Title: Muscle modifications in Fibromyalgic Patients revealed by Surface Electromyography (SEMG) Analysis

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1 Author's response to reviews Title: Muscle modifications in Fibromyalgic Patients revealed by Surface Electromyography (SEMG) Analysis Authors: Laura Bazzichi Marco Dini Alessandra Rossi Silvia Corbianco Francesca De Feo Camillo Giacomelli Cristina Zirafa Claudia Ferrari Bruno Rossi Stefano Bombardieri Version: 2 Date: 29 December 2008 Author's response to reviews: see over

2 Answers to Reviewer 1. 1) As we described in our paper surface Electromyography (SEMG) is a non-invasive technique which can provide useful information regarding a muscle s functional status. For this peculiar characteristic it has multiple application; it was been applied in estimation of muscle fatigue phenomena, in monitoring the physiological effects of rehabilitation and training (Kimura M 2007, Stylianou AP 2005, Burnett AF 2008, Chalmers GR 2008, Andersen LL 2008, Jaggi A in press, all cited in the text) and in diverse studies regarding low back pain (Thomas JS, 2007, Ritvanen T, 2007). There is a long-standing discussion among clinicians as to whether generalised and localised nonarthritic musculoskeletal pain, as in patients with fibromyalgia or shoulder-neck pain, represent different entities or are on a pain continuum with the same etiological factors (McCain GA and Scudds RA 1988; Wolfe F et al.,1992; Goldenberg DL, 1999; Buskila D, 2001). Nilsen KB et al. (2006) in their article concluded writing that fibromyalgic and chronic shoulder neck pain patients showed similar muscular or subjective responses to low-grade mental stress of 60 min duration. SEMG seems to be a non specific instrument particularly important to detect muscular response. In our study we showed that SEMG, even if not specific, may highlight a different fibers recruitment in fibromyalgic patients with respect to controls or an atrophy of type II fibers in patients. In this sense SEMG may support clinical diagnosis and might be used to compare baseline and the response after pharmacological or physical therapy. -Thomas JS, France CR, Sha D, Vander Wiele N, Moenter S, Swank K. The effect of chronic low back pain on trunk muscle activations in target reaching movements with various loads. Spine. 2007, 15;32:E Ritvanen T, Zaproudina N, Nissen M, Leinonen V, Hänninen O. Dynamic surface electromyographic responses in chronic low back pain treated by traditional bone setting and conventional physical therapy. J Manipulative Physiol Ther. 2007, 30: McCain GA, Scudds RA. The concept of primary fibromyalgia (fibrositis): clinical value, relation and significance to other chronic musculoskeletal pain syndromes. Pain. 1988, 33: Goldenberg DL. Fibromyalgia syndrome a decade later: what have we learned? Arch Intern Med. 1999, 159: Buskila D. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 2001, 13: Nilsen KB, Westgaard RH, Stovner LJ, Helde G, Rø M, Sand TH. Pain induced by low-grade stress in patients with fibromyalgia and chronic shoulder/neck pain, relation to surface electromyography. Eur J Pain. 2006, 10: ) The novelty of the study consists in the SEMG technique applied which utilized an artefact system suppression. Generally the possibility of analyzing the myoeletric signal registered during an electrical stimulation is severely limited by the presence of stimulation artefact, which may be so intense to make impossible to register M wave. We have utilized the artefact system suppression suggested by Knaflitz and Merletti (1998) which let us better evaluate the first seconds of the analysis that are crucial in the evaluation of II type fibers. (Knaflitz M, Merletti R. Suppression of stimulation artefacts from myoelectric evoked potential recordings. IEEE Trans. On BME, vol. 35, pp , 1998). 3) It is true that the histological data is well known, with our SEMG response we wanted to obtain indirect measurements of the fiber type distribution in FM muscles, reflecting the muscle functionality with respect to normal controls.

3 4) The introduction has been changed: now the first paragraph deals of SEMG technique, as you suggested and fibromyalgia s characteristics are reported in the following paragraph. Even if it is true that are standard concepts I believe that they may connect the first paragraph with the aim of the study. 5) Figs. 3 and 4 have been deleted as you suggested. 6) During a voluntary muscle contraction motor unit recruitment follows the Henneman principles (Henneman E, 1965, Milner-Brown et al. 1973, Desmet and Godaux, 1977): type I fibers are the first to be recruited at low force level (because they have a lower excitability threshold), while type II fibers are recruited after (because they have a higher excitability threshold). Some authors (Solomonow M, 1984) showed that during an involuntary muscle contraction (with electrical stimulation) the muscle fiber recruitment is reversed with respect to voluntary contraction and depends on stimulation level. At low Hz preferentially are recruited type I fiber and because no differences have been observed in these type fiber with our data, this is the reason why at 15 Hz we didn t see any differences. On the contrary, at higher frequency (35 Hz) it will be recruit first (5-6 sec) the type II fibers. So this is the cause we have chosen this frequency, only at 35 Hz we may highlight differences in the fiber recruitment between patients and controls. -Hennemann E., Somjen G., Carpenter D.O. Functional significance of cell size in spinal motoneurons. J. Neurophysiol. 28: , Milner-Brown H.S., Stein R.B., Yemm R. The orderly recruitment of human motor units during voluntary isometric contractions. J. Physiol. (London), 1973, 230: Desmet J.E., Godaux E. Ballistic contraction in man: Characteristics recruitment pattern of single motor units of the tibialis anterior muscle. J. Physiol. (London), 1977, 264: Solomonow M. External control of the neuromuscular system. IEEE Trans. Biomed. Eng, 1984, 31: ). 7) Paragraph 3 of the discussion section has been changed because redundant to the introduction as you suggested. 8) Published data (Goldenberg DL 2008, Valkeinen H 2008, Stephens S 2008, Alentorn-Geli E 2008) showed that aerobic exercise is a useful treatment for FM patients; in our research we speculate the efficacy of anaerobic exercise (in addition to aerobic exercise) on the basis of a hypothesized modified pattern of motor unit innervation in FM patients; in particular because FM patients might have atrophy of type II fibers, the white rapidly contracting fibers. 9) We have omitted the last paragraph of the discussion as you suggested.

4 Answers to Reviewer 2 1) The correction that you suggested has been made: the name of the technique used (surface electromyography) is written in full when appeared in the text for the first time, followed by its abbreviation in brackets (SEMG). 2) You are right, the last sentence of the conclusion (in the abstract) have been changed. 3) The phrase exercise induced symptom flares has been omitted because less specific than the other symptoms reported. 4) In the 2 nd paragraph some concepts have been added to clarify why SEMG can assess the modification of FM muscle. The phrase added is: Conduction velocity (CV) and median frequency (MDF) are the two parameters measured by SEMG. Because they have been shown to be indirect measurements of the diameter of muscle fibers and indirect means for inferring the fiber type muscle constitution, SEMG may be used to assess the modifications of FM muscle. 5) The methods section (in particular the section relative to Myoelectric measurement and experimental procedure ) has been changed as you suggested and now is clearer. 6) Exclusionary criteria have been added in the methods. The phrase is: Exclusionary criteria for normal volunteers were: any of the above ACR criteria for fibromyalgia; use of any medication. Exclusionary criteria for patients were: the presence of a major clinical condition other than fibromyalgia. Were excluded from the study patients and controls with recent or past history of psychiatric disorders, neuromuscular pathology, metabolic and endocrinological disorders, kidney, hepatic and heart failure and pregnant females. 7) Your observation is interesting, we too observed in some patients a lower pain threshold for tender points, but in our research we used the Fisher dolorimeter according to the literature. 8) The phrase regarding FIQ has been slightly changed and a reference for FIQ calculation has been added in the text. (Burckhardt CS, Clark SR, Bennett RM: The fibromyalgia impact questionnaire: development and validation. J Rheumatol. 1991, 18:728-33). 9) We used the SENIAM recommendations; we have utilized specific material and anatomical position as suggested by SENIAM. 10) We searched the better position for vectorial generation of force, which resulted in an angle of 110 for the tibialis anterior and an angle of 135 for vastus medialis obliquus according to the method used in a previous our research (Rossi B et al. Muscle modifications in Parkinson's disease: myoelectric manifestations. Electroencephalogr Clin Neurophysiol. 1996,101:211-8). 11) ME is myoelectric signal. It has been added in the text. 12) Your observation is right, FM is not a severity illness, but those patients which have higher tender point score feel worse. The text has been changed in: when patients feel worse we may suppose a smaller recruitment of type II fibers. 13) Control data have been included on paragraph and in tab.1.

5 14) Figs 3 and 4 have been deleted. 15) Results on Parkinson s disease (PD) have been obtained previously with respect this research, with the same method. We have hypothesized that FM patients have a different motor unit innervation like PD patients. Pain in FM patients might be related to an impaired balance between neurotrasmettitors included dopamine (probably in different cerebral region). 16) We didn t apply isometric exercise, we used stimulated exercise. We have utilized the artefact system suppression suggested by Knaflitz and Merletti (1998) which let us better evaluate the first seconds of the analysis that are crucial in the evaluation of II type fibers. (Knaflitz M, Merletti R. Suppression of stimulation artefacts from myoelectric evoked potential recordings. IEEE Trans. On BME, vol. 35, pp , 1998). We have used the SENIAM recommendations; we have utilized specific material and anatomical position as suggested by SENIAM. 17) You are right, FM and PD disease are different in many aspects, and it is not easy to explain, but our SEMG results (obtained by the same operator and the same method for both group of patients) showed similar muscular response, which let us suppose a similar metabolic state. 18) Limitations: even if SEMG is not specific for FM diagnosis, in a high (>70) percentage of patients shows altered pattern. The SEMG should be applied to different ages and during lifetime of disease. At this moment we don t know its usefulness in evaluating if therapies have beneficial effects. Moreover, it requires a specialist operator and appropriate spaces.

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