Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology

The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19-65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0-10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0-10) during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inteThis research was supported by grants and materials support from the following Brazilian agencies: (grants to; AD, JAD-S, FC) and material support. National Council for Scientific and Technological Development-CNPq (grants to ILdST, WC). Postgraduate Program in Medical Sciences at the School of Medicine of the Federal University of Rio Grande do Sul (material support). International Cooperation Program-CAPES-PGI-project (023-11). CAPES 129/2013 material support and grant for FP as visiting professor (AD, WC, PP). Postgraduate Research Group at the Hospital de Clinicas de Porto Alegre-PIPE HCPA (material support). Foundation for Support of Research at Rio Grande do Sul (FAPERGS) (material support). Brazilian Innovation Agency (FINEP) process number-1245/13 (ILdST, WC). Research grant: National Council for Scientific and Technological Development-CNPq (ILdS 302345/2011-6 and WC-301256/2013-6)

Descending Control of Nociceptive Processing in Knee Osteoarthritis Is Associated With Intracortical Disinhibition: An Exploratory Study

Abstract Based on the hypothesis that an imbalance in excitatory and inhibitory input is a central mechanism of knee osteoarthritis chronic pain (KOACP), this exploratory study had the following aims: to compare whether the function of the descending inhibitory pain pathway is associated with the state of inhibition in the corticospinal system indexed by the motor-evoked potential (MEP) and the cortical salient period (CSP) in patients with severe osteoarthritis (OA) and healthy controls; and to determine if there is correlation between the measures of intracortical inhibition (CSP, MEP) with changes on the numerical pain scale (NPS [0–10]) in KOACP during a conditioned pain modulation (CPM)-task considering the effect of self-reported function assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and analgesic use. In a cross-sectional study, we included females (n = 21), with disability by pain or stiffness due to KOACP and healthy controls (n = 10), aged 19 to 75 years. The motor cortex excitability parameters (MEP and CSP) were assessed using the transcranial magnetic stimulation. We assessed the pain and disability by the WOMAC, and change on NPS (0–10) during CPM-task. A Multivariate analysis of covariance revealed that the adjusted mean (SD) on the MEP amplitude was 13.53% higher in the OA than in healthy subjects (1.33 [0.49] vs 1.15 [0.13]), respectively (P = 0.16). The adjusted mean (SD) on the CSP observed in OA patients was 23.43% lower than in healthy subjects (54.54 [16.10] vs 70.94 [22.87]), respectively (P = 0.01). The function of the descending pain modulatory system assessed by change on NPS (0–10) during a CPM-task was negatively correlated with the cortical excitability parameter indexed by the CSP (P = 0.001). Also, the CSP was negatively correlated with the pain and disability assessed by the WOMAC index. These findings support the hypothesis that the change in cortical plasticity in KOACP is associated with less intracortical inhibition, as measured by the CSP. These results show that the neural change in the motor cortex in KOACP is associated with pain and disability levels, and also with decreased activation of the endogenous pain-modulating system by a CPM-task

Intramuscular electrical stimulus potentiates the motor cortex modulation effects on pain and descending inhibitory systems in knee osteoarthritis: a randomized, factorial, sham-controlled study

Maria da Graca-Tarragó,1,2 Mateus Lech,2 Letícia Dal Moro Angoleri,2 Daniela Silva Santos,2 Alícia Deitos,1,2 Aline Patrícia Brietzke,1,2 Iraci LS Torres,1,3 Felipe Fregni,4 Wolnei Caumo1,2,5,6 1Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 2Laboratory of Pain and Neuromodulation, HCPA, Porto Alegre, Brazil; 3Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 4Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA; 5Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 6Pain and Palliative Care Service, HCPA, Porto Alegre, Brazil Background: Neuroplastic changes in nociceptive pathways contribute to severity of symptoms in knee osteoarthritis (KOA). A new look at neuroplastic changes management includes modulation of the primary motor cortex by transcranial direct current stimulation (tDCS). Objectives: We investigated whether tDCS combined with intramuscular electrical stimulation (EIMS) would be more efficacious than a sham (s) intervention (s-tDCS/s-EIMS) or a single active(a)-tDCS/s-EIMS intervention and/or s-tDCS/a-EIMS in the following domains: pain measures (visual analog scale [VAS] score and descending pain modulatory system [DPMS], and outcomes, and analgesic use, disability, and pain pressure threshold (PPT) for secondary outcomes. Registration: The trial is registered in Clinical trials.gov: NCT01747070. Methods: Sixty women with KOA, aged 50–75 years old, randomly received five sessions of one of the four interventions (a-tDCS/a-EIMS, s-tDCS/s-EIMS, a-tDCS/s-EIMS, and s-tDCS/a-EIMS). tDCS was applied over the primary motor cortex (M1), for 30 minutes at 2 mA and the EIMS paraspinal of L1–S2. Results: A generalized estimating equation model revealed the main effect of the a-tDCS/a-EIMS in the VAS pain scores at end treatment compared with the other three groups (P<0.0001). There existed a significant effect of time and a significant interaction between group and time (P<0.01 for both). The delta-(Δ) pain score on VAS in the a-tDCS/a-EIMS group was –3.59, 95% CI: –4.10 to –2.63. The (Δ) pain scores on VAS in the other three groups were: a-tDCS/s-EIMS=−2.13, 95% CI: −2.48 to –1.64; s-tDCS/a-EIMS=−2.25, 95% CI: −2.59 to –1.68; s-tDCS/s-EIMS MR =–1.77, 95% CI: –2.08 to –1.38. The a-tDCS/a-EIMS led to better effect in DPMS, PPT, analgesic use, and disability related to pain. Conclusion: This study provides additional evidence regarding additive clinical effects to improve pain measures and descending pain inhibitory controls when the neuromodulation of the primary motor cortex with tDCS is combined with a bottom-up modulation with EIMS in KOA. Also, it improved the ability to walk due to reduced pain and reduced analgesic use. Keywords: osteoarthritis, electroacupuncture, pain pressure threshold, conditioned pain modulation, CPM, transcranial direct current stimulation, tDC

Effectiveness of percutaneous electrical nerve stimulation for musculoskeletal pain: A systematic review and meta-analysis

Background and Objective: To evaluate the effects of percutaneous electrical stimulation (PENS) alone or as an adjunct with other interventions on pain and related disability in musculoskeletal pain conditions. Databases and Data Treatment: Search of MEDLINE, EMBASE, AMED, CINAHL, EBSCO, PubMed, PEDro, Cochrane Library, SCOPUS and Web of Science databases. Randomized controlled trials where at least one group received any form of PENS for musculoskeletal condition. Studies had to include humans and collect outcomes on pain and related disability in musculoskeletal pain. Risk of bias was assessed by the Cochrane Guidelines, the quality of evidence by using the GRADE approach. Standardized mean differences (SMD) were calculated. Results: Sixteen studies were included and included heterogeneous musculoskeletal conditions with short- or midterm follow-ups. PENS alone had a large effect (SMD −1.22, 95% CI −1.66 to −0.79) on pain and a small effect (SMD −0.33, 95% CI −0.61 to −0.06) on related disability at short-term as compared with sham. A moderate effect of PENS alone (SMD −0.71, 95% CI −1.23 to −0.19) on pain when compared with other interventions was observed. The inclusion of PENS with other interventions had a moderate effect for decreasing pain at short- (SMD −0.70, 95% CI −1.02 to −0.37) and midterm (SMD −0.68, 95% CI −1.10 to −0.27). No effect at midterm (SMD −0.21, 95% CI −0.52 to 0.10) on related disability was seen. The risk of bias was generally low; but the heterogenicity of the results downgraded the level of evidence. Conclusion: There is low level of evidence suggesting the effects of PENS alone or in combination for pain, but not related disability, in musculoskeletal pain. Level of Evidence: Therapy, level 1a. Registration number: CRD42019131331. Significance: This meta-analysis investigating the effectiveness of PENS for the management of pain and related disability in musculoskeletal pain conditions found that PENS could decrease level of pain intensity but not relateddisability in musculoskeletal pain disorders