These changes were paralleled by an increase in the strength of the corticospinal projections. CONCLUSIONS: These observations suggest that corticomotor changes can be observed in individuals suffering from CRPS and that some of the clinical manifestations observed in these patients (e.g., pain, disability) could possibly be linked to these neurophysiological changes.

Contexte: La réorganisation du système nerveux central des réseaux cérébraux, en particulier ceux liés à la somatosensation, est connue comme une caractéristique importante du syndrome douloureux régional complexe (SDRC).But: Dans la présente étude de cas, nous avons évalué le système corticomoteur d'une femme souffrant du SDRC, du début à la fin de sa réadaptation, afin de déterminer si le SDRC pouvait aussi être lié à des changements dans les réseaux moteurs.Méthode: La patiente, une femme âgée de 58 ans, avait reçu un diagnostic de SDRC au niveau de la main droite. Des mesures de stimulation magnétique transcrânienne reflétant la force des projections corticospinales ont été évaluées avant, pendant et après un programme d'imagerie motrice progressive (IMP) d'une durée de huit semaines.Résultats: Avant le traitement, la patiente rapportait douleur et une incapacité importantes, et la force de ses projections corticospinales du premier interosseux dorsal de la main affectée, comparativement à la main saine, non affectée était réduite. La douleur et l'incapacité ont diminué pendant le programme d'IMP. Parallèllement à ces changements, une augmentation de la force des projections corticospinales a été observée.Conclusions: Ces observations suggèrent que des changements corticomoteurs peuvent être observés chez des individus souffrant de SDRC, et que certaines manifestations cliniques observées chez ces patients (ex.: la douleur, l'incapacité) pourraient être liées à ces changements neurophysiologiques.

Can We Quickly and Thoroughly Assess Pain with the PACSLAC-II? A Convergent Validity Study in Long-Term Care Residents Suffering from Dementia.

A previous study found that the modified version of the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC-II) is a valid tool to assess pain in elderly individuals suffering from dementia and who are unable to communicate verbally. The primary objective of this study was to confirm the convergent validity of the PACSLAC-II using direct evaluation of long-term care residents in real-life situations, using two other well-validated pain assessment scales (i.e., PACSLAC and Pain Assessment in Advanced Dementia [PAINAD]). A secondary objective was to document and compare the time required to complete and score each assessment scale. During two potentially painful procedures (i.e., transfer/mobilization), 46 long-term care residents (mean age = 83 ± 10 years) suffering from dementia were observed by three independent evaluators, each using one of the assessment scales (randomly assigned). Correlational analyses and analysis of variance were used to evaluate the association between each scale and to compare scoring time. The PACSLAC (r = 0.61) and the PAINAD (r = 0.65) were both moderately associated with the PACSLAC-II (all p values < .001). The PAINAD's average scoring time (63 ± 19 seconds) was lower than the PACSLAC-II's (96 ± 2 seconds), which was lower than the PACSLAC's (135 ± 53 seconds) (all p values < .001). These results suggest that the PACSLAC-II is a valid tool for assessing pain in individuals with dementia. The time required to complete and score the PACSLAC-II was reasonable, supporting its usefulness in clinical settings.

Non-invasive stimulation techniques to relieve abdominal/pelvic pain: Is more always better?

Chronic abdominal and pelvic pain is a common condition that has significant impact on quality of life, and causes billions of dollars in direct and indirect costs. Emerging data suggest that transcranial direct current stimulation (tDCS), alone or in combination with transcutaneous electrical nerve stimulation (TENS), could be a promising therapeutic avenue to reduce chronic pain. The encouraging results coming from these studies prompted us to try combining TENS and tDCS in 4 of our patients who suffered from chronic abdominal/pelvic pain and to compare the effect with 5 other patients who received TENS alone. Pain intensity was assessed with a visual analog scale before, during and after the stimulation. We observed that there was a slight decrease in pain which was similar in both patient groups (TENS alone and TENS combined with tDCS). These observations suggest that combining TENS and tDCS in patients suffering from chronic pelvic and/or abdominal pain produces no additional benefit, compared to TENS alone. Future studies, looking at the effect of several/consecutive TENS and tDCS sessions should be conducted.

Can we improve pain and sleep in elderly individuals with transcranial direct current stimulation? - Results from a randomized controlled pilot study.

BACKGROUND: The prevalence of chronic pain and sleep disturbances substantially increases with age. Pharmacotherapy remains the primary treatment option for these health issues. However, side effects and drug interactions are difficult to control in elderly individuals. AIMS: The objective of this study was to assess the feasibility of conducting a randomized sham-controlled trial and to collect preliminary data on the efficacy of transcranial direct current stimulation (tDCS) to reduce pain and improve sleep in older adults suffering from chronic pain. METHODS: Fourteen elderly individuals (mean age 71±7 years) suffering from chronic pain and sleep complaints were randomized to receive either anodal tDCS, applied over the primary motor cortex (2 mA, 20 minutes), or sham tDCS, for 5 consecutive days. Pain was measured with visual analog scales, pain logbooks and questionnaires, while sleep was assessed with actigraphy, sleep diaries and questionnaires. RESULTS: There were no missing data for pain and sleep measures, except for actigraphy, that generated several missing data. Blinding was maintained throughout the study, for both the evaluator and participants. Active but not sham tDCS significantly reduced pain (P<0.05). No change was observed in sleep parameters, in both the active and sham tDCS groups (all P≥0.18). CONCLUSION: The present study provides guidelines for the implementation of future tDCS studies in larger populations of elderly individuals. M1 anodal tDCS in this population appears to be effective to reduce pain, but not to improve sleep.

Unravelling the effect of experimental pain on the corticomotor system using transcranial magnetic stimulation and electroencephalography.

The interaction between pain and the motor system is well-known, with past studies showing that pain can alter corticomotor excitability and have deleterious effects on motor learning. The aim of this study was to better understand the cortical mechanisms underlying the interaction between pain and the motor system. Experimental pain was induced on 19 young and healthy participants using capsaicin cream, applied on the middle volar part of the left forearm. The effect of pain on brain activity and on the corticomotor system was assessed with electroencephalography (EEG) and transcranial magnetic stimulation (TMS), respectively. Compared to baseline, resting state brain activity significantly increased after capsaicin application in the central cuneus (theta frequency), left dorsolateral prefrontal cortex (alpha frequency), and left cuneus and right insula (beta frequency). A pain-evoked increase in the right primary motor cortex (M1) activity was also observed (beta frequency), but only among participants who showed a reduction in corticospinal output (as depicted by TMS recruitment curves). These participants further showed greater beta M1-cuneus connectivity than the other participants. These findings indicate that pain-evoked increases in M1 beta power are intimately tied to changes in the corticospinal system, and provide evidence that beta M1-cuneus connectivity is related to the corticomotor alterations induced by pain. The differential pattern of response observed in our participants suggest that the effect of pain on the motor system is variable from on individual to another; an observation that could have important clinical implications for rehabilitation professionals working with pain patients.

High- and low-frequency transcutaneous electrical nerve stimulation does not reduce experimental pain in elderly individuals.

Despite its widespread clinical use, the efficacy of transcutaneous electrical nerve stimulation (TENS) remains poorly documented in elderly individuals. In this randomized, double-blind crossover study, we compared the efficacy of high-frequency (HF), low-frequency (LF), and placebo (P) TENS in a group of 15 elderly adults (mean age: 67 ± 5 years). The effect of HF-, LF-, and P-TENS was also evaluated in a group of 15 young individuals (26 ± 5 years; same study design) to validate the effectiveness of the TENS protocols that were used in the elderly group. Each participant came to the laboratory on 3 separate occasions to receive, in random order, HF-, LF-, and P-TENS. Pain intensity and pain perception thresholds were assessed before, during, and after TENS, using an experimental heat pain paradigm. For the young group, there was a significant decrease in pain intensity during and after HF- and LF-TENS when compared with baseline, with both HF- and LF-TENS being superior to P-TENS. In the older group, HF- and LF-TENS did not reduce pain when compared with baseline and no difference was observed between the 2 active TENS sessions and P-TENS. High-frequency, LF-, and P-TENS all increased pain thresholds in young individuals, whereas in older individuals, only LF-TENS increased pain thresholds. Taken together, these results suggest that TENS is effective in young, but not in older, individuals. Future studies should be conducted to confirm these results in pain populations and to identify strategies that could enhance the effect of TENS in the elderly.