Melatonin is a biomarker of circadian dysregulation and is correlated with major depression and fibromyalgia symptom severity

Wolnei Caumo,1–3 Maria Paz Hidalgo,4,5 Andressa Souza,6 Iraci LS Torres,1,7 Luciana C Antunes8 1School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; 2Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre (HCPA), Laboratory of Pain and Neuromodulation at UFRGS, Porto Alegre, Brazil; 3Pain and Anesthesia in Surgery Department, School of Medicine, UFRGS, Porto Alegre, Brazil; 4Psychiatry Department, School of Medicine, UFRGS, Porto Alegre, Brazil; 5Laboratorio de Cronobiologia e Sono do Hospital de Clinicas de Porto Alegre; Porto Alegre, Brazil; 6Postgraduate Program in Health and Human Development, La Salle Universitary Center, Canoas, Brazil; 7Pharmacology Department, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Brazil; 8Centro de Ciências da Saúde – Departamento de Nutrição da Universidade Federal De Santa Catarina, Florianopolis, Brazil Objective: This study compared urinary 6-sulfatoxymelatonin (aMT6s) over 24 hours among fibromyalgia (FM), major depression disorder (MDD), and healthy control (HC) groups, and examined whether rhythm is correlated with depressive symptoms. To answer this question we compared the rhythm of urinary aMT6s secretion among each group in four time series: morning (06:00–12:00 hours), afternoon (12:00–18:00 hours), evening (18:00–24:00 hours), and night (24:00–06:00 hours). In the FM subjects, we assessed if the rhythm of urinary aMT6s secretion is associated with pain severity, sleep quality, number of trigger points (NTPs), and the pain pressure threshold (PPT). Patients and methods: We included 54 women, aged 18–60 years with diagnosis of FM (n=18), MDD (n=19), and HC (n =17). The 24-hour urinary aMT6s was evaluated according to four standardized periods. The assessment instruments were the Hamilton Depression Rating Scale (HDRS), Pittsburgh Sleep Quality Index, and Fibromyalgia Impact Questionnaire. Results: A generalized estimating equation revealed no difference in the daily load of aMT6s secretion among the three groups (P=0.49). However, at the daily time (06:00–18:00 hours), the load secretion of aMT6s reached 41.54% and 60.71% in the FM and MDD, respectively, as compared to 20.73% in the HC (P<0.05). A higher score in the HDRS was positively correlated with the amount of aMT6s secretion during daytime (06:00–18:00 hours). Also, multivariate linear regression revealed that in FM subjects, the aMT6s secretion during daytime (06:00–18:00 hours) was negatively correlated with the PPTlog (partial η2=0.531, P=0.001). However, it was positively correlated with depressive symptoms (partial η2=0.317, P=0.01); PQSI (partial η2=0.306, P=0.017), and NTPs (partial η2=0.23, P=0.04). Conclusion: A more significant load of aMT6s secretion during daytime hours was observed in MDD and FM subjects compared to HC. These findings help to comprehend the biological basis of these disorders and show how disruption in melatonin secretion is positively correlated with clinical symptoms. Keywords: fibromyalgia, depression, pain, melatonin, 6 sulfatoxymelatonin (aMT6s)

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

The Central Sensitization Inventory validated and adapted for a Brazilian population: psychometric properties and its relationship with brain-derived neurotrophic factor

Wolnei Caumo,1–4 Luciana C Antunes,1 Jéssica Lorenzzi Elkfury,1 Evelyn G Herbstrith,5 Raquel Busanello Sipmann,6 Andressa Souza,7 Iraci LS Torres,1,8 Vinicius Souza dos Santos,1 Randy Neblett9 1Postgraduate Program in Medical Sciences, School of Medicine, 2Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre, 3Laboratory of Pain and Neuromodulation, 4Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, 5School of Psychology, Pontifícia Universidade Católica do Rio Grande do Sul, 6School of Medicine, Universidade Federal do Rio Grande do Sul, 7Postgraduate Program in Health and Human Development, La Salle University Center, Canoas, 8Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 9PRIDE Research Foundation, Dallas, TX, USA Objectives: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, reproducibility, and factor structure) of the Central Sensitization Inventory (CSI), adapted and validated for a Brazilian population (CSI-BP). Additionally, we evaluated the relationship between the CSI-BP and the serum brain-derived neurotrophic factor (BDNF) and determined if the symptoms elicited by the CSI-BP discriminate between subjects who do/do not respond to the conditioned pain modulation (CPM) task, as assessed by change in numeric pain scale (0–10) score. Patients and methods: A cross-sectional study was conducted in a pain clinic in a tertiary teaching hospital. A total of 222 adults with chronic musculoskeletal pain and 63 healthy control subjects completed the CSI-BP and the Brazilian Portuguese pain-catastrophizing scale (BP-PCS). A team of experts translated the CSI according to the international guidelines. Test–retest, item analysis, convergent validity, and factor analysis were performed. Later, a random subsample (n=77) was used to correlate the CSI-BP adjusted index with change in numeric pain-scale score during the CPM task and a BDNF blood sample. Results: The CSI-BP presented strong psychometric properties (test–retest reliability 0.91, Cronbach’s a=0.91). Confirmatory factor analysis yielded a four-factor structure, supporting the original English version. The CSI-BP adjusted index showed moderate positive correlation with the BP-PCS, and classified more than 80% of patients correctly vs healthy controls. Serum BDNF levels explained 27% of the variation in the CSI-BP adjusted index. Subjects with impairment in the descending modulatory system had higher CSI-BP adjusted index scores than subjects who responded normally to the CPM task: 49.35 (12.1) vs 39.5 (12.33), respectively (P<0.05). Conclusion: The CSI-BP was found to be a psychometrically strong and reliable instrument, with primary evidence of validity. Higher scores on the CSI-BP were correlated positively with serum BDNF and with greater dysfunction of the descending pain-modulatory system. Keywords: confirmatory factor analysis, cross-cultural adaptation, conditioned pain modulation, serum brain-derived neurotrophic factor, central sensitization, chronic pai