ORIGINAL ARTICLE

Habituation deficit of auditory N100m in patients with

fibromyalgia
W. Choi1, M. Lim2, J.S. Kim3, C.K. Chung1,2,3,4
1 Interdisciplinary Program in Neuroscience, Seoul National University College of Natural Sciences, Seoul, Korea
2 Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea
3 Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Korea
4 Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea

Correspondence Abstract
Chun Kee Chung
E-mail: chungc@snu.ac.kr Background: Habituation refers to the brain’s inhibitory mechanism
against sensory overload and its brain correlate has been investigated in the
Funding sources form of a well-defined event-related potential, N100 (N1). Fibromyalgia is
This research was supported by Basic an extensively described chronic pain syndrome with concurrent
Science Research Program through the
manifestations of reduced tolerance and enhanced sensation of painful and
National Research Foundation of Korea (NRF)
non-painful stimulation, suggesting an association with central
funded by the Ministry of Science, ICT and
future Planning (2014R1A2A1A11049662) amplification of all sensory domains. Among diverse sensory modalities, we
and the National Research Foundation of utilized repetitive auditory stimulation to explore the anomalous sensory
Korea (NRF) grant funded by the Korea gov- information processing in fibromyalgia as evidenced by N1 habituation.
ernment (MSIP) (No. 2010-0028631). Methods: Auditory N1 was assessed in 19 fibromyalgia patients and age-,
education- and gender-matched 21 healthy control subjects under the
Conflict of interest
duration-deviant passive oddball paradigm and magnetoencephalography
None declared.
recording. The brain signal of the first standard stimulus (following each
deviant) and last standard stimulus (preceding each deviant) were
Accepted for publication analysed to identify N1 responses. N1 amplitude difference and adjusted
13 March 2016 amplitude ratio were computed as habituation indices.
Results: Fibromyalgia patients showed lower N1 amplitude difference
doi:10.1002/ejp.883 (left hemisphere: p = 0.004; right hemisphere: p = 0.034) and adjusted
N1 amplitude ratio (left hemisphere: p = 0.001; right hemisphere:
p = 0.052) than healthy control subjects, indicating deficient auditory
habituation. Further, augmented N1 amplitude pattern (p = 0.029)
during the stimulus repetition was observed in fibromyalgia patients.
Conclusions: Fibromyalgia patients failed to demonstrate auditory N1
habituation to repetitively presenting stimuli, which indicates their
compromised early auditory information processing. Our findings
provide neurophysiological evidence of inhibitory failure and cortical
augmentation in fibromyalgia.
What’s already known about this topic?:
• Fibromyalgia has been associated with altered filtering of irrelevant
somatosensory input. However, whether this abnormality can extend
to the auditory sensory system remains controversial.
• N!00, an event-related potential, has been widely utilized to assess the
brain’s habituation capacity against sensory overload.
What does this study add?:
• Fibromyalgia patients showed defect in N100 habituation to repetitive
auditory stimuli, indicating compromised early auditory functioning.
• This study identified deficient inhibitory control over irrelevant
auditory stimuli in fibromyalgia.

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Auditory habituation deficit in fibromyalgia
1. Introduction
Habituation refers to the ability of the central
nervous system to filter out irrelevant sensory infor-
mation, as characterized by a suppression of neural
activity following repetition of identical stimuli
(N€a€at€anen and Picton, 1987; Ulanovsky et al., 2004).
This distinct neural phenomenon is often viewed as
the brain’s protective mechanism against sensory
overload whose dysfunction is ascribed to over-
whelmed high-order mechanism for sensory percep-
tion and cognition (Venables, 1964; Adler et al., 1982;
Freedman et al., 1987). Accordingly, habituation has
been regarded as a high-priority research for probing
individual and group differences of sensory processing
and cognition in clinical studies.
N100 (N1) is an obligate mid-latency sensory-
evoked component, deflecting approximately 100 ms
after a stimulus onset (N€ a€
at€
anen and Picton, 1987).
Without subjects’ conscious intervention, N1 and its
magnetic equivalent (N1m) have been measured
mainly via electroencephalography and magnetoen-
cephalography (MEG), reflecting neuronal aggregates
for sensory processes at the early phase (Anokhin
et al., 2007). Changes in N1m amplitude measure
habituation, based on the evidence of declined N1m
amplitude in healthy control (HC) subjects (Boutros
et al., 2009). Meanwhile, various clinical popula-
tions, including pain disorders, did not show a
response decrement following stimulus repetition, as
compared to a robust habituation in HC subjects,
suggestive of the clinical utility of examining N1
habituation (Ambrosini et al., 2003; Shin et al.,
2012; Coppola et al., 2013a,b).
Evidence for centrally mediated disturbance to
both painful and non-painful stimulation in patients
with fibromyalgia (FM) has been provided by several
manifestations of reduced tolerance and exaggerated
sensation (Gracely et al., 2002; Desmeules et al.,
2003; Geisser et al., 2008). The abnormalities are
thought to be associated either with deficient modu-
lation of descending inhibitory pathway or excessive
activation of afferent pathway for sensory stimuli
(Julien et al., 2005). Neurochemical and neuroimag-
ing studies have indicated that lower levels of
antinociceptive neurotransmitters and the brain’s
structural and functional alterations may cause an
inhibitory failure over the unwanted input (Clauw
et al., 2011). However, the precise pathophysiology
remains unclear, and whether the disturbance could
apply to every stimulus domain has not been tested.
Until now, investigations of the brain correlate for
habituation, and inhibition effects using the auditory
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stimulation in FM have been limited. Thus, we exam-
ined habituation by auditory N1m, which also reflects
an inhibitory function. Specifically, we aimed to
explicitly address the following hypotheses: (1)
patients with FM would exhibit aberrant N1m
responses, as compared with HC subjects; and (2)
N1m responses are of functional significance, showing
associations with the symptoms of FM. Previously, in
the aspect of mismatch negativity (MMN), we
revealed that pre-attentive auditory processing is
compromised in patients with FM (Choi et al., 2015),
the same dataset which the present study has also uti-
lized. Nevertheless, little is yet known about the brain
responses following repetitive auditory stimuli in FM.
As an initial exploration of auditory N1m under the
oddball paradigm, this study would provide further
insight to the anomalous characteristics of auditory
processing and could suggest clinical implications of
sensory processing disturbances in FM.
2. Methods
2.1 Study subjects
Nineteen patients satisfying the American College of
Rheumatology 1990 criteria for primary FM, and 21
HC subjects group-matched for age, gender (all
women), education and handedness were enrolled
(Wolfe et al., 1990). All the patients were recruited
from the outpatient clinics of the rheumatology
departments of the Seoul National University Hospi-
tal (SNUH) and Hallym University Sacred Heart
Hospital. They were examined at the SNUH for the
reliability of the study results. Inclusion criteria for
the patients consisted of widespread pain (duration:
at least 3 months but less than 10 years), age
between 30 and 60 years, averaged pain intensity
over the past week > 40 mm according to 0–
100 mm pain visual analogue scale (VAS: 0 = no
pain, 100 = worst pain imaginable) and agreement
to stop taking medication (e.g. analgesics, antidepres-
sants and anticonvulsants) at least 3 days prior to
the experiments. Exclusion criteria for both patients
and HC subjects were the signs of secondary FM
associated with inflammatory arthritis, history of
psychiatric disorders, disability of hearing, pregnancy
or breastfeeding, and contraindications for MEG
and/or magnetic resonance imaging (MRI) assess-
ments. All study subjects provided informed written
consent prior to the experiment.
The study protocol was approved by the institu-
tional review board at the SNUH (H-1107-013-367)
and Hallym University Sacred Heart Hospital
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W. Choi et al.
(2011-I048) and was conducted in compliance with
the Declaration of Helsinki. Analysis of MMN for
the 21 HC subjects and 18 patients with FM has
been published in the previous study (Choi et al.,
2015).
2.2 Self-reported questionnaires
All subjects were asked to report their personal
information for use in the analyses. Clinical and
psychological characteristics were assessed by using
the following inventories. Patients with FM were
assessed with the Fibromyalgia Impact Question-
naire (FIQ), a multidimensional measure of the
overall severity of FM (Burckhardt et al., 1991).
Averaged pain over the previous week for each
patient was obtained with the VAS. For every sub-
ject, treating rheumatologist determined the num-
ber of tender points (total 18 sites) by manual
palpation (Wolfe et al., 1990). Additional measures
included the Edinburgh Handedness Inventory,
Beck Depression Inventory (BDI) and Beck Anxiety
Inventory (BAI) (Beck et al., 1961, 1988; Oldfield,
1971).
2.3 MEG and MRI acquisitions
The MEG examination was performed at the SNUH
using Neuromag 306-channel device (VectorViewTM;
Elekta Neuromag, Helsinki, Finland) containing 204
planar gradiometers and 102 magnetometers. Each
subject sat comfortably with her head in the helmet-
shaped whole-head coverage system located in a
magnetically shielded room. The measurement set-
tings were identical to our previous study (Choi
et al., 2015). Before the recording, the positions of
four head-position indicator coils relative to three
anatomical fiducials were measured using 3-D digi-
tizer (FASTRAKTM; Polhemus, Colchester, VT, USA).
The relative head position to the MEG helmet was
determined by the four indicator coils, and the spa-
tial information was assigned along the medial–lat-
eral (x), posterior–anterior (y) and inferior–superior
(z) axes for integrating MEG sources and individual
magnetic resonance images (MRIs). The magnetic
signals were recorded with 0.1–300 Hz band-pass
filter and were digitized at 1 kHz. To reduce external
noises, we applied the spatiotemporal signal space
separation method under MaxFilter software version
2.2.1 (Elekta Neuromag) (Taulu and Simola, 2006;
Lim et al., 2014).
Magnetic resonance imagings (except for one HC
subject due to claustrophobia) were acquired in the
sagittal plane on a 3-T scanner (Siemens Magnetom
© 2016 European Pain Federation - EFICâ
Auditory habituation deficit in fibromyalgia
TrioTim, Erlangen, Germany). The T1-weighted
scans were obtained at the SNUH (TR: 1670 ms; TE:
1.89 ms; slice thickness: 1.0 mm; flip angle: 9° and
acquisition matrix: 256 9 256).
2.4 Duration-deviant passive auditory oddball
paradigm
For all subjects, the auditory tones were delivered
binaurally using earphones with STIM2 sound gen-
erator system (Neuroscan, El Paso, TX, USA). The
auditory stimulus is divided into three types: (1) first
standard stimulus (SSF); (2) last standard stimulus
(SSL) and (3) deviant stimulus. The standard and
deviant stimuli differed in the presentation ratio and
duration (standard: 81.8%, 50 ms; deviant: 18.2%,
100 ms), both of which were delivered with
1000 Hz, 80 dB sound pressure level, 10 ms of
increase/decrease and 300 ms of stimulus onset
asynchrony (Shin et al., 2009; Choi et al., 2015).
The standard stimulus that followed each deviant
stimulus was labelled as SSF, and the one preceding
each deviant stimulus was labelled as SSL (Fig. 1)
(Shin et al., 2009). Without any task requirements,
the subjects watched the picture slides (examples
from a book of ‘Where’s Wally?’) provided by video
projector (NEC VT770) from outside the shielded
room in order to distract their attention from the
sounds and to reduce their eye movements (Light
and Braff, 2005; Shin et al., 2009, 2012; Choi et al.,
2015).
2.5 Data analyses
Continuous MEG responses (100 to 300 ms, based
on the stimulus onset) were averaged separately for
each auditory stimulation type (SSF, SSL, deviant).
Among the three types, data of SSF and SSL were
used to assess N1m habituation in this study as fol-
lows. The epochs exceeding 3000 fT/cm in the MEG
channels or 150 lV in the electrooculogram chan-
nels were rejected as artefacts. Subsequently, 30-Hz
band-pass filtering and 100 to 0 ms baseline adjust-
ment were applied. To identify auditory-evoked
brain sources, a single dipole for SSF was analysed
by fitting an equivalent current dipole (ECD) using a
subset of planar gradiometers over the temporal cor-
tex. For the localization accuracy, every dipole was
superimposed on individual MRI, and we identified
their locations near the superior temporal cortex
(N€a€
at€
anen and Picton, 1987). Only ECDs with good-
ness-of-fit values exceeding 80% were accepted for
the subsequent analyses. N1m responses of SSL were
identified by applying the same location and orienta-
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Auditory habituation deficit in fibromyalgia
Figure 1 Schematic illustration of passive auditory oddball paradigm. Specifications of stimulus features are illustrated. Auditory stimulus is sym-
bolized by a bar and its duration by bar width. L, left hemisphere; R, right hemisphere.
tion of SSF dipole. The single ECDs were then
brought into a multi-dipole model, characterizing
N1m sources to the entire averaging time period
and to all gradiometers. Based on individual
source-waveforms, we retrieved the peak amplitude
and latency of N1m within 50–150 ms.
Individual MRI was spatially normalized in the
Talairach coordinates by BrainVoyager QX software
version 1.1 (Brain Innovation, Maastricht, Nether-
lands) (Talairach et al., 1988). N1m source locations
in the head coordinates were transformed into the
Talairach coordinates with Brain Electrical Source
Analysis software version 5.1.8 (MEGIS, Munich,
Germany) (Lim et al., 2012).
N100m habituation index was expressed as (1)
N1m amplitude difference and (2) adjusted N1m
amplitude ratio. The calculation was done for each
hemisphere by using the equations below.
N1m amplitude difference ðnAm) ¼ F  L
FL
Adjusted N1m amplitude ratio ¼
FþL
In the equations, F and L stand for N1m amplitude
to SSF and SSL, respectively. A lower or more nega-
tive value is assumed to reflect deficient N1m habit-
uation, i.e. increase in N1m amplitude.
2.6 Statistical analyses
All the data were analysed with SPSS version 13.0
(Chicago, IL, USA). Demographic, clinical and psy-
chological information were compared between
groups using Student’s t-test. Subject distribution of
the highest educational level and marital status was
analysed by a chi-square test. To test the significant
differences of N1m amplitude (SSF, SSL) within each
group, a paired t-test was performed. N1m ampli-
tudes and latencies were compared between groups
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using one-way repeated-measures analyses of vari-
ance (ANOVA) (within-subject factor: hemisphere;
between-subject factor: group). Then, Student’s t-test
was used to compare group mean of N1m ampli-
tudes and latencies. For N1m habituation indices,
between-group differences were analysed by one-
way repeated-measures ANOVA. For between-group
analyses of N1m, Bonferroni correction for multiple
comparisons was used, and all reported p-values are
uncorrected with significance threshold p < 0.05/2
or 0.025 unless otherwise stated. Normality of data
was confirmed by Mauchly’s test of sphericity. Inter-
relationships among (1) N1m habituation indices
and N1m amplitude and (2) N1m habituation indices
and FM characteristics (VAS, pain duration, tender
point, FIQ, BAI, BDI) were assessed, in an explora-
tory manner, using Pearson’s r correlation coeffi-
cient. p < 0.05 was considered significant in the
correlational analyses.
3. Results
3.1 Demographic and clinical information
Table 1 provides demographic, clinical and psycho-
logical characteristics of the study subjects. All had
normal hearing level confirmed by self-reports. The
patients had suffered from FM for an average almost
3 years, and they reported more depressive and anx-
iety symptoms than HC subjects.
3.2 N1m
Fig. 2 depicts N1m source location in the vicinity of
the superior temporal gyrus. Auditory-evoked mag-
netic responses (SSF and SSL) are described in a head
model with spatial information of MEG channels
(Fig. 3A). Fig. 3B shows individual source wave-
forms for N1m peak identification.
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Table 1 Characteristics of the study subjects.

Group
FM HC difference
Variable n = 19 n = 21 p-value

Demographic
Age (year) 44.9 [8.3] 44.8 [8.2] NSa
Edinburgh score 83.0 [19.8] 84.5 [27.2] NSa
Highest educational level NSb
Elementary school 0 (0%) 1 (4.8%)
Middle school 2 (10.5%) 1 (4.8%)
High school 9 (47.4%) 12 (57.1%)
College 8 (42.1%) 7 (33.3%)
Marital status NSb
Single 2 (10.5%) 2 (9.5%)
Married 16 (84.2%) 17 (80.9%)
Divorced 1 (5.3%) 1 (4.8%)
Separated 0 (0%) 1 (4.8%)
Clinical
VAS of the day 53.4 [21.6] NA NA
(mm, 0–100)
Pain duration (month) 35.6 [31.1] NA NA Figure 2 N1m source localization. Single equivalent current dipoles
Tender point 15.7 [1.8] 1.7 [2.3] < 0.001a corresponding to N1m from each group were mapped onto magnetic
(number, 0–18) resonance imaging (horizontal plane) of 1 representative healthy con-
FIQ (score, 0–100) 62.5 [13.2] NA NA trol subject.
Psychological
BAI (score, 0–63) 23.3 [10.8] 1.8 [2.0] < 0.001a (1,38) < 0.001; p = 0.983], hemisphere [F
BDI (score, 0–63) 19.0 [6.8] 2.8 [3.9] < 0.001a
(1,38) = 2.057; p = 0.160] and hemisphere 9 group
All the values are expressed as mean [standard deviation] or n (%), interaction [F(1,38) = 0.291; p = 0.593].
unless otherwise indicated. NS, not significant; NA, not applicable; In both hemispheres, N1m latency to SSF and SSL
VAS, visual analogue scale; FIQ, fibromyalgia impact questionnaire; did not differ between groups.
BAI, beck anxiety inventory; BDI, beck depression inventory.
The inter-group comparison of N1m amplitude dif-
a
Independent samples t-test.
b ference revealed a significant group effect [F
Chi-square test.
(1,38) = 12.479; p = 0.001] (Fig. 4A and B); how-
ever, there were no effects for hemisphere [F
Bilaterally, N1m amplitude to SSF was higher than (1,38) = 0.834; p = 0.367] and hemisphere 9 group
SSL in the HC group, which reflects normal habitua- interaction [F(1,38) = 0.378; p = 0.542]. N1m ampli-
tion [left: t(20) = 2.452, p = 0.024; right: t tude difference (left) was significantly lower in the
(20) = 2.731, p = 0.013]. However, N1m habituation FM group relative to the HC group both before and
was deficient in the FM group along with evidence after Bonferroni correction [t(38) = 3.111;
of N1m amplitude augmentation [left: t p = 0.004]. For the right hemisphere, the FM group
(18) = 2.368, p = 0.029; right: t(18) = 0.131, also showed lower value of N1m amplitude differ-
p = 0.897] (Table 2). ence than the HC group; however, this was only sig-
Then, N1m amplitude was compared between nificant at the significant threshold p < 0.05 (before
groups (Fig. 4A). With respect to SSF amplitude, a Bonferroni correction) [t(38) = 2.199; p = 0.034].
repeated-measures ANOVA found a significant effect As with adjusted N1m amplitude ratio, a repeated-
of group [F(1,38) = 16.051; p < 0.001], while the measures ANOVA revealed a group effect [F
effects of hemisphere [F(1,38) = 0.976; p = 0.329] (1,38) = 17.513; p < 0.001]; however, there were no
and hemisphere 9 group interaction [F significant effects of either hemisphere [F
(1,38) = 2.057; p = 0.160] were not significant. The (1,38) = 3.405; p = 0.073] or hemisphere 9 group
FM group displayed lower SSF activity than the HC interaction [F(1,38) = 1.363; p = 0.250]. Adjusted
group in both hemispheres [left: t(38) = 3.778, N1m amplitude ratio of the left hemisphere was
p = 0.001; right: t(38) = 2.913, p = 0.006], and this found lower in the FM group than in the HC group
difference withstood Bonferroni correction. Mean- [t(38) = 3.667; p = 0.001], which approached the
while, no group difference was identified for SSL Bonferroni-adjusted significance threshold. At the
amplitude, considering no effects for group [F significance level p < 0.05 only, adjusted N1m

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Auditory habituation deficit in fibromyalgia W. Choi et al.

Figure 3 Spatial distribution and source-waveform of N1m. (A) Auditory-evoked magnetic fields to SSF (blue) and SSL (red) of one representative
subject from both groups (healthy control, left panel; fibromyalgia, right panel) were displayed in the head sphere model (top view). The vertical
lines in each channel indicate the stimulus onset (0 ms). Two signal traces from temporal magnetoencephalography (MEG) channels from each
hemisphere (a–d) are magnified. The MEG channel layouts (middle panel) represent the planar gradiometers and the ones in grey were used for
dipole fitting. (B) N1m source waveforms from the same representative subjects are illustrated. The corresponding time window is 100 to
300 ms based on the stimulus presentation (0 ms) marked by the dotted vertical lines. The triangles indicate the selected peaks of N1m.

amplitude ratio of the right hemisphere tended to be
lower in the FM group than in the HC group [t
(38) = 2.002; p = 0.052].
3.3 Correlational analyses
In the FM group, bivariate correlations between
N1m amplitude and N1m habituation indices
revealed a positive correlation between SSF
amplitude and N1m amplitude difference (left:
r = 0.468, p = 0.043; right: r = 0.497, p = 0.03). Fur-
ther, SSF amplitude correlated positively with
adjusted N1m amplitude ratio (left: r = 0.537,
p = 0.018; right: r = 0.412, p = 0.079) with trend-
level significance in the right hemisphere. On the
contrary, as with SSL amplitude, no significant asso-
ciation was found both with N1m amplitude differ-
ence and adjusted N1m amplitude ratio. These
results indicate that N1m habituation defect in FM is
highly dependent on the reduced SSF amplitude.
A negative correlation between BAI score and
adjusted N1m amplitude ratio (r = 0.469; p = 0.04)
of the left hemisphere was found in the FM group.
Thus, patients with FM who displayed more defi-
cient N1m habituation tended to have higher anxi-
ety levels. However, no other significant
relationships were found between the N1m habitua-
tion indices and FM-related variables (VAS, pain
duration, tender point, FIQ and BDI).

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Table 2 Mean amplitude, latency and Talairach coordinate of N1m.

Left hemisphere Right hemisphere

FM HC p-value FM HC p-value

Amplitude, nAm
SSF 6.7 [4.2] 15.2 [9.1] 0.001 9.8 [4.6] 15.3 [6.9] 0.006
SSL 9.1 [3.7] 9.9 [6.5] 0.660 9.6 [5.1] 9.4 [6.3] 0.892
Latency, ms
SSF 75.8 [26.0] 95.3 [37.2] 0.065 89.2 [31.7] 101.5 [33.3] 0.239
SSL 76.5 [28.5] 96.9 [36.0] 0.055 86.3 [27.8] 98.9 [30.3] 0.180
Talairach coordinate, mm
x 54.3 [8.8] 49.7 [10.1] 0.134 52.3 [7.1] 51.0 [6.3] 0.548
y 12.3 [9.1] 15.3 [5.3] 0.209 10.9 [9.4] 14.6 [6.2] 0.152
z 8.6 [9.2] 7.6 [5.4] 0.683 8.9 [7.0] 6.2 [8.2] 0.282

All the values are expressed as mean [standard deviation], and data in bold are significantly different between the two groups (N1m amplitude
and latency: p < 0.05/2; Talairach coordinate: p < 0.05/3). Data from 20 healthy control subjects were used to calculate the group mean Talairach
coordinates for N1m sources.

Figure 4 Group comparison of N1m amplitudes and habituation indices. (A) Boxplots showing lower N1m amplitude to SSF in the FM group rela-
tive to the healthy control group. (B and C) Habituation indices are compared between groups in each hemisphere. The solid line within each box
marks the mean value, and the box boundaries indicate the 25th and 75th percentiles. The whiskers above and below each box represent the 10th
and 90th percentiles, respectively. *p < 0.05/2.

4. Discussion Deficient habituation in FM seems to be accrued

Abnormal sensory information processing of non-
specific stimuli associated with exaggerated percep-
tion is a principal feature of FM (Clauw, 2009;
Clauw et al., 2011). We determined whether the
abnormality extends to auditory domain and identi-
fied degraded habituation to auditory stimulation in
patients with FM as indexed by N1m.
to the reduced SSF amplitude, and such observation
is in line with migraine studies (Coppola et al., 2005,
2013a,b; de Tommaso et al., 2014). SSF amplitude of
patients with FM showed an association with N1m
habituation indices with no evidence of normal
habituation pattern. As N1m represents a cortical
component for early sensory processing, lower SSF

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Auditory habituation deficit in fibromyalgia
amplitude might reflect attenuated baseline func-
tioning of sensory encoding and/or registration
mechanism in support of findings from migraine
studies (Coppola et al., 2005, 2013a,b; de Tommaso
et al., 2014). Recent functional MRI studies showing
that non-painful stimulation reduced activation of
primary sensory cortices and that functional connec-
tivity was weakened within the sensory cortex at
rest (without any experimental stimulation) pro-
vided further evidence in favour of the speculation
(Lopez-Sola et al., 2014; Pujol et al., 2014).
Disturbances in hierarchically high-order domains
for sensory perception could also be ascribed to the
decreased initial amplitude in FM (Venables, 1964;
Anokhin et al., 2007). Our findings strengthen the
evidence of sensory processing dysfunction at the
early level in FM, wherein inadequate response to
SSF is ascribed as a causal factor.
The first sensory input drives inhibitory interneu-
rons that suppress the brain activity for subsequent
stimulus repetition (Miller and Freedman, 1995;
Boutros et al., 2009). Thus, weakened response to
SSF may point to defective inhibitory regulation as
characterized in FM (Jensen et al., 2009; Schmidt-
Wilcke and Clauw, 2011; Lim et al., 2015). In partic-
ular, alterations in functional connectivity and acti-
vation level within the inhibitory network (e.g.
rostral anterior cingulate cortex and periaqueductal
grey), concentration of inhibitory neurotransmitters
(e.g. serotonin and c-aminobutyric acid) and
endogenous opioid system have been reported
(Bazzichi et al., 2006; Harris et al., 2007; Jensen
et al., 2009, 2012; Foerster et al., 2012; Pujol et al.,
2014). The present observations, therefore, indicate
the patients’ inability to recruit inhibitory and self-
defensive circuits against sensory repetition. In other
chronic pain disorders (e.g. migraine, irritable bowel
syndrome, cardiac syndrome X) whose common
symptoms include the compromised inhibitory func-
tioning, reduced habituation has been demonstrated
similar to the present study (Valeriani et al., 2005;
Coppola et al., 2013a,b; de Tommaso et al., 2014;
Lowen et al., 2015). Therefore, habituation deficit
and its underlying phenomenon seem to involve
generalized abnormal chronic pain pathophysiology
in the context of impaired sensory information pro-
cessing, rather than be FM specific.
Unpleasantness and reduced tolerance to non-nox-
ious auditory stimulation have been commonly
reported among patients with FM (Carrillo-de-la-
Pe~na et al., 2006; Geisser et al., 2008; Wilbarger and
Cook, 2011; Iikuni et al., 2013). However, none of
the above has been diagnosed precisely in clinical
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W. Choi et al.
settings. Based on the theory that FM is central in
origin, more neuroimaging studies are necessary to
directly address the decisive role of the brain regard-
ing the invalid aetiology of auditory impairments.
All study subjects confirmed normal hearing level
prior to the assessments; hence, it seems unlikely
that peripheral acoustic dysfunction affected our
results. Investigations of auditory ERP at an initial
processing stage could bridge the gap between the
observations of abnormal auditory functioning in the
periphery and central levels in FM and contribute to
a better understanding of its pathophysiology.
Studies on auditory ERP in FM have found abnor-
mal P300 and MMN responses, highlighting impaired
auditory processing at the pre-attentive and attentive
levels (Ozgocmen et al., 2003; Alanoglu et al., 2005;
Choi et al., 2015). Since there is a direct or indirect
relation among electrophysiological phenomena (e.g.
sensory gating, habituation) following stimulus repe-
tition, one could expect of any plausible explana-
tions to associate the present findings with what has
been observed on the same issue in FM. For
instance, in migraine, it has been speculated that
habituation deficit is dependent on a failure to prop-
erly gate the response to irrelevant sensory stimulus
(Ambrosini et al., 2001; Siniatchkin et al., 2003).
Considering thalamic involvement in sensory gating
process, deterioration of thalamocortical activity in
patients with migraine substantiate the hypothesized
link between auditory sensory gating and habitua-
tion (Krause et al., 2003; Coppola et al., 2013a). As
for FM, reduction in both sensory gating and habitu-
ation has been demonstrated across multiple sensory
modalities (Montoya et al., 2006; Smith et al., 2008;
de Tommaso et al., 2011), and both structural and
functional abnormalities regarding thalamic and tha-
lamocortical region have been reported (Valdes
et al., 2010; Jensen et al., 2012). Accordingly, habit-
uation deficit in FM may reflect the overlapping
domain of dysfunction with auditory sensory gating
in the control of incoming stimulus. One recently
published auditory P50 study showing intact sensory
gating in FM, however, does not seem to correspond
with the present results of N1m habituation deficit
(Carrillo-de-la-Pe~
na et al., 2015). That the sensor-
level analysis of auditory ERP (i.e. Cz electrode) is
not suited to demonstrate the hemispheric contribu-
tion (Huotilainen et al., 1998), and that altered later-
alization of auditory ERP has previously been found
in FM note that sensory gating deficit presumably
confined to one hemisphere may have not been
detected (Choi et al., 2015). In addition, in a com-
parison with other studies employing the similar
© 2016 European Pain Federation - EFICâ
W. Choi et al.
experimental stimulation and analysis, P50 sensory
gating index of HC group was somewhat higher and
that of FM group was almost identical with migraine
patients (Ambrosini et al., 2001; Siniatchkin et al.,
2003). Thus, instead of rejecting the potential associ-
ation between sensory gating and habituation, we
believe that further studies need to be carried out
with a variety of experimental settings and larger
samples, which would reconcile the partly disparate
results in FM.
We designed the experimental paradigm and
processed the data so as to negate confounding factors
and maintain validity of the study results. Nonethe-
less, there are several limitations to consider. One pos-
sible limitation is that the correlation results are not
adjusted for multiple testing. This was because we
aimed to explore potential relationships between N1m
habituation and FM-related symptoms as an explora-
tory study, and not to confirm any pre-specified
hypotheses. Given that prior FM studies and the pre-
sent study have revealed the similar association (Mon-
toya et al., 2006; de Tommaso et al., 2011), future
investigations consisting of more FM-related variables
and experimental stimulation designs would elucidate
the specific factor responsible for aberrant N1m
response in FM. Second, 3-day medication washout
does not ensure the lack of residual medication effect.
However, to date, there are no reports of medication
affecting auditory N1m habituation. As a result, a bias
related to medication is unlikely.
In summary, patients with FM showed lower N1m
amplitude difference and adjusted N1m amplitude
ratio than HC subjects, pointing to a failure of habit-
uation to auditory stimulation. Moreover, they dis-
played augmented pattern of N1m amplitude
following stimulus repetition, an effect driven by
low response to SSF. This observation would provide
new neurophysiological insights on inhibitory failure
during auditory processing in FM in line with find-
ings from other pain disorders. Future effort is
required to elucidate how specific pathophysiology
influences sensory information processing, which
would further expand the initial identification of
auditory augmentation in generalized sensory distur-
bance in FM.
Author contributions
C.K.C. had full access to all the study data and takes
responsibility for the integrity and accuracy of the analysed
data. M.L., J.S.K. and C.K.C. conceived and designed the
study and collected the data. W.C., M.L., J.S.K. and C.K.C.
performed the data analyses and interpretation. W.C.
© 2016 European Pain Federation - EFICâ
Auditory habituation deficit in fibromyalgia
drafted the article. All authors were involved in revising
the article critically for important intellectual content and
approved the final version to be published.
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