Are you listening? Facilitation of the auditory blink response in people with fibromyalgia

ARE YOU LISTENING? FACILITATION OF THE AUDITORY BLINK RESPONSE IN PEOPLE WITH FIBROMYALGIA Carolyn Berryman ab , Sarah B Wallwork b , Alberto Marcos Heredia Rizo c , Emma Knight a , Danny Camfferman d , Leslie Russek e , G. Lorimer Moseley b a. The University of Adelaide, School of Medicine, North Tce, Adelaide, 5005; [email protected]; [email protected]. b. IIMPACT in Health, University of South Australia, North Tce, Adelaide, 5001; lorimer.mosele[email protected].au; [email protected] c. Physiotherapy Department, Faculty of Nursing, Physiotherapy and Podiatry, University of Seville, c/ Avicena s/n 41009, Seville, Spain; [email protected] d. Country and Outback Health, Henley Beach Rd, Thebarton, South Australia, 5031; [email protected] e. Physical Therapy Department, Clarkson University, Potsdam, New York, USA 13699- 5880; [email protected] Short Title: Auditory blink response in people with FM Corresponding Author: Carolyn Berryman: ph +61419817494 Conflict of Interest GLM has received support from: Reality Health, Connect Health UK, Seqirus, Kaiser Permanente, Workers’ Compensation Boards in Australia, Europe and North America, AIA Australia, the International Olympic Committee, Port Adelaide Football Club, Arsenal Football Club. Professional and scientific bodies have reimbursed him for travel costs related to presentation of research on pain at scientific conferences/symposia. He has received speaker fees for lectures on pain and rehabilitation. He receives book Permanent and speaker fees for lectures on pain and rehabilitation. Financial Support Funding: CB was supported by the National Health and Medical Research Council of Australia (NHMRC) [Grant Number 1127155]; GLM and SBW were supported by a Leadership Investigator grant from the NHMRC of Australia [Grant Number 1178444]; AMHR was supported by the VI Plan Propio de Investigación, Universidad de Sevilla, Spain [Grant Number PP2016-5922]. Abstract The purpose of the current study was to determine whether auditory prepulse inhibition (PPI) and/or prepulse facilitation (PPF) were altered in people with fibromyalgia (FM) when compared with controls Eyeblink responses were recorded from 29 females with FM and 27 controls, while they listened to three blocks of auditory stimuli that delivered pulses with either PPI or PPF. Using a linear mixed model, our main findings were that there was a GROUP*CONDITION interaction (F4, 1084 = 4.01, p = .0031) indicating that the difference in amplitude between FM group and control group changed depending on the condition (PPI or PPF). Post hoc t ests revealed no differences between the groups in response to PPI. The FM group showed a greater reactivity of response to the PPF conditioned stimulus than the control group did (t(39.7) = 2.03, p = .0494). Augmentation of PPF, as demonstrated by the FM group is thought to be linked to alterations in information processing mediated by an autonomically driven general orienting process. Activities that decrease autonomic drive or rebalance autonomic and parasympathetic tone such as vagal stimulation might be pursued as effective interventions for people with FM. Perspective This article presents evidence of preservation of neural circuitry that underpins response suppression and evidence of neural circuit disturbance mediated by autonomic drive in people with FM. These results are important because intact circuitry underpins the effectiveness of therapies and may be harnessed, and rebalancing autonomic drive may be indicated. Keywords: Fibromyalgia, prepulse inhibition, prepulse facilitation, auditory blink response, autonomic drive Introduction Fibromyalgia (FM) is a complex, chronic disorder characterised by widespread pain and hypersensitivity to noxious (hyperalgesia) and non-noxious (allodynia) stimuli including heat, pressure, and touch 14 . FM is also associated with other debilitating symptoms such as fatigue, cognitive impairment (commonly referred to as ‘fibro fog’), anxiety, and low mood. Comorbidities include sleep disorders, endometriosis 1 , and irritable bowel syndrome 21 . All age prevalence estimates vary between 4 and 8 % 68 (men:women = 1:2) 14 . Diagnosis of FM is usually established by the treating primary care physician and may be validated by a self-report score of >13/31 on the American College of Rheumatologists’ FM diagnostic criteria71. The mechanisms that contribute to FM symptoms remain to be clearly understood. Current thinking characterises FM as a central nervous system driven disorder of amplified sensory processing 19 with contributions from immune-inflammatory pathways 2 and genetic susceptibility 17 . Guidelines for treatment promote early education and nonpharmacological therapies 44 . If pain and disability persist or increase then progression to tailored treatment options that include psychological, pharmacological, and multimodal therapies is recommended although the effect of most therapies is modest 44 . Deeper understanding of the mechanisms underpinning FM is necessary to develop more targeted and effective interventions. An established pathophysiological feature of FM is altered somatosensory (i.e., sense of touch and body position) information processing in the central nervous system 13, 18, 25 . Brain imaging studies have reported differences between people with FM and controls in the patterns of brain activity evoked by experimental noxious stimuli 27, 28, 30, 51 . Differences in brain activity during processing of non-noxious tactile and auditory stimuli have also been documented 42 . Multimodal sensitivities are common in FM, and deficiencies in endogenous analgesia in such paradigms as conditioned pain modulation 24 raise the question of whether the mechanisms that underpin changes in information processing arise in conjunction with insufficient inhibition and/or overactive facilitation of sensory processing. A robust method of investigating inhibition and facilitation is to examine the modulation of an eye-blink response to a startling stimulus (i.e., fast rising auditory tone) that is preceded by a non-startling stimulus (i.e., non-startling auditory tone). A phenomenon known as prepulse inhibition (PPI) occurs when the discrete preceding stimulus is presented less than 500 ms (the lead latency) before the startling stimulus 66 . A different phenomenon, prepulse facilitation (PPF), occurs when a continuous stimulus (particularly one of the same modality) is presented longer than 1000ms before the startling stimulus 9 . PPI is thought to be a brainstem-level inhibitory mechanism that indexes sensorimotor gating for the protection of first come information. This mechanism promotes a focus on important sensory information without being overwhelmed by trivial sensory inputs 59 ; deficits are likely to result in cognitive overload and fragmentation of information 5, 73 . Functionally, there is now compelling evidence for the role of cortico-striato-pallidopontine circuitry in the inhibitory impact of the lead stimulus in PPI 61, 62 . PPF is less well understood. Motor facilitation with a continuous, long (>1000ms) lead stimulus occurs across species and is thought to be mediated by the reticular activating system 29 . Further, at lead stimulus onset, heart rate decelerates, reflecting an autonomically driven general orienting process 23 . This raises the possibility that higherlevel processing may be involved in the PPF response, as though the subject is waiting vigilantly for startle stimulus onset, being unable to predict the length of the continuous lead signal 23 . The aim of the current study was to determine whether auditory PPI and/or PPF were altered in people with FM when compared with controls. We hypothesised that people with FM would demonstrate (i) less suppression of the auditory eye-blink response to PPI, and (ii) more facilitation of the PPF response, than controlscontrols. Methods Participants Twenty-nine females with FM, diagnosed according to a self-report survey based on criteria in the 2011 modification of the FM diagnostic criteria set by the American College of Rheumatology 14 were recruited. Participants were recruited via advertisements on social media sites, appeals made to rheumatologists, advertisements posted in pain and musculoskeletal inpatient clinics and by word of mouth. Participants were asked to continue their normal medication in order for their pain to be controlled during testing and thus avoid any increased muscle tension that would invalidate the neurophysiological trace. The type and dose of medication was recorded for all participants. Participants with FM were matched with controls on three factors: age, gender and handedness. Twentyseven participants without a history of psychiatric or neurological disorders and who reported being healthy were purposively included in the control group. All participants in this group also completed the self-report survey for the assessment of FM as above. Control participants were recruited from University and Hospital staff and their relatives and through word of mouth. All participants were requested to avoid caffeine intake for two hours prior to the study, had normal hearing bilaterally without the use of hearing aids, had normal or corrected vision, reported manual dexterity sufficient for normal daily activities, and were fluent in English. No participants reported central nervous system disorders such as stroke, or Parkinson’s Disease, or any condition that affected facial muscles in a manner that would affect the blink reflex. All participants were naïve to the task and recruitment occurred over the period of 2016 to 2017. Neurophysiological Investigation Prepulse paradigms are particularly suitable for investigating neurophysiological mechanisms in people with FM because the set-up and procedures are easily tolerated, robust and non-invasive. The same investigator (CB) carried out all neurophysiological investigations. Participants were seated comfortably in a collection room with a measured ambient noise level of 44 dB. The experimental procedure was explained to all participants and signed informed consent was obtained. To control for any effect of attention wander, participants were instructed to keep their gaze directed forwards at a cross on the wall during presentation of the three blocks of stimuli. The room was dimly lit and the participants were instructed not to speak during the testing. Electromyography and stimulus delivery The activity of the orbicularis oculi muscle to sound pulses was recorded by single sweeps of nonrectified electromyographic (EMG) data recorded with SynAmps RT (Compumedics®, Abbotsford, Australia) and collected from three small electrodes. One 10mm surface Ag/AgCl electrode was placed under the middle of the right eye over the mid portion of the orbicularis oculi muscle, and another was placed at the outer canthus of the right eye a finger-width away from the first. The earth electrode was placed over the mastoid process behind the right ear. Participants were instructed how to roll and squash the foam earplugs between their thumb and forefinger allowing them to make a small enough shape to insert to an adequate depth into their ear canals. One earplug was inserted by the participant into each ear and fit and comfort were checked by CB once the earplugs had expanded in place. The earplugs served the dual purpose of delivering the sound pulses and attenuating the effects of any environmental noises. The EMG signal was amplified and sampled at a rate of 10 kHz. Threshold testing In order to determine the blink response threshold, six sound pulses of various intensities (80 dB, 85 dB, 90 dB, 95 dB, 100 dB, and 105 dB) were generated using STIM2 Sound Editor (Compumedics, USA, Charlotte, NC). Pulses were delivered using STIM2 audio system (Compumedics, USA, Charlotte, NC; model 1140) via earphones and foam ear inserts (Etymotic Research foam ear inserts; ER 3A ABR Insert Earphone, Compumedics USA, Charlotte, NC) three times in pseudorandom order (i.e. a random number sequence was generated for the presentation of the 18 sound pulses (6 pulses delivered 3 times)), with an inter-stimulus interval ranging from 5 to 25 seconds. Non-responders, defined as those who consistently did not respond to 105dB, were excluded from further EMG testing. Any participants who found the noise unbearable were instructed to let the researcher know during or after the trial and were given the option to withdraw. Prepulse inhibition and facilitation testing Background noise of 40 dB was delivered via earplugs for 2mins prior to the testing sequence for each block. To test PPI, a discrete, low-intensity 70 dB prepulse stimulus was delivered at lead latency times of 70, 100 and 160 ms ((3 conditions – short, medium and long lead intervals) before the delivery of a 105 dB startling pulse. The prepulse was an immediate rise rectangular pulse of 40 ms and the startling pulse was an immediate rise rectangular pulse of 50ms. To test PPF a 4.5 second continuous stimulus of 70 dB preceded the same 105 dB 50 ms startling pulse (1 condition, see Figure 1). Stimuli were delivered across three blocks (A, B and C), with each condition (total of 4 conditions) delivered four times per block (16 conditioned stimuli per block), thus each condition was delivered a total of 12 times. Five single pulses of 105 dB were also delivered within each block, one at the beginning, one at the end and three within the block to control for habituation (total of 15 single pulses across the three blocks). These single pulses also acted as a baseline condition. The interstimulus interval was between 10 and 25 seconds. Stimuli were delivered in pseudorandom order and blocks were delivered ten minutes apart to minimize startle habituation and participant fatigue (see data repository Table 1 and 2 (resp) for the order of delivery for each block, and which order each participant received). Participants engaged in gentle stretching, rehydration and completed the questionnaires during this time. A continuous sweep of non-rectified EMG data was recorded for each block. Questionnaires All participants provided demographic information and health history. Because there is no unified approach to clinimetric evaluation of FM 55 , and much heterogeneity in presentation 72 we followed recommendations of the field 20 to capture phenotypic characteristics of our sample and obtained a multidimensional assessment of our participants. We also assessed sleep and medication because these factors are known to influence the outcomes of PPI and we planned a priori to use them in our data modelling. Functional status was assessed using the Fibromyalgia Impact Questionnaire – Revised (FIQ_R), which provides a total score from 0 to 100, across 21 items 11 . A score of 100 indicates that FM has a severe impact on daily function. We asked participants in the control group to report their level of function with reference to any current impairments using this questionnaire. All participants completed the Central Sensitization Inventory (CSI), which was developed to alert clinicians to the presence of symptoms that might indicate upregulation of central pain mechanisms 47 , such as allodynia, hyperalgesia and spread of pain to uninjured tissue. Five responses measure how frequently you have felt each of 25 items in the last month (never, rarely, sometimes, often, always). The questionnaire is psychometrically sound with high test-retest reliability and internal consistency (Pearson’s r = 0.817; Cronbach’s alpha = 0.879) 47, 48 and high construct validity 57 . A clinically significant score of >40 has been shown to identify central sensitivity syndromes in an outpatient chronic pain sample48. Depression, Anxiety and Stress were assessed using the DASS – 21, a 21-item selfadministered questionnaire. The DASS –- 21 asks respondents to score the extent to which each of the 21 statements have applied over the past week and higher scores indicate increasing severity. Measures for internal consistency and stability over time of the subscales Depression, Anxiety and Stress are high 10, 43 . All participants completed the Primary Care Post Traumatic Stress Disorder Screen (PCPTSD), which is a psychometrically sound screening tool to identify PTSD in primary care 52 . The screen comprises four questions that probe the manner in which a frightening, horrible or upsetting event might intrude into the respondent’s life. The respondent answers yes or no to having experienced nightmares, avoidance behaviour, watchfulness and/or numbness in the past month that they would associate with the traumatic event. A cut off score of 3/4 positive responses indicates that further investigations are warranted. Positive and negative affect was examined in all participants using two 10 item scales consisting of words that describe feelings and emotions (Positive Affect and Negative Affect Scale (PANAS) 70 ). Participants were asked to indicate to what extent they feel that way at the moment using a 1-5 ranking ranging from “very slightly or not at all” to “extremely”. The PANAS is internally consistent and has excellent convergent and discriminant validity with lengthier mood measures 70 . Normative data for momentary positive affect (mean = 29.7 (sd = 7.9)), and negative affect (mean = 14.8 (sd = 5.4)). All participants completed the Pain Catastrophising Scale (PCS), which is a reliable and stable index of the psychological processes that lead to heightened physical and psychological distress in response to aversive stimulation 58 . The scale can be completed in 5 minutes and includes 13 items. Participants are asked to reflect on a past painful experience and rate the 13 items by the degree to which they experienced each item from “not at all” to ”all the time”, a five point scale. By summing all the responses, a PCS total score is calculated, and if greater than 30 is deemed clinically relevant. The subjective quality of sleep was evaluated in all participants using the Pittsburgh Sleep Quality Index (PSQI). This index contains 19 self-rated questions, combined to form seven “component scores” each of which is rated within a range of 0-3. One global score is calculated by summing the seven component scores and a cut-off of > 5 is clinically meaningful for identifying participants with altered sleep patterns 12 . Noise sensitivity was measured in all participants using the Weinstein’s Noise Sensitivity Scale 6B (WNS – 6B). This scale comprises six questions to which the participant replies Yes or No (scored 1 and 0 respectively), the response reflecting how you felt about that noise situation this week. A global score is calculated and a noise sensitive group is determined by a median of 5 or greater 32 . There are also limitations to the current study. The influence of medications was not controlled for because all participants were allowed to remain on their medication. In particular, gabaergic medication has been shown to modulate PPI response, although using a linear mixed model approach we were able to test for the effect and found none. We instructed participants to maintain a caffeine and nicotine free window prior to testing, but we could not verify that they had. Finally, we did not lock our protocol prior to commencing data collection. This important practice has only recently been recognised, and is now recommended, in the pain field 39 . We commenced the current study while we were still naïve to this practice and we acknowledge this oversight limits the transparency of this report. Conclusion People with FM did not demonstrate less suppression of the auditory eye-blink response to PPI than controls, but they did demonstrate more facilitation of the PPF response. This result provides confidence that therapies designed to suppress responses that are mediated through auditory channels such as mindfulness scripts and body scans have intact circuitry through which to act. Augmentation of PPF, as demonstrated by the FM group is linked to alterations in information processing mediated by an autonomically driven general orienting process. Activities that decrease autonomic drive or rebalance autonomic and parasympathetic tone such as vagal stimulation might be considered for people with FM. PPF may present a robust marker for vulnerability to FM and or of the effectiveness of these interventions. 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FM = Fibromyalgia, HC = Healthy Controls, AUD = Australian dollars, FIQ_R = Fibromyalgia Impact Questionnaire – Revised, CSI = Central Sensitivity Index, DASS = Depression Anxiety Stress Scale, PANAS = Positive and Negative Affect Scale, WNS-6B = Weinstein’s Noise Sensitivity Scale (6 binary coded response options), NMDA = N-methyl D- aspartate, NSAIDS = non-steroidal anti-inflammatory drugs. Other medications include hormone replacement therapy, contraceptive medication, thyroid medication, cardiac medication and medication for acid reflux. Table 2 Num DF = numerator degrees of freedom, Den DF = denominator degrees of freedom, Sig =significance. Bold indicates significant finding. Table 3 Between and within group differences for all conditions. People with FM responded with greater facilitation to the PPF (4500) condition than HC. Within group comparisons demonstrated that there was a significant effect of PPI (Conditions 120, 150, and 210) and PPF (Condition 4500) compared to baseline amplitude (Condition 0), in the expected direction (smaller for inhibition and larger for facilitation). Within group differences between all conditions except between 120 and 150 were evident. FM = Fibromyalgia, HC = Healthy controls, Cond = condition, I/F – inhibition/facilitation, Est = estimate of the difference of least squares means, CI = 95% confidence interval, SE = standard error, DF = degrees of freedom, Sig = significance, Bonferroni corrected for multiple comparisons. Figure 1 Schematic of Prepulse Conditions Figure 2 Adjusted means plot of amplitude by pulse type (condition