Prepulse inhibition of the blink reflex in functional neurological disorder and fibromyalgia

© The Author(s) 2025. Published by Oxford University Press on behalf of The Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Prepulse inhibition of the blink reflex in functional 1 neurological disorder and fibromyalgia 2 Lucia Nováková,1 Petr Sojka,1 David Voženílek,2 Tomáš Sieger,1,3 Lenka Hasíková,4 Ladislav 3 Šenolt,4 Jakub Závada,4 Mark J. Edwards5 and Tereza Serranová1 4 Abstract 5 Prepulse inhibition reflects subcortical sensory integration, where a low-intensity peripheral 6 stimulus (prepulse) reduces the amplitude of a reflex response to a subsequent high-intensity 7 stimulus. As a measure of pre-attentive sensory gating, prepulse inhibition has been found to be 8 altered in small cohorts of patients with functional disorders, including functional motor disorder 9 and fibromyalgia, suggesting a shared deficit in sensory information processing. However, prior 10 studies have not demonstrated consistent associations between prepulse inhibition abnormalities 11 and clinical measures. 12 We hypothesized that widespread pain and somatic symptoms in somatic symptom disorders may 13 result from a general deficit in the interpretation of bodily signals, potentially linked to 14 abnormalities in sensory filtering as measured by prepulse inhibition. 15 In this study, we examined 140 participants across four ageand sex-matched groups: 35 patients 16 clinically categorized with functional motor disorder without fibromyalgia, 35 with both functional 17 motor disorder and fibromyalgia, 35 with fibromyalgia only, and 35 healthy controls. A weak 18 electrical stimulus to the index finger served as the prepulse, delivered 100 ms before supraorbital 19 nerve stimulation to elicit the R2 component of the blink reflex. Prepulse inhibition was calculated 20 as the percent reduction in R2 amplitude. 21 Across all groups, lower prepulse was significantly associated with higher scores on the 22 Fibromyalgia Severity Scale, consisting of Widespread Pain Index and Symptom Severity Scale. 23 In patients with functional motor disorder, no association was found between prepulse inhibition 24 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 2 size and objectively rated motor symptom severity. 1 These findings suggest that impaired early sensory processing at subcortical level is related to 2 “fibromyalgianess” in people with functional motor disorder and fibromyalgia. Abnormal prepulse 3 inhibition may serve as an objective transdiagnostic marker of fibromyalgia symptomatology or 4 fibromyalgianess, including widespread pain and other non-motor symptoms in functional 5 disorders, highlighting a potential role of sensory gating deficits in the pathophysiology of 6 fibromyalgia-spectrum manifestations. 7 8 Author affiliations: 9 1 Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General 10 University Hospital in Prague, Prague, 128 08, Czech Republic 11 2 Central European Institute of Technology, Masaryk University, Brno, 601 77, Czech Republic 12 3 Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University in 13 Prague, Prague, 128 00, Czech Republic 14 4 Institute of Rheumatology, Prague, Czech Republic, 128 00, Czech Republic 15 5 Institute of Psychiatry, Psychology and Neuroscience at King's College London, London, SE5 16 8AB, UK 17 18 Correspondence to: Tereza Serranová 19 Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General 20 University Hospital in Prague, Kateřinská 30, Prague 128 08, Czech Republic 21 E-mail: [email protected] 22 23 Running title: Sensory gating in functional disorders 24 Keywords: functional movement disorder; fibromyalgia; prepulse inhibition; pain; sensory 25 processing 26 27 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 3 Introduction 1 Integration of competing sensory inputs is crucial: it helps prevent sensory overload and allows 2 more effective processing of relevant information.1 Prepulse Inhibition (PPI) is a robust 3 neurophysiological phenomenon in which a sensory stimulus (the prepulse) too weak to trigger a 4 reflex on its own, reduces the intensity of a reflex response to a stronger stimulus presented 30 to 5 500 milliseconds later (Fig. 1). PPI is widely accepted as a key measure of sensorimotor gating, a 6 physiological mechanism that regulates sensory input by integration of competing stimuli.2 The 7 top-down regulation of PPI appears to have a critical relationship with the cortico-striatal-pallidal8 thalamic network (or more broadly forebrain) input to brainstem.2. 9 PPI has been found consistently reduced in people with schizophrenia, obsessive-compulsive 10 disorder, anxiety disorders, post-traumatic stress disorder, Huntington's disease, and Tourette 11 syndrome.3 Interestingly, PPI has also been found abnormal in two major subtypes of functional 12 neurological disorders (FNDs): functional seizures and functional motor disorders (FMD)4,5 as well 13 as in somatic symptom disorders with pain such as fibromyalgia, 6interstitial cystitis7 and irritable 14 bowel syndrome.8 While the primary symptoms of FND relate to motor disorders, seizures and 15 sensory loss, pain is also commonly present in people with FND and is typically rated by patients 16 as a major contributor to disability and impaired quality of life.9 Chronic pain conditions including 17 fibromyalgia, which is characterized by widespread pain seem to be more frequent in people with 18 FND.10 FND and fibromyalgia share common non-motor symptoms, including fatigue, cognitive 19 issues, sleep disturbances, and headaches.11-13 FND and other somatic symptom disorders are 20 associated with alterations in the functioning of brain networks and are now believed to share 21 underlying pathophysiological mechanisms. Recent theoretical models based on predictive coding 22 accounts of brain function suggest functional symptoms arise from the development of abnormal 23 predictions about motor and sensory states including pain, driven by an abnormal allocation of 24 attention.14 People with FMD also exhibit poor sensory discrimination, compatible with 25 underweighting of incoming sensory evidence, especially if the inputs are noisy.15,16 26 Deficient PPI found in people with different functional symptoms/syndromes might suggest that 27 an impairment in ability to integrate sensory inputs could be a common neural mechanism 28 operating at subcortical level under control of top-down forebrain influences. A lack of sufficient 29 filtering or integration could result in increased sensory noise, which in turn could more easily be 30 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 4 over-ridden by prior expectations.5 1 In studies examining PPI in people with functional symptoms (FND and somatic symptom 2 disorders) only a limited number have assessed the relationship between PPI deficits and clinical 3 measures.4,5 Notably, these studies have not found significant correlations between PPI 4 abnormalities and symptom severity. For instance, research on patients with FMD reported no 5 significant association between motor and non-motor symptom measures (including pain intensity) 6 and PPI size. 7 Recent advances in fibromyalgia research have led to revision of diagnostic criteria and to 8 development of a diagnostic self-reported measures of pain widespreadness and number and 9 severity of other non-motor symptoms such as fatigue, poor sleep, mood and cognitive 10 problems.12,17 Fibromyalgia is increasingly viewed not as a discrete disease but as a spectrum of 11 “fibromyalgianess”, defined by pain widespreadness and symptom severity scores, and extending 12 to individuals with symptoms who do not meet full diagnostic criteria across clinical and non13 clinical populations.18 We hypothesized that widespread pain and perceived symptom burdens 14 could result from a general deficit in misinterpretation of bodily signals in people diagnosed with 15 fibromyalgia and FND linked to insufficient filtering of sensory information as measured by PPI. 16 The aim of this study was to perform a comprehensive investigation of PPI in fibromyalgia and 17 FND, with a particular focus on the relationship between PPI abnormalities and symptom severity 18 rather than on differences between groups with different categorical diagnoses. To achieve this, we 19 studied the association of PPI magnitude and fibromyalgia-related symptom severity on a 20 continuum of fibromyalgianess in three groups of patients with clinically diagnosed FMD and/or 21 fibromyalgia together with age and sex-matched healthy individuals. In addition, association 22 between PPI size and objectively rated motor symptom severity was studied in patients with FMD, 23 both with and without comorbid fibromyalgia. 24 25 Materials and methods 26 One hundred and forty subjects were recruited to the study between January 2022 and March 2024. 27 Exclusion criteria for both the control and patient groups included being under 18 years old, 28 language difficulties, severe learning disabilities or cognitive impairment, significant illnesses 29 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 5 associated with non-motor symptoms, substance dependence, psychosis, or a history of organic 1 neurological brain disorders and medication known to affect PPI, such as dopamine receptor 2 antagonists. All participants gave their written consent to take part in the study. The project was 3 approved by the Ethics Committee of the General Teaching Hospital in Prague, approval number: 4 37/19 Grant AZV VES 2020 1. LF UK. 5 Individuals with fibromyalgia were recruited directly by a rheumatologist (co-authors JZ, LH, LŠ) 6 from Institute of Rheumatology in Prague (n = 6) or through an online support group for patients 7 with fibromyalgia (n = 29). All individuals recruited online had rheumatological assessment and 8 provided a medical report. The diagnosis of fibromyalgia in all fibromyalgia patients was also 9 validated by a fibromyalgia diagnostic questionnaire.17 10 FMD patients were recruited at the specialized outpatient service for FMD at the Neurology 11 Department, 1st Faculty of Medicine and General University Hospital in Prague to match 12 fibromyalgia patients by age and sex. Two groups of FMD patients were recruited with and without 13 comorbid fibromyalgia, which was diagnosed using the current criteria based on fibromyalgia 14 diagnostic questionnaire.17 15 Control subjects matching the FMD and fibromyalgia patients for age and sex were identified in a 16 directory of healthy individuals willing to participate in clinical studies operated at the Neurology 17 Department. They underwent a thorough screening process, including a complete medical history 18 and a full neurological examination, ensuring that none had sensorimotor symptoms or objective 19 signs of neurological disorders. All control subjects received financial compensation of $25. 20 All subjects underwent a full neurological assessment including a detailed clinical interview and 21 examination by a neurologist with expertise in FMD (co-authors TS, LN), focusing on positive 22 signs of functional weakness or abnormal movements that were inconsistent and incongruent with 23 known movement disorders. FMD diagnosis was established using the Gupta and Lang criteria for 24 a clinically definite FMD.19 In each individual diagnosed with FMD, we evaluated and categorized 25 motor symptoms phenomenologically as functional weakness, tremor, dystonia/spasm, myoclonus, 26 gait abnormalities, or speech difficulties. We noted the primary motor symptom type along with 27 any additional motor symptoms exhibited. 28 Assessment of fibromyalgia was performed using the 2016 Fibromyalgia Survey Questionnaire, 29 which allowed to diagnose fibromyalgia based on the 2016 revised American College of 30 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 6 Rheumatology diagnostic criteria.17 To meet the criteria for fibromyalgia diagnosis, the individual 1 must have a Widespread Pain Index (WPI) of 7 or higher and a Symptom Severity Scale (SSS) 2 score of 5 or higher. Alternatively, if the WPI is between 4 and 6, the SSS score must be 9 or higher. 3 The individual must also have generalized pain, defined as pain in at least four of five regions, and 4 symptoms must have been generally present for at least three months. The Symptom Severity Scale 5 includes the following symptoms: fatigue, waking unrefreshed, cognitive symptoms, headaches, 6 pain or cramps in the lower abdomen, and depression.17 The WPI and SSS scores can also be 7 combined to provide a Fibromyalgia Severity Score (FSS), which is used as a continuous measure 8 of fibromyalgianess ranging between 0 and 31. 9 Individuals with fibromyalgia, FMD and fibromyalgia, FMD alone and HC were age and sex 10 matched. 11 All participants included in the study completed questionnaires for depression, anxiety, and 12 subjective cognitive complaints. 13 The Beck Depression Inventory (BDI-II) was used to measure depressive symptoms. It consists of 14 21 items with total score range of 0 to 63.20 15 We assessed anxiety levels using the State-Trait Anxiety Inventory trait scale specifically the STAI 16 X-2: a 20-item measure of trait anxiety with a possible score range of 20 to 80.21 17 Motor disorder severity was assessed using the Simplified FMD Rating Scale (S-FMDRS). 18 Abnormal movements were recorded across seven body regions and rated based on the severity 19 and duration of symptoms, with a maximum possible score of 54.22 20 Furthermore, all subjects' pharmacological history (SSRI, SNRI, SARI, NaSA, TCA, 21 anticonvulsants, DA, BDZ, opioids, NSA, medical cannabis) was recorded in detail (See 22 Supplementary Table S1.). None of the subjects used medication known to affect PPI, such as 23 dopamine receptor antagonists.23-25 24 A structured interview was conducted to identify medical comorbidities, family history, current 25 medications (including hormonal contraceptives), drug use, smoking habits, caffeine 26 consumption, and handedness. Participants were asked to refrain from caffeine and smoking for 27 3–4 hours prior to PPI testing to minimize known acute effects of these substances on 28 sensorimotor gating and reduce interindividual variability.6,26-28 29 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 7 Neurophysiological examination 1 The neurophysiological examination was conducted under standard conditions in a moderately lit 2 and quiet room. The subject was seated comfortably, ensuring that the electromyographic device 3 was not within their line of sight to prevent anticipation of the stimuli delivery. The subject was 4 informed in advance about the different types of stimuli. The recording was performed using a 5 routinely employed electrodiagnostic device (Synergy, CareFusion, London, United Kingdom). 6 The band-pass filters were set to frequencies ranging from 30 Hz to 30,000 Hz, with a sampling 7 frequency of 2,000 Hz. 8 Paradigm 9 The examination involved electromyographic recording of muscle activity in the orbicularis oculi 10 using 10 mm gold surface electrodes with conductive gel. The active electrode was placed along 11 the midline under the eye, dividing the muscle into two symmetrical parts, while the reference 12 electrode was positioned 2 cm laterally toward the outer corner of each eye. To elicit the blink 13 reflex, a 0.5 ms rectangular pulse of constant current was delivered to the right supraorbital nerve. 14 The cathode was placed over the supraorbital incisura, and the anode was positioned 3 cm laterally 15 along the nerve's path over the eyebrow. 16 The stimulation intensity applied was 10 times the individual's sensory threshold, which is defined 17 as the smallest stimulus intensity perceived by the subject in at least 4 out of 8 applications. A 18 prepulse stimulus, consisting of a 0.2 ms rectangular pulse of constant current, was applied 100 ms 19 before the supraorbital nerve stimulation, using ring electrodes attached to the right index finger 20 over the proximal and medial phalanges. A 100 ms interval between the prepulse and the startle 21 stimulus was used to ensure reliable inhibition of the blink reflex and consistency with previous 22 PPI studies of the blink reflex in FMD and fibromyalgia.5,6,29 The prepulse stimulation intensity 23 was set at twice the subject's sensory threshold. Each subject underwent 9 stimulations of the 24 supraorbital nerve alone (baseline blink reflex) and 9 stimulations with a prepulse preceding the 25 supraorbital nerve stimulation (blink reflex with prepulse), with approximately 8-10 second pauses 26 between individual stimulations. 27 During the baseline trials and prepulse trial, the morphology of blink reflex (R1, R2, and R3 28 components) was carefully assessed, and only trials from individuals with the R1 component 29 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 8 demonstrating no change or increase in the prepulse trials were included in the study. The 1 examination also involved assessing the subject's perceived discomfort or pain using the Numerical 2 Rating Scale for Pain (NRS), where 0 indicates no discomfort and 10 represents unbearable pain. 3 Analysis 4 Electromyographic recordings were rectified and analysed offline. Each subject underwent 18 5 stimulations (9 for the blink reflex and 9 for the blink reflex with prepulse). The early R1 and late 6 R2 components were identified in each ipsilateral EMG recording of the blink reflex, with the R2 7 component also recorded contralaterally (R2c). The magnitude of the R2 and R2c blink reflexes 8 was measured as the area under the curve (ms/mV) and averaged. In some recordings, an R3 9 component, a late polyphasic part of the blink reflex, was also observed but was not included in 10 the analysis. 11 To evaluate PPI, we calculated the average blink reflex magnitude (R2 and R2c areas) for each 12 trial. For each individual, we averaged the values from nine trials per condition (baseline and 13 prepulse). 14 To normalize data among subjects, we expressed the change in blink reflex magnitude during 15 prepulse trials relative to baseline trials as a percentage of the baseline trials (%PPI = mean blink 16 reflex magnitude in prepulse trials / mean blink reflex magnitude in baseline trials × 100). The 17 primary outcome, PPI size, was calculated as the difference in blink reflex magnitude between the 18 prepulse (%PPI) and baseline trials (100 %), i.e. PPI size = 100% - %PPI. The PPI size value 19 represents the primary outcome and reflects the degree of prepulse inhibition in a given subject. 20 Blink reflex recordings from all participants were of sufficient quality to allow for further analysis. 21 Statistics 22 Multiple linear regression model of FSS as measure of fibromyalgianess was fitted with PPI as the 23 predictor, adjusting for age and sex to account for potential confounding effects. Additionally, we 24 also fitted similar models of WPI and SSS. Because depression and anxiety are strongly associated 25 with chronic pain 30 and may act as mediators of the relationship between PPI size and fibromyalgia 26 symptoms, we did not include them as covariates in these models. We also examined whether PPI 27 size was associated with motor symptom severity in a subset of patients with FMD, including those 28 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 9 with comorbid fibromyalgia (n = 70), to assess whether reduced PPI size is specific to pain 1 symptoms within FMD or also relates to motor symptom severity. 2 Additionally, group differences in demographic and clinical characteristics (age, illness duration, 3 FSS, WPI, SSS, S-FMDRS, BDI-II, and STAI-X2) were assessed using analysis of variance with 4 Tukey post hoc tests. Pearson’s correlation was used to assess the relationship between PPI size 5 and other symptom measures, including the BDI-II, STAI-X2, and S-FMDRS. Analyses were 6 performed in R (Version 4.4).31 P-values arising from multiple statistical testing were corrected 7 using the Holm-Bonferroni method.32 8 9 Ethical Compliance Statement 10 The study was approved by the local Ethics Committee of the General University Hospital in 11 Prague (Approval Nr. 37/19) and all participants gave their written consent to take part in the study. 12 We confirm that we have read the Journal’s position on issues involved in ethical publication and 13 affirm that this work is consistent with those guidelines. 14 15 Results 16 A total of 140 participants were included in the analysis, comprising 35 subjects per patient group 17 and 35 healthy controls. All patient cohorts and healthy controls were matched for key 18 demographics with no differences in age or sex among the groups. Demographic data and clinical 19 scores are summarized in Supplementary Table S2. Post hoc tests showed that the illness duration 20 was significantly longer in fibromyalgia patients as compared to FMD with fibromyalgia (P = 0.01) 21 and FMD patients (P < 0.001), but the illness duration between FMD and FMD with fibromyalgia 22 did not differ (P = 0.61). Healthy controls reported significantly lower FSS, WPI, SSS, BDI-II, and 23 STAI-X2 scores compared to all patient cohorts (P < 0.001). Fibromyalgia only and FMD with 24 fibromyalgia patients had significantly higher FSS, WPI, SSS scores (P < 0.001), BDI-II and STAI25 X2 scores (P < 0.01) compared to FMD group. S-FMDRS was significantly higher in FMD with 26 fibromyalgia patients compared to FMD only patients (P < 0.001). There were no significant 27 differences in the clinical scales between fibromyalgia only and FMD with fibromyalgia patients. 28 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 16 intercellular adhesion molecule1 (sICAM-1), and a specific neuroimaging pattern correlating with 1 fibromyalgianess has been identified.78 It may be, like PPI, that such markers are not specific to 2 fibromyalgia or even to the presence of widespread pain but might also occur in people with FND 3 without fibromyalgia. 4 In conclusion, we found a deficit of PPI that suggests abnormal early processing of somatosensory 5 inputs in FND and fibromyalgia. A lower PPI size was associated with more fibromyalgianess i.e. 6 pain widespreadness and higher levels of non-motor symptoms in people with fibromyalgia and 7 FMD. PPI thus could represent a valuable objective marker of generalised chronic pain and 8 associated non-motor symptoms in this clinical population. 9 10 Acknowledgement 11 The thumbnail image for the online table of contents was created in BioRender. Nováková, L. 12 (2025) https://BioRender.com/3ed8qi1. 13 14 Data availability 15 The data that support the findings of this study are available on request from the corresponding 16 author. All data will be anonymized. 17 18 Funding 19 Supported by the Czech Ministry of Health Project AZV NW24-04-00456, the project National 20 Institute for Neurological Research (Programe EXCELES, ID Project No. LX22NPO5107) - 21 Funded by the European Union – Next Generation EU; Charles University: Cooperatio Program in 22 Neuroscience; General University Hospital in Prague project MH CZ-DRO-VFN64165 and by the 23 ERDF-Project Brain Dynamics, No. CZ.02.01.01/00/22_008/0004643. 24 25 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025 17 Competing interests 1 The authors report no competing interests. 2 3 Supplementary material 4 Supplementary material is available at Brain online. 5 6 References 7 1. Takahashi H, Hashimoto R, Iwase M, Ishii R, Kamio Y, Takeda M. 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Prepulse inhibition is a neurophysiological phenomenon in 23 which a reflexive response (e.g. the startle response or the blink reflex) to a strong stimulus (pulse) 24 is significantly reduced when preceded by a weaker stimulus (prepulse) within 30 to 500 25 milliseconds. The prepulse alone is too weak to elicit a reflex but effectively modulates the 26 subsequent response. Prepulse inhibition serves as a key measure of sensorimotor gating, a 27 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf437/8339512 by Institute of Computer Science/Academy of Sciences user on 08 December 2025