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Correlating cognition and cortical excitability with pain in fibromyalgia: a case control study

Correlating cognition and cortical excitability with pain in fibromyalgia: a case control study Background: Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal symptoms, primarily attributed to sensitization of somatosensory system carrying pain. Few reports have investigated the impact of fibromyalgia symptoms on cognition, corticomotor excitability, sleepiness, and the sleep quality — all of which can deteriorate the quality of life in fibromyalgia. However, the existing reports are underpowered and have conflicting directions of findings, limiting their generalizability. Therefore, the present study was designed to compare measures of cognition, corticomotor excitability, sleepiness, and sleep quality using standardized instruments in the recruited patients of fibromyalgia with pain-free controls. Methods: Diagnosed cases of fibromyalgia were recruited from the Rheumatology department for the cross- sectional, case-control study. Cognition (Mini-Mental State Examination, Stroop color-word task), corticomotor excitability (Resting motor threshold, Motor evoked potential amplitude), daytime sleepiness (Epworth sleepiness scale), and sleep quality (Pittsburgh sleep quality index) were studied according to the standard procedure. Results: Thirty-four patients of fibromyalgia and 30 pain-free controls were recruited for the study. Patients of fibromyalgia showed decreased cognitive scores (p = 0.05), lowered accuracy in Stroop color-word task (for color: 0.02, for word: 0.01), and prolonged reaction time (< 0.01, < 0.01). Excessive daytime sleepiness in patients were found (< 0.01) and worsened sleep quality (< 0.01) were found. Parameters of corticomotor excitability were comparable between patients of fibromyalgia and pain-free controls. Conclusions: Patients of fibromyalgia made more errors, had significantly increased reaction time for cognitive tasks, marked daytime sleepiness, and impaired quality of sleep. Future treatment strategies may include cognitive deficits and sleep disturbances as an integral part of fibromyalgia management. Keywords: Fibromyalgia, Chronic Pain, Cognition, Stroop Test, Reaction Time, Sleep, Sleepiness, Cortical Excitability, Evoked Potential, Pain Measurement, Cross-Sectional Studies, Case-Control Studies Introduction pain and the presence of typical tender points through- Fibromyalgia syndrome is a common neurological condi- out the body. The prevalence has been estimated to be tion that is characterized by widespread musculoskeletal up to 1.75% in general population [1] and remains one of the common reasons for rheumatological referrals [2]. Despite many decades of research, the diagnosis and treatment of fibromyalgia remains a contentious topic. * Correspondence: renuaiims28@gmail.com; renubhatia@aiims.edu At its core, fibromyalgia is characterized by a height- Pain Research and TMS Laboratory, Department of Physiology, All India ened pain response to non-nociceptive (allodynia) or Institute of Medical Sciences, New Delhi, India Full list of author information is available at the end of the article nociceptive stimuli (hyperalgesia) [3]. In addition to © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 2 of 8 increased pain, more than 70% of patients of fibro- Materials & methods myalgia present a complex symptomatology compris- Study design ing of fatigue [4], cognitive problems [5, 6], and It was a cross-sectional case-control study conducted in sleep disturbances [7]. In recognition of their im- a tertiary health care centre. Diagnosed patients of portance, the latest definition of fibromyalgia has fibromyalgia were recruited according to the latest defin- undergone major revisions [8, 9]. The driving force ition, based on 2010/2011 criteria with modifications of the revision of definition criteria was to broaden suggested in 2016, given by the American college of thesymptom rangeofpatientsoffibromyalgiaand rheumatology [8, 9]. Age- and sex- matched pain-free ease the diagnostic process at the clinical level [10]. controls were recruited from following sources: at- From a research point of view, however, the complex tendees & care-givers of the patients (genetically unre- symptomatology brings in a few complications: lated), and other hospital staff (unrelated to the study). firstly, the symptom profile has become too varied, especially in terms of the nature and extent of co- Participant recruitment morbidities; secondly, it can make the management Right-handed female participants between 18 to 65 years strategy very complicated. were recruited after taking their medical history. Patients An ongoing experience of pain symptoms is tradition- of fibromyalgia and pain-free controls were excluded if ally believed to interfere in the cognitive abilities by lim- they had other chronic diseases such as major psychi- iting the neuronal circuitries available to carry out atric disorders, autoimmune diseases, rheumatic disease; cognitive functions, especially for attention, psycho- or were contraindicated to transcranial magnetic stimu- motor speed, inhibition, and interference. Thus, a pro- lation (metallic implants, pacemaker, history of sub- gressive decline in cognitive functions in patients stance abuse, epileptic seizure, head injury or brain of chronic pain is a logical assumption [11]. Mini-Mental surgery, pregnancy, use of antidepressants or anticonvul- State Examination is a common instrument for assess- sants) [44]. All tests were conducted between 09:30 am ment of mild cognitive impairments [12]. Stroop test to 11:30 am in a dedicated assessment laboratory at the evaluates various components of cognition such as pro- same health care centre. The participants were asked to cessing speed, selective/task attention, automaticity, and refrain from taking analgesics and other neuro-active parallel processing [13]. Closely related to musculoskel- substances (caffeine, nicotine, or alcohol) 24 h prior to etal pain is the poor quality of sleep. In fact, self- the investigations. Since hormonal fluctuations could reported unrefreshed sleep is one of the oldest reported affect these outcomes, the tests were scheduled between th rd symptoms of fibromyalgia. It is believed that the inability the 18 to 23 days of the menstrual cycle, keeping st to sleep would lead to daytime excessive sleepiness and start of the last menstrual period as the 1 day. Pain easy fatiguability. Several attempts have been made to characteristics were recorded as intensity of pain (using document cognitive decline [5, 6, 14–19] and disrupted 11-pt Numerical pain rating scale), number of tender sleep [20–26]; however, the cognitive decline in relation points (using manual palpation), and detailed evaluation to sleep has not been extensively studied yet. of pain perception (using McGill pain questionnaire). People with chronic pain often adopt a sedentary Methodological details for pain assessments have been lifestyle resulting in a decrease in muscular strength detailed in a recent paper from our group [45]. and dysfunction due to the restriction of activities [27, 28]. In addition to myographic changes [29], re- Cognitive assessment cent evidence suggests altered structure [30–34]and function [35–37] of the motor system in patients of i) Mini-Mental State Examination; was used to screen fibromyalgia. Under laboratory conditions, parameters mild to moderate impairments in cognitive of corticomotor excitability using transcranial mag- functions [12]. The vernacular version allows netic stimulation can be used to quantify changes in cognitive screening instrument of people of wide the excitability of corticomotor and corticospinal literacy and age range [46]. It has 19-items that tracts [38]. Few reports have assessed corticomotor have a binary response - ‘Yes’ or ‘No’. One mark excitability in patients of fibromyalgia [39–42]with was given for every correct and zero for an incor- conflicting results [43]. The present report is a part rect response resulting in a maximum score of 30. of a larger project to investigate the role of putative It is a simple bedside test with capacity to examine treatment options for the managmenet of fibromyal- cognitive functions including attention, registration, gia. However, given the current problem of varied orientation, recall, and calculation. symptomatology, it is imperative to conduct an inves- ii) Stroop color-word test; was a cognitive parameter tigation of the co-morbidities and the relation they that tests for attention span and task execution [13]. share with pain symptoms prior to a clinical trial. The task was designed and adminstered using Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 3 of 8 SuperLab software (version 5.1; Cedrus Corpor- Sleepiness ation, Arizona, USA) on the computer screen [47]. Sleepiness was measured using Epworth sleepiness scale The initial phase of the test acclimatized the sub- in subjects. The questionnaire comprised of situations jects to the monitor, response keys, pattern of the commonly encountered in daily life situations and had task. It also helped us evaluate adequate color per- four responses to each item. The investigator gave a ception, and comprehension of the word. Congru- score to the option wherein, ‘0’ implies ‘would never ent stimuli were words that meant the same as the doze off’, and ‘3’ implies ‘high chances of dozing’, result- color of the font, for example, RED written in red ing in scoring ranging from 0 to 24. Total scores of color. While in the incongruent stimuli, the two as- Epworth sleepiness scale were obtained by summing the pects were mismatched. The principal of the task is all the responses. It is well established and validated that incongruent stimuli generates conflict that is score in Indian population [52]. then modulated and resolved by top-down cognitive control. During the test phase, the congruent stim- Sleep quality uli were presented interleaved with incongruent Pittsburgh sleep quality index was used to assess sleep stimuli. Participants were asked to correspond to quality and disturbances during the month preceding font color (in one block), or word comprehension the evaluation. There were 19 individual items, each (in another block) with instructions displayed before with four options, in increasing order of severity. Add- each block. The following parameters were re- itionally, various aspects of sleep quality like subjective corded for color-word blocks: (a) Accuracy; per- sleep quality, sleep latency, sleep duration, habitual sleep centage of correct responses was calculated as the efficiency, sleep disturbances, use of sleeping medica- number of correct responses averaged across three tions, and daytime dysfunction have also been reported. trials; (b) Reaction time; average time taken to re- Each item is scored on a 0–3 interval scale. The global spond correctly. Pittsburgh sleep quality index score is then calculated by summating the seven component scores, providing an overall score ranging from 0 to 21, where lower scores Corticomotor excitability denote a healthier sleep quality [53]. It also validated in Participants were made to sit on a chair and asked to the Indian population with an excellent internal relax as much as possible with the arm muscles ad- consistency and test-retest reliability [54]. equately supported with cushions. Scalp landmarks were used to tentatively determine the most excitable region Statistical analysis on the scalp overlying the representative area on the Data summary has been presented as the proportions, motor cortex for the thumb muscles, also known as the mean ± standard deviation, or median (q1 – q3). Patients ‘motor hotspot’. A figure-of-8 coil (70 mm) transcranial of fibromyalgia and pain-free control groups were com- magnetic stimulation (NeuroSoft Neuro-MS/D magnetic pared using Chi-squared goodness-of-fit test, unpaired stimulator, Ivanovo, Russia; max 4 T) coil was placed Student’s t-tests, or Mann-Whitney U-rank tests, as ap- such that antero-posteriorly and navigated in small steps propriate. The effect size has been presented as partial eta to locate the actual ‘hotspot’ of the motor cortex. The squared (η2) and interpretated as: less than or equal to point was marked with a pen to ensure the coil position 0.003 as no effect, 0.10 to 0.039 as small effect, 0.060 to and orientation throughout the experiment. Biphasic 0.110 as intermediate effect, and 0.140 to 0.200 as large ef- pulses were delivered at an interval of 5–7s [48–50]. fect [56]Spearman’s rank test was used for correlation of the independent variables. Strength of association was (i) Resting motor threshold; was defined as the interpreted as: less than 0.1 as a small association, less or minimum stimulus intensity that elicited an evoked equal to 0.3 as a medium association, less than or equal to potential with a peak-to-peak amplitude of at least 0.5 as a large association [55]. P-value less than 0.05 was 50 μV in at least five out of ten trials, while main- considered statistically significant, and all tests were per- taining quiescence on the electromyography. Values formed using GraphPad Prism version 8.00 for Mac OS have been expressed as a percentage of maximum (GraphPad Software, California US). stimulator output. (ii) Motor evoked potential; was identified as the peak- Results to-peak amplitude elicited by averaging ten con- Thirty-four patients of fibromyalgia and 30 pain-free secutive stimuli [51] acquired at 100% resting motor controls were recruited for the study, Fig. 1 shows the threshold. Acquisition window for each trial had a details of the recruitment. The mean age was 38.6 ± 9.0 width of 100 msec pre-stimulus and 200 msec post- with 80% population being urban (all of controls and 21 stimulus. of patients). Three-fourths of the population belonged to Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 4 of 8 a middle or higher-middle socioeconomic stratum. All compared to controls (p value = 0.054, U-statistic = participants were literate, with 26% of the subjects being 382.5, z-score = 4.069, η = 0.046, small effect). For the graduates (9 controls and 8 patients) and 29% being Stroop color-word task, all participants required three post-graduates (11 controls and 8 patients). No differ- familiarity runs before the actual task. There was a sig- ences were found between patients of fibromyalgia and nificant difference between patients of fibromyalgia and controls. Table 1 shows the sociodemographic features controls in all the four Stroop color-word test parame- of the participants. ters. The reaction time for correct answers was pro- On average, patients of fibromyalgia reported moder- longed (color: p value < 0.001, U-statistic = 24, z-score = ate to severe pain 7.4 ± 1.3 (range 5 to 9) on the 11- 6.531, η = 0.668, intermediate effect | word: p value < point Numerical pain rating scale. The time since the 0.001, U-statistic = 27.5, z-score = 6.484, η = 0.658, onset of symptoms was 6.8 ± 2.9 years. The total score of intermediate effect), and the percentage of accuracy was McGill pain questionnaire was 32.6 ± 5.3 (range 25 to lower for participants with fibromyalgia (color: p value 48). Clinical examination showed that they had an aver- < 0.001, U-statistic = 342.5, z-score = 6.531, η = 0.079, age of 10.5 ± 2.0 tender points (range 8 to 14). The most intermediate effect | word: p value 0.001, U-statistic = common sites of tender points were lower back and calf, 272.5, z-score = 6.531, η = 0.16, small effect). forearm and elbow regions. Few patients also reported mild headaches intermittently throughout the day; each bout of pain was felt as dull, boring and aching that often Corticomotor excitability caused the patient to feel extremely tired. The symp- Most participants were able to tolerate the transcranial toms were aggravated by prolonged sitting, emo- magnetic stimulation pulses comfortably. Resting motor tional distress, and cold weather. Some degree of threshold and motor evoked potential amplitudes p relief was felt after using analgesic drugs, local pres- value = 0.111, U-statistic = 395, z-score = 4.069, η = sure or bandage, and sprays were used to reduce the pain. 0.037, small effect) were found to be statistically com- parable between patients of fibromyalgia and pain-free Cognitive assessment controls. Few participants reported mild headache last- There was a significant difference in Mini-Mental State ing up to 24 h after the test. No transcranial magnetic Examination scores of patients of fibromyalgia when stimulation-induced adverse effects were noted. Fig. 1 Strengthening the reporting of observational studies in epidemiology 2007 (STROBE) flow chart. TMS Transcranial magnetic stimulation Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 5 of 8 Table 1 Demographic parameters comparison between patients of fibromyalgia and pain-free controls Characteristics Fibromyalgia Controls p-value (n = 34) (n = 30) Age (yr) 40.6 ± 8.7 36.5 ± 9.2 0.050 Weight (kg) 65.6 ± 13.5 64.3 ± 9.9 0.572 Height (cm) 151.8 ± 10.2 154.1 ± 7.8 0.918 BMI (kg/m ) 28.8 ± 6.7 26.6 ± 5.3 0.155 SBP (mm Hg) 121.5 ± 15.9 119.9 ± 14.9 0.608 DBP (mm Hg) 81.4 ± 10.8 79.2 ± 11.1 0.430 Pulse rate 81.0 ± 11.3 78.5 ± 11.1 0.278 Respiratory rate 20.0 ± 2.1 19.4 ± 2.5 0.209 Geographical location (Urban: rural) 21:13 22:08 0.325 Data were compared using unpaired t-test or Chi-squared goodness-of-fit test, as applicable. Level of significance was set at 5%. Values represented as mean ± standard deviation or as proportions. BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure Sleepiness and sleep quality statistic = 22, z-score = 6.558, η = 0.673, intermediate There were significant differences in Epworth sleepiness effect), duration (p value < 0.001, U-statistic = 81, z- scale scores of fibromyalgia when compared to the con- score = 5.764, η = 0.52, intermediate effect), efficiency (p trols (p value < 0.001, U-statistic = 207, z-score = 4.069, value < 0.001, U-statistic = 42.5, z-score = 6.282, η = η = 0.724, intermediate effect). Total scores of the Pitts- 0.618, intermediate effect), disturbances (p value < 0.001, burgh sleep quality index were significantly different (p U-statistic = 60, z-score = 6.047, η = 0.573, small effect), value < 0.001, U-statistic = 100.5, z-score = 5.502, η = medication (p value < 0.001, U-statistic = 450, z-score = 0.046, intermediate effect). On comparing the domains, 6.047, η = 0.046, small effect). Only the daytime sleep significant differences were found for sleep quality (p was comparable for patients of fibromyalgia and controls 2 2 value < 0.001, U-statistic = 142, z-score = 4.944, η = (p value 0.116, U-statistic = 48, z-score = 6.208, η = 0.474, small effect), latency (p value < 0.001, U- 0.604, intermediate effect). Table 2 shows a summary of Table 2 Parameters of cognition, corticomotor excitability, and sleep parameters compared between participants with fibromyalgia and controls Characteristics Fibromyalgia Pain-free Controls p-value (n = 34) (n = 30) MMSE scores 22.5 (15.0, 29.0) 23.0 (19.0, 28.0) 0.054* Stroop Task Color- reaction time (s) 2.9 (1.9, 4.5) 1.4 (0.6, 2.7) < 0.001* Word- reaction time (s) 2.9 (2.0, 4.0) 1.6 (0.9, 2.5) < 0.001* Color- correct response (%) 60.5 (41.0, 67.0) 63.0 (51.0, 76.0) 0.023* Word- correct response (%) 55.0 (41.0, 63.0) 59.0 (48.0, 71.0) 0.001* RMT (% MSO) 52.0 (38.0, 70.0) 55.0 (35.0, 65.0) 0.121 MEP amplitude (uV) 67.0 (55.0, 87.0) 72.7 (56.7, 98.0) 0.111 PSQI scores 12.0 (6.0, 20.0) 3.0 (2.0, 5.0) < 0.001* Subjective sleep quality 2.0 (1.0, 3.0) 1.0 (1.0, 2.0) < 0.001* Sleep latency 2.0 (1.0, 3.0) 0.0 (0.0, 1.0) < 0.001* Sleep duration 2.0 (1.0, 3.0) 1.0 (0.0, 1.0) < 0.001* Habitual sleep efficiency 1.0 (0.0, 3.0) 0.0 (0.0, 1.0) < 0.001* Sleep disturbances 2.0 (1.0, 3.0) 1.0 (0.0, 1.0) < 0.001* Use of sleep medications 0.0 (0.0, 2.0) 0.0 (0.0, 0.0) 0.116 Daytime sleepiness 2.0 (1.0, 3.0) 1.0 (0.0, 1.0) < 0.001* ESS scores 7.5 (2.0, 15.0) 3.0 (1.0, 5.0) < 0.001* Data were analysed using Mann-Whitney U-rank test. Asterisk(*) shows significance at 5%. Values represented as median (q1 - q3). MMSE Total scores of Mini- mental examination scale; RMT Resting motor threshold, MSO Maximum stimulator output, MEP Motor evoked potential, PSQI Total scores of Pittsburgh sleep quality index, ESS Epworth sleepiness scale Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 6 of 8 the comparisons between the pain-free controls and pa- scores, cognitive, and emotional modulation of pain in tients of fibromyalgia. fibromyalgia patients. Structural brain changes in pa- tients of fibromyalgia, indexed using voxel-based morph- Correlation ometry, found that central sensitization is correlated No significant correlations were found between pain with reduced gray matter volume in specific brain re- symptoms (intensity, duration, tender points) and other gions such as anterior cingulate cortex and prefrontal outcome variables (cognition, corticomotor excitability, cortex [32, 33]. Decreased scores in Stroop test indicates or sleep). However, total scores of Mini-Mental State that fibromyalgia symptoms could affected the function- Examination showed a negative correlation with the total ing of anterior cingulate cortex and dorsolateral pre- score of Pittsburgh sleep quality index (r = − 0.37, p = frontal cortex. 0.029). Also, reaction time for word task in Stroop No significant changes in corticomotor excitability pa- color-word task was negatively correlated with sleep rameters like resting motor threshold and motor evoked duration (r = − 0.36, p = 0.038) and sleep disturbance potential amplitude were found in patients of fibromyal- (r = − 0.35, p = 0.045) components of Pittsburgh sleep gia. This is in contradiction to existing literature [39– quality index. All three associations were medium in 42]. The discrepancies in the findings may be attributed strength. to pain characteristics such as chronicity of pain. Latest studies have shown that the time since onset of painful disease could influence the changes in the corticomotor Discussion excitability [58]. Another source of dissimilarity could be The present study was aimed at investigating the pain- the methodological differences. Salerno et al., [39] de- induced symptoms of cognition, corticomotor excitabil- fined resting motor threshold as at least 100 μV ampli- ity, sleepiness, and sleep quality in the fibromyalgia pa- tude in at least 50% of trials, whereas we used 50 μV tients compared to pain-free controls. Cognition and cut-off as per the latest guidelines for recording cortico- sleep quality were found to be negatively correlated with motor excitability by International Federation of Clinical each other. No differences were found for the para- Neurophysiology [49]. Another difference was the site of meters of corticomotor excitability. recording taken for our study is the abductor policies The Mini-Mental State Examination indicated that pa- brevis, while the earlier studies used first dorsal interos- tients of fibromyalgia have mild cognitive impairments; sei [39–41] or flexor muscle of forearm [42]. Although it also, the participants performed poorly in all parameters is still unclear if using a different muscle group of the of the Stroop Test. The results show that self-reported hand recording can contribute to the differences in find- cognitive decline (the Mini-Mental State Examination ings [43] or the differences in the patient cohort being scores) are in concordance with the objective test, the tested is the main cause of discrepancy. Stroop Test. The study is in line with case-control stud- Currently available pharmacotherapy for fibromyal- ies [14] and previous meta-analyses of cognitive deficits gia includes pregabalin, duloxetine, milnacipran, amitrip- in fibromyalgia patients [5, 6]. Imaging studies reported tyline, cyclobenzaprine and tramadol but remain far that anterior cingulate cortex and dorsolateral prefrontal from satisfactory [59] In the same way, the present co- cortex are among the main areas involved. Decision hort of the patients was also allowed to continue the rec- making and response evaluation are specific domains ommended drug as a part of the standard of care [45] controlled by dorsal anterior cingulate cortex. These (see supplementary file 1). The rationale is based on the areas are also reported for pain perception and modula- fact that these drugs have demonstrated a moderate-to- tion. Anterior cingulate cortex has vital role in various large effect size for pain symptoms and somewhat on behavioral responses such as processing of attention and sleep quality, at least in the short term. Evidence sug- anticipation of pain [56]. This activity may correspond gests that long-term use of neuro-active drugs may in- to shared neural pain representations that allow deduc- duce cognitive deficits. A decline in cognitive ability has tion of the affective state of the pain and facilitating em- also been found to result in interference in daily activ- pathy [57]. Dorsolateral prefrontal cortex has shown ities, low coping, and poorer treatment outcomes. If the activation, when resolving conflicts and catching errors, evidence can be extended to patients of fibromyalgia , also it assists in memory and other executive functions, then the current management may compound the issue so ultimately affects cognition. Dorsolateral prefrontal at hand [59–61]. But cognitive abilities as outcome mea- cortex is involved in encoding and modulating acute sures of the randomized controlled trials are currently pain perception. Elevated high-frequency oscillatory ac- missing from the literature. Going forward, an ideal tivities in the dorsolateral prefrontal cortex and orbito- treatment strategy must address pain symptoms and, at frontal cortex correspond with higher affective pain least to some degree, the associated co-morbidities. Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 7 of 8 Limitations Consent for publication Consent to publish was also obtained from all the participants included in The findings of the study only pertain to middle-aged, the study. regularly menstruating females with fibromyalgia who were refractory to standard of care regime. Factors like Competing interests age and past treatments can affect pain perception, cog- No potential conflict of interest was relevant to this manuscript. nition, and sleep quality. Thus, more studies in patients Author details of fibromyalgia are required to see the generalizability of 1 Pain Research and TMS Laboratory, Department of Physiology, All India our findings. Institute of Medical Sciences, New Delhi, India. Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India. Stress and Cognition Electroimaging Laboratory, Department of Physiology, Conclusions All India Institute of Medical Sciences, New Delhi, India. Department of Nuclear Magnetic Resonance and MRI Facility, All India Institute of Medical The study confirms a decline in cognitive function and Sciences, New Delhi, India. sleep quality in patients of fibromyalgia. Most of the current treatments for fibromyalgia may have some ef- Received: 9 September 2020 Accepted: 2 January 2021 fect on pain perception and to some extent, sleep qual- ity. Introducing adjunct therapies that can help References overcome issues of refractoriness and cognitive decline 1. Walitt B, Nahin RL, Katz RS, Bergman MJ, Wolfe F. The prevalence and may have better outcomes. More research into treat- characteristics of fibromyalgia in the 2012 National Health Interview Survey. PLoS One. 2015;10:e0138024. ments that address cognitive deficits vis-à-vis pain and 2. Al-Allaf AW, Dunbar KL, Hallum NS, Nosratzadeh B, Templeton KD, Pullar T. other symptoms need to be conducted. A case-control study examining the role of physical trauma in the onset of fibromyalgia syndrome. Rheumatology. 2002;41:450–3. 3. Üçeyler N, Burgmer M, Friedel E, Greiner W, Petzke F, Sarholz M, et al. Etiology Supplementary Information and pathophysiology of fibromyalgia syndrome: updated guidelines 2017, The online version contains supplementary material available at https://doi. overview of systematic review articles and overview of studies on small fiber org/10.1186/s42358-021-00163-x. neuropathy in FMS subgroups. Schmerz. 2017;31:239–45. 4. Arnold LM, Clauw DJ, McCarberg BH. Improving the recognition and Additional file 1. diagnosis of fibromyalgia. Mayo Clin Proc. 2011;86:457–64. 5. Bell T, Trost Z, Buelow MT, Clay O, Younger J, Moore D, et al. Meta-analysis of cognitive performance in fibromyalgia. J Clin Exp Neuropsychol. 2018;40: Acknowledgements 698–714. The authors acknowledge the contributions of Dr. Danveer Bhadu and Dr. 6. Wu Y-LL, Huang C-JJ, Fang S-CC, Ko L-HH, Tsai P-SS. Cognitive impairment Sandeep for patient recruitment, Dr. Ragini Adhikari for scoring the in fibromyalgia: a meta-analysis of case-control studies. Psychosom Med. questionnaires, Dr. Suman Tanwar for helping with the review of literatue, 2018;80:432–8. Dr. Vinay Chitturi for helping paradigm design, and Ms. Chaithanya Leon for 7. Lawson K. Sleep dysfunction in fibromyalgia and therapeutic approach interpreting the Stroop Test analysis. options. OBM Neurobiol. 2020;4:16. 8. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RL, et al. Authors’ contributions 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Study was conceived and designed by RB; proposal writing and ethical Arthritis Rheum. 2016;46:319–29. clearance was obtained by VKT, SN, and RB; standardization of methodology 9. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. was done by VKT, RS, SSK, and RB; participant diagnosis was done by UK; The American College of Rheumatology preliminary diagnostic criteria for recruitment of participants was done by VKT and SA; data was acquired by fibromyalgia and measurement of symptom severity. Arthritis Care Res. VKT and SA; data processing done by VKT and SN with help of RS, SSK, and 2010;62:600–10. RB; statistical analysis was done by VKT and SN. Data interpretation, 10. Häuser W, Ablin J, Perrot S, Fitzcharles MA. Management of fibromyalgia: manuscript writing, and revision was done by all authors. RB takes key messages from recent evidence-based guidelines. Pol Arch Intern Med. responsibility for the correspondence, further queries, and guarantee of the 2017;127:47–56. study. All authors(s) read and approved the final manuscript. 11. Hedges D, Farrer TJ, Bigler ED, Hopkins RO, Hedges D, Farrer TJ, et al. Chronic pain and cognition. In: The brain at risk. Basel: Springer Funding International Publishing; 2019. p. 113–24. No funding to declare. 12. Folstein MF, Folstein SE, McHugh PR. “Mini-mental status”. A practical method for grading the cognitive state of patients for the clinician. J Availability of data and materials Psychiatr Res. 1975;12:189–98. The authors confirm that the data supporting the findings of this study are 13. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. available within the article and additional information can be provided if 1935;18:643–62. requested. 14. Rodríguez-Andreu J, Ibez-Bosch R, Portero-Vzquez A, Masramon X, Rejas J, Glvez R. Cognitive impairment in patients with fibromyalgia syndrome as Ethics approval and consent to participate assessed by the mini-mental state examination. BMC Musculoskelet Disord. The study was conducted at the Pain Research and TMS Laboratory, 2009;10:162. Department of Physiology, All India Institute of Medical Sciences, New Delhi, 15. Martinsen S, Flodin P, Berrebi J, Lö fgren M, Bileviciute-Ljungar I, Ingvar M, India. Human Ethics committee of the AIIMS, New Delhi (Ref No: IECPG-15/ et al. Fibromyalgia patients had normal distraction related pain inhibition 16.02.2017RT-27/26.04.2017) approved the research protocol in 2017. The but cognitive impairment reflected in caudate nucleus and hippocampus study was also registered in the Clinical Trials Registry of India (CTRI; Ref No: during the Stroop color word test. PLoS One. 2014;9:e108637. CTRI/2017/09/009827). All procedures performed during study involving hu- 16. Walteros C, Sánchez-Navarro JP, Muñoz MA, Martínez-Selva JM, Chialvo D, man participants were in accordance with the ethical standards of the Hu- Montoya P. Altered associative learning and emotional decision making in man Ethics committee of the All India Institute of Medical Sciences, New fibromyalgia. J Psychosom Res. 2011;70:294–301. Delhi, India. Participants were required to sign written, informed consent for 17. González JL, Mercado F, Barjola P, Carretero I, López-López A, Bullones MA, the study. et al. Generalized hypervigilance in fibromyalgia patients: an experimental Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 8 of 8 analysis with the emotional Stroop paradigm. J Psychosom Res. 2010;69: 43. Parker R, Lewis G, Rice D, Stimulation PM. Is motor cortical excitability 279–87. altered in people with chronic pain? A systematic review and meta-analysis. 18. Suhr JA. Neuropsychological impairment in fibromyalgia: relation to Brain Stimul. 2016;9:488–500. depression, fatigue, and pain. J Psychosom Res. 2003;55:321–9. 44. Klein MM, Treister R, Raij T, Pascual-Leone A, Park L, Nurmikko T, et al. Transcranial magnetic stimulation of the brain: guidelines for pain treatment 19. Gelonch O, Garolera M, Valls J, Rosselló L, Pifarré J. Executive function in research. Pain. 2015;156:1601–14. fibromyalgia: comparing subjective and objective measures. Compr 45. Tiwari VK, Nanda S, Arya S, Kumar U, Bhatia R. Effect of repetitive transcranial Psychiatry. 2016;66:113–22. magnetic stimulation in male patients of fibromyalgia. Indian J Rheumatol. 20. Pimentel MJ, Gui MS, Reimão R, Rizzatti-Barbosa CM. Sleep quality and facial 2020;15:134–40. pain in fibromyalgia syndrome. J Craniomandib Pract. 2015;33:122–8. 46. Ganguli M, Ratcliff G, Chandra V, Sharma S, Gilby J, Pandav R, et al. A hindi 21. Bigatti SM, Hernandez AM, Cronan TA, Rand KL. Sleep disturbances in version of the MMSE: the development of a cognitive screening instrument fibromyalgia syndrome: relationship to pain and depression. Arthritis Care for a largely illiterate rural elderly population in India. Int J Geriatr Psychiatry. Res. 2008;59:961–7. 1995;10:367–77. 22. Mutlu P, Zateri Ç, Zöhra A, Özerdoǧan Ö, Mirici AN. Prevalence of 47. Algom D, Chajut E. Reclaiming the stroop effect back from control to input- obstructive sleep apnea in female patients with fibromyalgia. Saudi Med J. driven attention and perception. Front Psychol. 2019;10:1683. 2020;41:740–5. 48. Chipchase L, Schabrun S, Cohen L, Hodges P, Ridding M, Rothwell J, et al. A 23. Choy EHS. The role of sleep in pain and fibromyalgia. Nat Rev Rheumatol. checklist for assessing the methodological quality of studies using 2015;11:513–20. transcranial magnetic stimulation to study the motor system: an 24. Keskindag B, Karaaziz M. The association between pain and sleep in international consensus study. Clin Neurophysiol. 2012;123:1698–704. fibromyalgia. Saudi Med J. 2017;38:465–75. 49. Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, et al. A 25. Jennum P, Drewes AM, Andreasen A, Neilsen DK. Sleep and other practical guide to diagnostic transcranial magnetic stimulation: report of an symptoms in primary fibromyalgia and in healthy controls. J Rheumatol. IFCN committee. Clin Neurophysiol. 2012;123:858–82. 1993;20:1956–9. 50. Rossini PM, Rossi S. Transcranial magnetic stimulation: diagnostic, 26. Wu YL, Chang LY, Lee HC, Fang SC, Tsai PS. Sleep disturbances in fibromyalgiaA therapeutic, and research potential. Neurology. 2007;68:484–8. meta-analysis of case-control studies. J Psychosom Res. 2017;96:89–97. 51. Cavaleri R, Schabrun SM, Chipchase LS. The number of stimuli required to 27. Nijs J, Daenen L, Cras P, Struyf F, Roussel N, Oostendorp RAB. Nociception reliably assess corticomotor excitability and primary motor cortical affects motor output: a review on sensory-motor interaction with focus on representations using transcranial magnetic stimulation (TMS): a systematic clinical implications. Clin J Pain. 2012;28:175–81. review and meta-analysis. Syst Rev. 2017;6:48. 28. Chang WJ, O’Connell NE, Beckenkamp PR, Alhassani G, Liston MB, Schabrun 52. Bajpai G, Shukla G, Pandey R, Gupta A, Afsar M, Goyal V, et al. Validation of a SM. Altered primary motor cortex structure, organization, and function in modified Hindi version of the Epworth sleepiness scale among a north chronic pain: a systematic review and meta-analysis. J Pain. 2018;19:341–59. Indian population. Ann Indian Acad Neurol. 2016;19:499. 29. Umay E, Gundogdu I, Ozturk EA. What happens to muscles in fibromyalgia 53. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh syndrome. Ir J Med Sci. 2020;189:749–56. sleep quality index: a new instrument for psychiatric practice and research. 30. Martínez E, Aira Z, Buesa I, Aizpurua I, Rada D, Azkue JJ. Embodied pain in Psychiatry Res. 1989;28:193–213. fibromyalgia: disturbed somatorepresentations and increased plasticity of 54. Manzar MD, Moiz JA, Zannat W, Spence DW, Pandi-Perumal SR, Bahammam the body schema. PLoS One. 2018;13:e0194534. AS, et al. Validity of the Pittsburgh sleep quality index in Indian university 31. Fallon N, Chiu Y, Nurmikko T, Stancak A. Functional connectivity with the students. Oman Med J. 2015;30:193–202. default mode network is altered in fibromyalgia patients. PLoS One. 2016; 55. Cohen J. Statistical power analysis for the behavioural science. 2nd ed. 11:e0159198. London: Lawrence Erlbaum Associates, Publishers; 1988. 32. Robinson ME, Craggs JG, Price DD, Perlstein WM, Staud R. Gray matter 56. Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML. The anterior cingulate volumes of pain-related brain areas are decreased in fibromyalgia cortex and pain processing. Front Integr Neurosci. 2014;8:35. syndrome. J Pain. 2011;12:436–43. 57. Gougeon V, Gaumond I, Goffaux P, Potvin S, Marchand S. Triggering 33. Sundermann B, Dehghan Nayyeri M, Pfleiderer B, Stahlberg K, Jünke L, Baie descending pain inhibition by observing ourselves or a loved-one in pain. L, et al. Subtle changes of gray matter volume in fibromyalgia reflect Clin J Pain. 2016;32:238–45. chronic musculoskeletal pain rather than disease-specific effects. Eur J 58. Schabrun SM, Christensen SW, Mrachacz-Kersting N, Graven-Nielsen T. Neurosci. 2019;50:3958–67. Motor cortex reorganization and impaired function in the transition to 34. Wood PB, Glabus MF, Simpson R, Patterson JC. Changes in gray matter density sustained muscle pain. Cereb Cortex. 2016;26:1878–90. in fibromyalgia: correlation with dopamine metabolism. J Pain. 2009;10:609–18. 59. Calandre EP, Rico-Villademoros F, Slim M. Pharmacological treatment of 35. Gentile E, Brunetti A, Ricci K, Delussi M, Bevilacqua V, M de T. Mutual fibromyalgia: is the glass half empty or half full? Pain Manag. 2017;7:5–10. interaction between motor cortex activation and pain in fibromyalgia: EEG- 60. Calandre EP, Rico-Villademoros F, Rodríguez-López CM. Monotherapy or fNIRS study. PLoS One. 2020;15:e0228158. combination therapy for fibromyalgia treatment. Curr Rheumatol Rep. 2012; 36. Hsiao FJ, Wang SJ, Lin YY, Fuh JL, Ko YC, Wang PN, et al. Altered insula– 14:568–75. default mode network connectivity in fibromyalgia: a resting-state 61. Kravitz HM, Katz RS. Fibrofog and fibromyalgia: a narrative review and magnetoencephalographic study. J Headache Pain. 2017;18:89. implications for clinical practice. Rheumatol Int. 2015;35:1115–25. 37. Ichesco E, Quintero A, Clauw DJ, Peltier S, Sundgren PM, Gerstner GE, et al. Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: a pilot study. Headache. 2012;18:89. Publisher’sNote 38. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of Springer Nature remains neutral with regard to jurisdictional claims in human motor cortex. Lancet. 1985;325:1106–7. published maps and institutional affiliations. 39. Salerno A, Thomas E, Olive P, Blotman F, Picot MC, Georgesco M. Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia. Clin Neurophysiol. 2000;111:994–1001. 40. Mhalla A, de Andrade DC, Baudic S, Perrot S, Bouhassira D. Alteration of cortical excitability in patients with fibromyalgia. Pain. 2010;149:495–500. 41. Caumo W, Deitos A, Carvalho S, Leite J, Carvalho F, Dussán-Sarria JA, et al. Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology. Front Hum Neurosci. 2016;10:357. 42. Schwenkreis P, Voigt M, Hasenbring M, Tegenthoff M, Vorgerd M, Kley RA. Central mechanisms during fatiguing muscle exercise in muscular dystrophy and fibromyalgia syndrome: a study with transcranial magnetic stimulation. Muscle Nerve. 2011;43:479–84. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Correlating cognition and cortical excitability with pain in fibromyalgia: a case control study

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Abstract

Background: Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal symptoms, primarily attributed to sensitization of somatosensory system carrying pain. Few reports have investigated the impact of fibromyalgia symptoms on cognition, corticomotor excitability, sleepiness, and the sleep quality — all of which can deteriorate the quality of life in fibromyalgia. However, the existing reports are underpowered and have conflicting directions of findings, limiting their generalizability. Therefore, the present study was designed to compare measures of cognition, corticomotor excitability, sleepiness, and sleep quality using standardized instruments in the recruited patients of fibromyalgia with pain-free controls. Methods: Diagnosed cases of fibromyalgia were recruited from the Rheumatology department for the cross- sectional, case-control study. Cognition (Mini-Mental State Examination, Stroop color-word task), corticomotor excitability (Resting motor threshold, Motor evoked potential amplitude), daytime sleepiness (Epworth sleepiness scale), and sleep quality (Pittsburgh sleep quality index) were studied according to the standard procedure. Results: Thirty-four patients of fibromyalgia and 30 pain-free controls were recruited for the study. Patients of fibromyalgia showed decreased cognitive scores (p = 0.05), lowered accuracy in Stroop color-word task (for color: 0.02, for word: 0.01), and prolonged reaction time (< 0.01, < 0.01). Excessive daytime sleepiness in patients were found (< 0.01) and worsened sleep quality (< 0.01) were found. Parameters of corticomotor excitability were comparable between patients of fibromyalgia and pain-free controls. Conclusions: Patients of fibromyalgia made more errors, had significantly increased reaction time for cognitive tasks, marked daytime sleepiness, and impaired quality of sleep. Future treatment strategies may include cognitive deficits and sleep disturbances as an integral part of fibromyalgia management. Keywords: Fibromyalgia, Chronic Pain, Cognition, Stroop Test, Reaction Time, Sleep, Sleepiness, Cortical Excitability, Evoked Potential, Pain Measurement, Cross-Sectional Studies, Case-Control Studies Introduction pain and the presence of typical tender points through- Fibromyalgia syndrome is a common neurological condi- out the body. The prevalence has been estimated to be tion that is characterized by widespread musculoskeletal up to 1.75% in general population [1] and remains one of the common reasons for rheumatological referrals [2]. Despite many decades of research, the diagnosis and treatment of fibromyalgia remains a contentious topic. * Correspondence: renuaiims28@gmail.com; renubhatia@aiims.edu At its core, fibromyalgia is characterized by a height- Pain Research and TMS Laboratory, Department of Physiology, All India ened pain response to non-nociceptive (allodynia) or Institute of Medical Sciences, New Delhi, India Full list of author information is available at the end of the article nociceptive stimuli (hyperalgesia) [3]. In addition to © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 2 of 8 increased pain, more than 70% of patients of fibro- Materials & methods myalgia present a complex symptomatology compris- Study design ing of fatigue [4], cognitive problems [5, 6], and It was a cross-sectional case-control study conducted in sleep disturbances [7]. In recognition of their im- a tertiary health care centre. Diagnosed patients of portance, the latest definition of fibromyalgia has fibromyalgia were recruited according to the latest defin- undergone major revisions [8, 9]. The driving force ition, based on 2010/2011 criteria with modifications of the revision of definition criteria was to broaden suggested in 2016, given by the American college of thesymptom rangeofpatientsoffibromyalgiaand rheumatology [8, 9]. Age- and sex- matched pain-free ease the diagnostic process at the clinical level [10]. controls were recruited from following sources: at- From a research point of view, however, the complex tendees & care-givers of the patients (genetically unre- symptomatology brings in a few complications: lated), and other hospital staff (unrelated to the study). firstly, the symptom profile has become too varied, especially in terms of the nature and extent of co- Participant recruitment morbidities; secondly, it can make the management Right-handed female participants between 18 to 65 years strategy very complicated. were recruited after taking their medical history. Patients An ongoing experience of pain symptoms is tradition- of fibromyalgia and pain-free controls were excluded if ally believed to interfere in the cognitive abilities by lim- they had other chronic diseases such as major psychi- iting the neuronal circuitries available to carry out atric disorders, autoimmune diseases, rheumatic disease; cognitive functions, especially for attention, psycho- or were contraindicated to transcranial magnetic stimu- motor speed, inhibition, and interference. Thus, a pro- lation (metallic implants, pacemaker, history of sub- gressive decline in cognitive functions in patients stance abuse, epileptic seizure, head injury or brain of chronic pain is a logical assumption [11]. Mini-Mental surgery, pregnancy, use of antidepressants or anticonvul- State Examination is a common instrument for assess- sants) [44]. All tests were conducted between 09:30 am ment of mild cognitive impairments [12]. Stroop test to 11:30 am in a dedicated assessment laboratory at the evaluates various components of cognition such as pro- same health care centre. The participants were asked to cessing speed, selective/task attention, automaticity, and refrain from taking analgesics and other neuro-active parallel processing [13]. Closely related to musculoskel- substances (caffeine, nicotine, or alcohol) 24 h prior to etal pain is the poor quality of sleep. In fact, self- the investigations. Since hormonal fluctuations could reported unrefreshed sleep is one of the oldest reported affect these outcomes, the tests were scheduled between th rd symptoms of fibromyalgia. It is believed that the inability the 18 to 23 days of the menstrual cycle, keeping st to sleep would lead to daytime excessive sleepiness and start of the last menstrual period as the 1 day. Pain easy fatiguability. Several attempts have been made to characteristics were recorded as intensity of pain (using document cognitive decline [5, 6, 14–19] and disrupted 11-pt Numerical pain rating scale), number of tender sleep [20–26]; however, the cognitive decline in relation points (using manual palpation), and detailed evaluation to sleep has not been extensively studied yet. of pain perception (using McGill pain questionnaire). People with chronic pain often adopt a sedentary Methodological details for pain assessments have been lifestyle resulting in a decrease in muscular strength detailed in a recent paper from our group [45]. and dysfunction due to the restriction of activities [27, 28]. In addition to myographic changes [29], re- Cognitive assessment cent evidence suggests altered structure [30–34]and function [35–37] of the motor system in patients of i) Mini-Mental State Examination; was used to screen fibromyalgia. Under laboratory conditions, parameters mild to moderate impairments in cognitive of corticomotor excitability using transcranial mag- functions [12]. The vernacular version allows netic stimulation can be used to quantify changes in cognitive screening instrument of people of wide the excitability of corticomotor and corticospinal literacy and age range [46]. It has 19-items that tracts [38]. Few reports have assessed corticomotor have a binary response - ‘Yes’ or ‘No’. One mark excitability in patients of fibromyalgia [39–42]with was given for every correct and zero for an incor- conflicting results [43]. The present report is a part rect response resulting in a maximum score of 30. of a larger project to investigate the role of putative It is a simple bedside test with capacity to examine treatment options for the managmenet of fibromyal- cognitive functions including attention, registration, gia. However, given the current problem of varied orientation, recall, and calculation. symptomatology, it is imperative to conduct an inves- ii) Stroop color-word test; was a cognitive parameter tigation of the co-morbidities and the relation they that tests for attention span and task execution [13]. share with pain symptoms prior to a clinical trial. The task was designed and adminstered using Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 3 of 8 SuperLab software (version 5.1; Cedrus Corpor- Sleepiness ation, Arizona, USA) on the computer screen [47]. Sleepiness was measured using Epworth sleepiness scale The initial phase of the test acclimatized the sub- in subjects. The questionnaire comprised of situations jects to the monitor, response keys, pattern of the commonly encountered in daily life situations and had task. It also helped us evaluate adequate color per- four responses to each item. The investigator gave a ception, and comprehension of the word. Congru- score to the option wherein, ‘0’ implies ‘would never ent stimuli were words that meant the same as the doze off’, and ‘3’ implies ‘high chances of dozing’, result- color of the font, for example, RED written in red ing in scoring ranging from 0 to 24. Total scores of color. While in the incongruent stimuli, the two as- Epworth sleepiness scale were obtained by summing the pects were mismatched. The principal of the task is all the responses. It is well established and validated that incongruent stimuli generates conflict that is score in Indian population [52]. then modulated and resolved by top-down cognitive control. During the test phase, the congruent stim- Sleep quality uli were presented interleaved with incongruent Pittsburgh sleep quality index was used to assess sleep stimuli. Participants were asked to correspond to quality and disturbances during the month preceding font color (in one block), or word comprehension the evaluation. There were 19 individual items, each (in another block) with instructions displayed before with four options, in increasing order of severity. Add- each block. The following parameters were re- itionally, various aspects of sleep quality like subjective corded for color-word blocks: (a) Accuracy; per- sleep quality, sleep latency, sleep duration, habitual sleep centage of correct responses was calculated as the efficiency, sleep disturbances, use of sleeping medica- number of correct responses averaged across three tions, and daytime dysfunction have also been reported. trials; (b) Reaction time; average time taken to re- Each item is scored on a 0–3 interval scale. The global spond correctly. Pittsburgh sleep quality index score is then calculated by summating the seven component scores, providing an overall score ranging from 0 to 21, where lower scores Corticomotor excitability denote a healthier sleep quality [53]. It also validated in Participants were made to sit on a chair and asked to the Indian population with an excellent internal relax as much as possible with the arm muscles ad- consistency and test-retest reliability [54]. equately supported with cushions. Scalp landmarks were used to tentatively determine the most excitable region Statistical analysis on the scalp overlying the representative area on the Data summary has been presented as the proportions, motor cortex for the thumb muscles, also known as the mean ± standard deviation, or median (q1 – q3). Patients ‘motor hotspot’. A figure-of-8 coil (70 mm) transcranial of fibromyalgia and pain-free control groups were com- magnetic stimulation (NeuroSoft Neuro-MS/D magnetic pared using Chi-squared goodness-of-fit test, unpaired stimulator, Ivanovo, Russia; max 4 T) coil was placed Student’s t-tests, or Mann-Whitney U-rank tests, as ap- such that antero-posteriorly and navigated in small steps propriate. The effect size has been presented as partial eta to locate the actual ‘hotspot’ of the motor cortex. The squared (η2) and interpretated as: less than or equal to point was marked with a pen to ensure the coil position 0.003 as no effect, 0.10 to 0.039 as small effect, 0.060 to and orientation throughout the experiment. Biphasic 0.110 as intermediate effect, and 0.140 to 0.200 as large ef- pulses were delivered at an interval of 5–7s [48–50]. fect [56]Spearman’s rank test was used for correlation of the independent variables. Strength of association was (i) Resting motor threshold; was defined as the interpreted as: less than 0.1 as a small association, less or minimum stimulus intensity that elicited an evoked equal to 0.3 as a medium association, less than or equal to potential with a peak-to-peak amplitude of at least 0.5 as a large association [55]. P-value less than 0.05 was 50 μV in at least five out of ten trials, while main- considered statistically significant, and all tests were per- taining quiescence on the electromyography. Values formed using GraphPad Prism version 8.00 for Mac OS have been expressed as a percentage of maximum (GraphPad Software, California US). stimulator output. (ii) Motor evoked potential; was identified as the peak- Results to-peak amplitude elicited by averaging ten con- Thirty-four patients of fibromyalgia and 30 pain-free secutive stimuli [51] acquired at 100% resting motor controls were recruited for the study, Fig. 1 shows the threshold. Acquisition window for each trial had a details of the recruitment. The mean age was 38.6 ± 9.0 width of 100 msec pre-stimulus and 200 msec post- with 80% population being urban (all of controls and 21 stimulus. of patients). Three-fourths of the population belonged to Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 4 of 8 a middle or higher-middle socioeconomic stratum. All compared to controls (p value = 0.054, U-statistic = participants were literate, with 26% of the subjects being 382.5, z-score = 4.069, η = 0.046, small effect). For the graduates (9 controls and 8 patients) and 29% being Stroop color-word task, all participants required three post-graduates (11 controls and 8 patients). No differ- familiarity runs before the actual task. There was a sig- ences were found between patients of fibromyalgia and nificant difference between patients of fibromyalgia and controls. Table 1 shows the sociodemographic features controls in all the four Stroop color-word test parame- of the participants. ters. The reaction time for correct answers was pro- On average, patients of fibromyalgia reported moder- longed (color: p value < 0.001, U-statistic = 24, z-score = ate to severe pain 7.4 ± 1.3 (range 5 to 9) on the 11- 6.531, η = 0.668, intermediate effect | word: p value < point Numerical pain rating scale. The time since the 0.001, U-statistic = 27.5, z-score = 6.484, η = 0.658, onset of symptoms was 6.8 ± 2.9 years. The total score of intermediate effect), and the percentage of accuracy was McGill pain questionnaire was 32.6 ± 5.3 (range 25 to lower for participants with fibromyalgia (color: p value 48). Clinical examination showed that they had an aver- < 0.001, U-statistic = 342.5, z-score = 6.531, η = 0.079, age of 10.5 ± 2.0 tender points (range 8 to 14). The most intermediate effect | word: p value 0.001, U-statistic = common sites of tender points were lower back and calf, 272.5, z-score = 6.531, η = 0.16, small effect). forearm and elbow regions. Few patients also reported mild headaches intermittently throughout the day; each bout of pain was felt as dull, boring and aching that often Corticomotor excitability caused the patient to feel extremely tired. The symp- Most participants were able to tolerate the transcranial toms were aggravated by prolonged sitting, emo- magnetic stimulation pulses comfortably. Resting motor tional distress, and cold weather. Some degree of threshold and motor evoked potential amplitudes p relief was felt after using analgesic drugs, local pres- value = 0.111, U-statistic = 395, z-score = 4.069, η = sure or bandage, and sprays were used to reduce the pain. 0.037, small effect) were found to be statistically com- parable between patients of fibromyalgia and pain-free Cognitive assessment controls. Few participants reported mild headache last- There was a significant difference in Mini-Mental State ing up to 24 h after the test. No transcranial magnetic Examination scores of patients of fibromyalgia when stimulation-induced adverse effects were noted. Fig. 1 Strengthening the reporting of observational studies in epidemiology 2007 (STROBE) flow chart. TMS Transcranial magnetic stimulation Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 5 of 8 Table 1 Demographic parameters comparison between patients of fibromyalgia and pain-free controls Characteristics Fibromyalgia Controls p-value (n = 34) (n = 30) Age (yr) 40.6 ± 8.7 36.5 ± 9.2 0.050 Weight (kg) 65.6 ± 13.5 64.3 ± 9.9 0.572 Height (cm) 151.8 ± 10.2 154.1 ± 7.8 0.918 BMI (kg/m ) 28.8 ± 6.7 26.6 ± 5.3 0.155 SBP (mm Hg) 121.5 ± 15.9 119.9 ± 14.9 0.608 DBP (mm Hg) 81.4 ± 10.8 79.2 ± 11.1 0.430 Pulse rate 81.0 ± 11.3 78.5 ± 11.1 0.278 Respiratory rate 20.0 ± 2.1 19.4 ± 2.5 0.209 Geographical location (Urban: rural) 21:13 22:08 0.325 Data were compared using unpaired t-test or Chi-squared goodness-of-fit test, as applicable. Level of significance was set at 5%. Values represented as mean ± standard deviation or as proportions. BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure Sleepiness and sleep quality statistic = 22, z-score = 6.558, η = 0.673, intermediate There were significant differences in Epworth sleepiness effect), duration (p value < 0.001, U-statistic = 81, z- scale scores of fibromyalgia when compared to the con- score = 5.764, η = 0.52, intermediate effect), efficiency (p trols (p value < 0.001, U-statistic = 207, z-score = 4.069, value < 0.001, U-statistic = 42.5, z-score = 6.282, η = η = 0.724, intermediate effect). Total scores of the Pitts- 0.618, intermediate effect), disturbances (p value < 0.001, burgh sleep quality index were significantly different (p U-statistic = 60, z-score = 6.047, η = 0.573, small effect), value < 0.001, U-statistic = 100.5, z-score = 5.502, η = medication (p value < 0.001, U-statistic = 450, z-score = 0.046, intermediate effect). On comparing the domains, 6.047, η = 0.046, small effect). Only the daytime sleep significant differences were found for sleep quality (p was comparable for patients of fibromyalgia and controls 2 2 value < 0.001, U-statistic = 142, z-score = 4.944, η = (p value 0.116, U-statistic = 48, z-score = 6.208, η = 0.474, small effect), latency (p value < 0.001, U- 0.604, intermediate effect). Table 2 shows a summary of Table 2 Parameters of cognition, corticomotor excitability, and sleep parameters compared between participants with fibromyalgia and controls Characteristics Fibromyalgia Pain-free Controls p-value (n = 34) (n = 30) MMSE scores 22.5 (15.0, 29.0) 23.0 (19.0, 28.0) 0.054* Stroop Task Color- reaction time (s) 2.9 (1.9, 4.5) 1.4 (0.6, 2.7) < 0.001* Word- reaction time (s) 2.9 (2.0, 4.0) 1.6 (0.9, 2.5) < 0.001* Color- correct response (%) 60.5 (41.0, 67.0) 63.0 (51.0, 76.0) 0.023* Word- correct response (%) 55.0 (41.0, 63.0) 59.0 (48.0, 71.0) 0.001* RMT (% MSO) 52.0 (38.0, 70.0) 55.0 (35.0, 65.0) 0.121 MEP amplitude (uV) 67.0 (55.0, 87.0) 72.7 (56.7, 98.0) 0.111 PSQI scores 12.0 (6.0, 20.0) 3.0 (2.0, 5.0) < 0.001* Subjective sleep quality 2.0 (1.0, 3.0) 1.0 (1.0, 2.0) < 0.001* Sleep latency 2.0 (1.0, 3.0) 0.0 (0.0, 1.0) < 0.001* Sleep duration 2.0 (1.0, 3.0) 1.0 (0.0, 1.0) < 0.001* Habitual sleep efficiency 1.0 (0.0, 3.0) 0.0 (0.0, 1.0) < 0.001* Sleep disturbances 2.0 (1.0, 3.0) 1.0 (0.0, 1.0) < 0.001* Use of sleep medications 0.0 (0.0, 2.0) 0.0 (0.0, 0.0) 0.116 Daytime sleepiness 2.0 (1.0, 3.0) 1.0 (0.0, 1.0) < 0.001* ESS scores 7.5 (2.0, 15.0) 3.0 (1.0, 5.0) < 0.001* Data were analysed using Mann-Whitney U-rank test. Asterisk(*) shows significance at 5%. Values represented as median (q1 - q3). MMSE Total scores of Mini- mental examination scale; RMT Resting motor threshold, MSO Maximum stimulator output, MEP Motor evoked potential, PSQI Total scores of Pittsburgh sleep quality index, ESS Epworth sleepiness scale Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 6 of 8 the comparisons between the pain-free controls and pa- scores, cognitive, and emotional modulation of pain in tients of fibromyalgia. fibromyalgia patients. Structural brain changes in pa- tients of fibromyalgia, indexed using voxel-based morph- Correlation ometry, found that central sensitization is correlated No significant correlations were found between pain with reduced gray matter volume in specific brain re- symptoms (intensity, duration, tender points) and other gions such as anterior cingulate cortex and prefrontal outcome variables (cognition, corticomotor excitability, cortex [32, 33]. Decreased scores in Stroop test indicates or sleep). However, total scores of Mini-Mental State that fibromyalgia symptoms could affected the function- Examination showed a negative correlation with the total ing of anterior cingulate cortex and dorsolateral pre- score of Pittsburgh sleep quality index (r = − 0.37, p = frontal cortex. 0.029). Also, reaction time for word task in Stroop No significant changes in corticomotor excitability pa- color-word task was negatively correlated with sleep rameters like resting motor threshold and motor evoked duration (r = − 0.36, p = 0.038) and sleep disturbance potential amplitude were found in patients of fibromyal- (r = − 0.35, p = 0.045) components of Pittsburgh sleep gia. This is in contradiction to existing literature [39– quality index. All three associations were medium in 42]. The discrepancies in the findings may be attributed strength. to pain characteristics such as chronicity of pain. Latest studies have shown that the time since onset of painful disease could influence the changes in the corticomotor Discussion excitability [58]. Another source of dissimilarity could be The present study was aimed at investigating the pain- the methodological differences. Salerno et al., [39] de- induced symptoms of cognition, corticomotor excitabil- fined resting motor threshold as at least 100 μV ampli- ity, sleepiness, and sleep quality in the fibromyalgia pa- tude in at least 50% of trials, whereas we used 50 μV tients compared to pain-free controls. Cognition and cut-off as per the latest guidelines for recording cortico- sleep quality were found to be negatively correlated with motor excitability by International Federation of Clinical each other. No differences were found for the para- Neurophysiology [49]. Another difference was the site of meters of corticomotor excitability. recording taken for our study is the abductor policies The Mini-Mental State Examination indicated that pa- brevis, while the earlier studies used first dorsal interos- tients of fibromyalgia have mild cognitive impairments; sei [39–41] or flexor muscle of forearm [42]. Although it also, the participants performed poorly in all parameters is still unclear if using a different muscle group of the of the Stroop Test. The results show that self-reported hand recording can contribute to the differences in find- cognitive decline (the Mini-Mental State Examination ings [43] or the differences in the patient cohort being scores) are in concordance with the objective test, the tested is the main cause of discrepancy. Stroop Test. The study is in line with case-control stud- Currently available pharmacotherapy for fibromyal- ies [14] and previous meta-analyses of cognitive deficits gia includes pregabalin, duloxetine, milnacipran, amitrip- in fibromyalgia patients [5, 6]. Imaging studies reported tyline, cyclobenzaprine and tramadol but remain far that anterior cingulate cortex and dorsolateral prefrontal from satisfactory [59] In the same way, the present co- cortex are among the main areas involved. Decision hort of the patients was also allowed to continue the rec- making and response evaluation are specific domains ommended drug as a part of the standard of care [45] controlled by dorsal anterior cingulate cortex. These (see supplementary file 1). The rationale is based on the areas are also reported for pain perception and modula- fact that these drugs have demonstrated a moderate-to- tion. Anterior cingulate cortex has vital role in various large effect size for pain symptoms and somewhat on behavioral responses such as processing of attention and sleep quality, at least in the short term. Evidence sug- anticipation of pain [56]. This activity may correspond gests that long-term use of neuro-active drugs may in- to shared neural pain representations that allow deduc- duce cognitive deficits. A decline in cognitive ability has tion of the affective state of the pain and facilitating em- also been found to result in interference in daily activ- pathy [57]. Dorsolateral prefrontal cortex has shown ities, low coping, and poorer treatment outcomes. If the activation, when resolving conflicts and catching errors, evidence can be extended to patients of fibromyalgia , also it assists in memory and other executive functions, then the current management may compound the issue so ultimately affects cognition. Dorsolateral prefrontal at hand [59–61]. But cognitive abilities as outcome mea- cortex is involved in encoding and modulating acute sures of the randomized controlled trials are currently pain perception. Elevated high-frequency oscillatory ac- missing from the literature. Going forward, an ideal tivities in the dorsolateral prefrontal cortex and orbito- treatment strategy must address pain symptoms and, at frontal cortex correspond with higher affective pain least to some degree, the associated co-morbidities. Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 7 of 8 Limitations Consent for publication Consent to publish was also obtained from all the participants included in The findings of the study only pertain to middle-aged, the study. regularly menstruating females with fibromyalgia who were refractory to standard of care regime. Factors like Competing interests age and past treatments can affect pain perception, cog- No potential conflict of interest was relevant to this manuscript. nition, and sleep quality. Thus, more studies in patients Author details of fibromyalgia are required to see the generalizability of 1 Pain Research and TMS Laboratory, Department of Physiology, All India our findings. Institute of Medical Sciences, New Delhi, India. Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India. Stress and Cognition Electroimaging Laboratory, Department of Physiology, Conclusions All India Institute of Medical Sciences, New Delhi, India. Department of Nuclear Magnetic Resonance and MRI Facility, All India Institute of Medical The study confirms a decline in cognitive function and Sciences, New Delhi, India. sleep quality in patients of fibromyalgia. Most of the current treatments for fibromyalgia may have some ef- Received: 9 September 2020 Accepted: 2 January 2021 fect on pain perception and to some extent, sleep qual- ity. Introducing adjunct therapies that can help References overcome issues of refractoriness and cognitive decline 1. Walitt B, Nahin RL, Katz RS, Bergman MJ, Wolfe F. The prevalence and may have better outcomes. More research into treat- characteristics of fibromyalgia in the 2012 National Health Interview Survey. PLoS One. 2015;10:e0138024. ments that address cognitive deficits vis-à-vis pain and 2. Al-Allaf AW, Dunbar KL, Hallum NS, Nosratzadeh B, Templeton KD, Pullar T. other symptoms need to be conducted. A case-control study examining the role of physical trauma in the onset of fibromyalgia syndrome. Rheumatology. 2002;41:450–3. 3. Üçeyler N, Burgmer M, Friedel E, Greiner W, Petzke F, Sarholz M, et al. Etiology Supplementary Information and pathophysiology of fibromyalgia syndrome: updated guidelines 2017, The online version contains supplementary material available at https://doi. overview of systematic review articles and overview of studies on small fiber org/10.1186/s42358-021-00163-x. neuropathy in FMS subgroups. Schmerz. 2017;31:239–45. 4. Arnold LM, Clauw DJ, McCarberg BH. Improving the recognition and Additional file 1. diagnosis of fibromyalgia. Mayo Clin Proc. 2011;86:457–64. 5. Bell T, Trost Z, Buelow MT, Clay O, Younger J, Moore D, et al. Meta-analysis of cognitive performance in fibromyalgia. J Clin Exp Neuropsychol. 2018;40: Acknowledgements 698–714. The authors acknowledge the contributions of Dr. Danveer Bhadu and Dr. 6. Wu Y-LL, Huang C-JJ, Fang S-CC, Ko L-HH, Tsai P-SS. Cognitive impairment Sandeep for patient recruitment, Dr. Ragini Adhikari for scoring the in fibromyalgia: a meta-analysis of case-control studies. Psychosom Med. questionnaires, Dr. Suman Tanwar for helping with the review of literatue, 2018;80:432–8. Dr. Vinay Chitturi for helping paradigm design, and Ms. Chaithanya Leon for 7. Lawson K. Sleep dysfunction in fibromyalgia and therapeutic approach interpreting the Stroop Test analysis. options. OBM Neurobiol. 2020;4:16. 8. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RL, et al. Authors’ contributions 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Study was conceived and designed by RB; proposal writing and ethical Arthritis Rheum. 2016;46:319–29. clearance was obtained by VKT, SN, and RB; standardization of methodology 9. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. was done by VKT, RS, SSK, and RB; participant diagnosis was done by UK; The American College of Rheumatology preliminary diagnostic criteria for recruitment of participants was done by VKT and SA; data was acquired by fibromyalgia and measurement of symptom severity. Arthritis Care Res. VKT and SA; data processing done by VKT and SN with help of RS, SSK, and 2010;62:600–10. RB; statistical analysis was done by VKT and SN. Data interpretation, 10. Häuser W, Ablin J, Perrot S, Fitzcharles MA. Management of fibromyalgia: manuscript writing, and revision was done by all authors. RB takes key messages from recent evidence-based guidelines. Pol Arch Intern Med. responsibility for the correspondence, further queries, and guarantee of the 2017;127:47–56. study. All authors(s) read and approved the final manuscript. 11. Hedges D, Farrer TJ, Bigler ED, Hopkins RO, Hedges D, Farrer TJ, et al. Chronic pain and cognition. In: The brain at risk. Basel: Springer Funding International Publishing; 2019. p. 113–24. No funding to declare. 12. Folstein MF, Folstein SE, McHugh PR. “Mini-mental status”. A practical method for grading the cognitive state of patients for the clinician. J Availability of data and materials Psychiatr Res. 1975;12:189–98. The authors confirm that the data supporting the findings of this study are 13. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. available within the article and additional information can be provided if 1935;18:643–62. requested. 14. Rodríguez-Andreu J, Ibez-Bosch R, Portero-Vzquez A, Masramon X, Rejas J, Glvez R. Cognitive impairment in patients with fibromyalgia syndrome as Ethics approval and consent to participate assessed by the mini-mental state examination. BMC Musculoskelet Disord. The study was conducted at the Pain Research and TMS Laboratory, 2009;10:162. Department of Physiology, All India Institute of Medical Sciences, New Delhi, 15. Martinsen S, Flodin P, Berrebi J, Lö fgren M, Bileviciute-Ljungar I, Ingvar M, India. Human Ethics committee of the AIIMS, New Delhi (Ref No: IECPG-15/ et al. Fibromyalgia patients had normal distraction related pain inhibition 16.02.2017RT-27/26.04.2017) approved the research protocol in 2017. The but cognitive impairment reflected in caudate nucleus and hippocampus study was also registered in the Clinical Trials Registry of India (CTRI; Ref No: during the Stroop color word test. PLoS One. 2014;9:e108637. CTRI/2017/09/009827). All procedures performed during study involving hu- 16. Walteros C, Sánchez-Navarro JP, Muñoz MA, Martínez-Selva JM, Chialvo D, man participants were in accordance with the ethical standards of the Hu- Montoya P. Altered associative learning and emotional decision making in man Ethics committee of the All India Institute of Medical Sciences, New fibromyalgia. J Psychosom Res. 2011;70:294–301. Delhi, India. Participants were required to sign written, informed consent for 17. González JL, Mercado F, Barjola P, Carretero I, López-López A, Bullones MA, the study. et al. Generalized hypervigilance in fibromyalgia patients: an experimental Tiwari et al. Advances in Rheumatology (2021) 61:10 Page 8 of 8 analysis with the emotional Stroop paradigm. J Psychosom Res. 2010;69: 43. Parker R, Lewis G, Rice D, Stimulation PM. Is motor cortical excitability 279–87. altered in people with chronic pain? A systematic review and meta-analysis. 18. Suhr JA. Neuropsychological impairment in fibromyalgia: relation to Brain Stimul. 2016;9:488–500. depression, fatigue, and pain. J Psychosom Res. 2003;55:321–9. 44. Klein MM, Treister R, Raij T, Pascual-Leone A, Park L, Nurmikko T, et al. Transcranial magnetic stimulation of the brain: guidelines for pain treatment 19. Gelonch O, Garolera M, Valls J, Rosselló L, Pifarré J. Executive function in research. Pain. 2015;156:1601–14. fibromyalgia: comparing subjective and objective measures. Compr 45. Tiwari VK, Nanda S, Arya S, Kumar U, Bhatia R. Effect of repetitive transcranial Psychiatry. 2016;66:113–22. magnetic stimulation in male patients of fibromyalgia. Indian J Rheumatol. 20. Pimentel MJ, Gui MS, Reimão R, Rizzatti-Barbosa CM. Sleep quality and facial 2020;15:134–40. pain in fibromyalgia syndrome. J Craniomandib Pract. 2015;33:122–8. 46. Ganguli M, Ratcliff G, Chandra V, Sharma S, Gilby J, Pandav R, et al. A hindi 21. Bigatti SM, Hernandez AM, Cronan TA, Rand KL. Sleep disturbances in version of the MMSE: the development of a cognitive screening instrument fibromyalgia syndrome: relationship to pain and depression. Arthritis Care for a largely illiterate rural elderly population in India. Int J Geriatr Psychiatry. Res. 2008;59:961–7. 1995;10:367–77. 22. Mutlu P, Zateri Ç, Zöhra A, Özerdoǧan Ö, Mirici AN. Prevalence of 47. Algom D, Chajut E. Reclaiming the stroop effect back from control to input- obstructive sleep apnea in female patients with fibromyalgia. Saudi Med J. driven attention and perception. Front Psychol. 2019;10:1683. 2020;41:740–5. 48. Chipchase L, Schabrun S, Cohen L, Hodges P, Ridding M, Rothwell J, et al. A 23. Choy EHS. The role of sleep in pain and fibromyalgia. Nat Rev Rheumatol. checklist for assessing the methodological quality of studies using 2015;11:513–20. transcranial magnetic stimulation to study the motor system: an 24. Keskindag B, Karaaziz M. The association between pain and sleep in international consensus study. Clin Neurophysiol. 2012;123:1698–704. fibromyalgia. Saudi Med J. 2017;38:465–75. 49. Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, et al. A 25. Jennum P, Drewes AM, Andreasen A, Neilsen DK. Sleep and other practical guide to diagnostic transcranial magnetic stimulation: report of an symptoms in primary fibromyalgia and in healthy controls. J Rheumatol. IFCN committee. Clin Neurophysiol. 2012;123:858–82. 1993;20:1956–9. 50. Rossini PM, Rossi S. Transcranial magnetic stimulation: diagnostic, 26. Wu YL, Chang LY, Lee HC, Fang SC, Tsai PS. Sleep disturbances in fibromyalgiaA therapeutic, and research potential. Neurology. 2007;68:484–8. meta-analysis of case-control studies. J Psychosom Res. 2017;96:89–97. 51. Cavaleri R, Schabrun SM, Chipchase LS. The number of stimuli required to 27. Nijs J, Daenen L, Cras P, Struyf F, Roussel N, Oostendorp RAB. Nociception reliably assess corticomotor excitability and primary motor cortical affects motor output: a review on sensory-motor interaction with focus on representations using transcranial magnetic stimulation (TMS): a systematic clinical implications. Clin J Pain. 2012;28:175–81. review and meta-analysis. Syst Rev. 2017;6:48. 28. Chang WJ, O’Connell NE, Beckenkamp PR, Alhassani G, Liston MB, Schabrun 52. Bajpai G, Shukla G, Pandey R, Gupta A, Afsar M, Goyal V, et al. Validation of a SM. Altered primary motor cortex structure, organization, and function in modified Hindi version of the Epworth sleepiness scale among a north chronic pain: a systematic review and meta-analysis. J Pain. 2018;19:341–59. Indian population. Ann Indian Acad Neurol. 2016;19:499. 29. Umay E, Gundogdu I, Ozturk EA. What happens to muscles in fibromyalgia 53. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh syndrome. Ir J Med Sci. 2020;189:749–56. sleep quality index: a new instrument for psychiatric practice and research. 30. Martínez E, Aira Z, Buesa I, Aizpurua I, Rada D, Azkue JJ. Embodied pain in Psychiatry Res. 1989;28:193–213. fibromyalgia: disturbed somatorepresentations and increased plasticity of 54. Manzar MD, Moiz JA, Zannat W, Spence DW, Pandi-Perumal SR, Bahammam the body schema. PLoS One. 2018;13:e0194534. AS, et al. Validity of the Pittsburgh sleep quality index in Indian university 31. Fallon N, Chiu Y, Nurmikko T, Stancak A. Functional connectivity with the students. Oman Med J. 2015;30:193–202. default mode network is altered in fibromyalgia patients. PLoS One. 2016; 55. Cohen J. Statistical power analysis for the behavioural science. 2nd ed. 11:e0159198. London: Lawrence Erlbaum Associates, Publishers; 1988. 32. Robinson ME, Craggs JG, Price DD, Perlstein WM, Staud R. Gray matter 56. Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML. The anterior cingulate volumes of pain-related brain areas are decreased in fibromyalgia cortex and pain processing. Front Integr Neurosci. 2014;8:35. syndrome. J Pain. 2011;12:436–43. 57. Gougeon V, Gaumond I, Goffaux P, Potvin S, Marchand S. Triggering 33. Sundermann B, Dehghan Nayyeri M, Pfleiderer B, Stahlberg K, Jünke L, Baie descending pain inhibition by observing ourselves or a loved-one in pain. L, et al. Subtle changes of gray matter volume in fibromyalgia reflect Clin J Pain. 2016;32:238–45. chronic musculoskeletal pain rather than disease-specific effects. Eur J 58. Schabrun SM, Christensen SW, Mrachacz-Kersting N, Graven-Nielsen T. Neurosci. 2019;50:3958–67. Motor cortex reorganization and impaired function in the transition to 34. Wood PB, Glabus MF, Simpson R, Patterson JC. Changes in gray matter density sustained muscle pain. Cereb Cortex. 2016;26:1878–90. in fibromyalgia: correlation with dopamine metabolism. J Pain. 2009;10:609–18. 59. Calandre EP, Rico-Villademoros F, Slim M. Pharmacological treatment of 35. Gentile E, Brunetti A, Ricci K, Delussi M, Bevilacqua V, M de T. Mutual fibromyalgia: is the glass half empty or half full? Pain Manag. 2017;7:5–10. interaction between motor cortex activation and pain in fibromyalgia: EEG- 60. Calandre EP, Rico-Villademoros F, Rodríguez-López CM. Monotherapy or fNIRS study. PLoS One. 2020;15:e0228158. combination therapy for fibromyalgia treatment. Curr Rheumatol Rep. 2012; 36. Hsiao FJ, Wang SJ, Lin YY, Fuh JL, Ko YC, Wang PN, et al. Altered insula– 14:568–75. default mode network connectivity in fibromyalgia: a resting-state 61. Kravitz HM, Katz RS. Fibrofog and fibromyalgia: a narrative review and magnetoencephalographic study. J Headache Pain. 2017;18:89. implications for clinical practice. Rheumatol Int. 2015;35:1115–25. 37. Ichesco E, Quintero A, Clauw DJ, Peltier S, Sundgren PM, Gerstner GE, et al. Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: a pilot study. Headache. 2012;18:89. Publisher’sNote 38. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of Springer Nature remains neutral with regard to jurisdictional claims in human motor cortex. Lancet. 1985;325:1106–7. published maps and institutional affiliations. 39. Salerno A, Thomas E, Olive P, Blotman F, Picot MC, Georgesco M. Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients with fibromyalgia. Clin Neurophysiol. 2000;111:994–1001. 40. Mhalla A, de Andrade DC, Baudic S, Perrot S, Bouhassira D. Alteration of cortical excitability in patients with fibromyalgia. Pain. 2010;149:495–500. 41. Caumo W, Deitos A, Carvalho S, Leite J, Carvalho F, Dussán-Sarria JA, et al. Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology. Front Hum Neurosci. 2016;10:357. 42. Schwenkreis P, Voigt M, Hasenbring M, Tegenthoff M, Vorgerd M, Kley RA. Central mechanisms during fatiguing muscle exercise in muscular dystrophy and fibromyalgia syndrome: a study with transcranial magnetic stimulation. Muscle Nerve. 2011;43:479–84.

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