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1. Original Article
Altered sensory nerve excitability in
fibromyalgia
Hao-Wen Teng a,b,c,1
, Jowy Tani a,b,d,1
, Tsui-San Chang a,b
,
Hung-Ju Chen a,b
, Yi-Chen Lin a,b
, Cindy Shin-Yi Lin e,f
,
Jia-Ying Sung a,b,
*
a
Department of Neurology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
b
Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei,
Taiwan
c
Department of Neurology, Cheng-Ching Hospital, Taichung, Taiwan
d
Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei
Medical University and National Health Research Institutes, Taiwan
e
Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University
and National Health Research Institutes, Taiwan
f
Translational Research Collectives, Faculty of Medicine and Health, Brain & Mind Centre, The
University of Sydney, Australia
Received 3 August 2020; received in revised form 23 December 2020; accepted 2 February 2021
KEYWORDS
Fibromyalgia;
Nerve excitability;
Potassium channel;
Pain;
Superexcitability
Background/purpose: To investigate nerve excitability changes in patients with fibromyalgia
and the correlation with clinical severity.
Methods: We enrolled 20 subjects with fibromyalgia and 22 sex and age-matched healthy sub-
jects to receive nerve excitability test and nerve conduction study to evaluate the peripheral
axonal function.
Results: In the fibromyalgia cohort, the sensory axonal excitability test revealed increased
superexcitability (%) (P Z 0.029) compared to healthy control. Correlational study showed a
negative correlation between increased subexcitability (%) (r Z 0.534, P Z 0.022) with fibro-
myalgia impact questionnaire (FIQ) score. Computer modeling confirmed that the sensory axon
excitability pattern we observed in fibromyalgia cohort was best explained by increased
BarretteBarrett conductance, which was thought to be attributed to paranodal fast Kþ
chan-
nel dysfunction.
* Corresponding author. Department of Neurology, Wan Fang Hospital, Taipei Medical University, No. 111, Sec. 3, Xinglong Rd., Wenshan
Dist., Taipei City 116, Taiwan. Fax: þ886 21 2930 2447.
E-mail address: sung.jiaying@tmu.edu.tw (J.-Y. Sung).
1
The two authors contributed equally to the article.
https://doi.org/10.1016/j.jfma.2021.02.003
0929-6646/Copyright ª 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jfma-online.com
Journal of the Formosan Medical Association 120 (2021) 1611e1619

2. Conclusion: The present study revealed that paranodal sensory Kþ
conductance was altered in
patients with fibromyalgia. The altered conductance indicated dysfunction of paranodal fast
Kþ
channels, which is known to be associated with the generation of pain.
Copyright ª 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Introduction
Fibromyalgia (FM), a common but easily overlooked
chronic widespread pain syndrome, was first introduced in
the 1970s to replace formal names such as “fibrositis,”
reflecting the lack of evidence of tissue inflammation in
patients with this condition.1
In addition to the hallmarks
of chronic diffuse pain, FM is also characterized by the
presence of many comorbid medical conditions, such as
sleep disorders, fatigue, mood, and cognitive distur-
bances.2
It occurs more commonly in females and is esti-
mated to affect approximately 0.5e9% of the general
population worldwide, depending on the diagnostic
criteria and study methods used.3e5
Chronic pain has
caused an enormous amount of economic costs and burden
to our society6,7
; in addition to high levels of comorbid-
ities, patients with FM have significantly impaired social
and occupational function and higher healthcare utiliza-
tion and costs.8,9
It was not until the 1990 and 2000s that the concept of
“central amplification of pain” was acknowledged as the
underlying pathophysiologic process of FM, based on
growing scientific evidence.10,11
Most of the evidence in-
dicates that the pain in patients with FM is amplified
“centrally” in the nociceptive nervous system, involving
alterations in the central processing of sensory input along
with aberrations in the endogenous inhibition of pain.12
In a
challenge to the “central amplification theory,” some
recent studies have demonstrated evidence of peripheral
nerve pathology in patients with FM, including reduced
intra-epidermal nerve fiber density, reduced dermal un-
myelinated nerve fiber diameter, and hyperexcitable C
nociceptors.13e18
However, it remains questionable how
these ultrastructural and electrophysiological abnormal-
ities observed in the peripheral nerve should be associated
with hypersensitivity to pain rather than a reduced sensa-
tion in these patients.
Considerable evidence links the generation of pain with
altered potassium (Kþ
) channel functions and increased
excitability in the primary afferent neurons.19e21
The
nerve excitability test, a technique that noninvasively
measures the membrane polarization, ion channel func-
tion, and paranodal/internodal condition of peripheral
nerves, has been able to elucidate pathophysiological
mechanisms in a variety of neuromuscular disorders,
including those with neuropathic pain.22,23
The technique
has the potential to yield novel insights into disease
mechanisms and treatment strategies for FM. The present
study aims to use the technique to assess peripheral nerve
membrane and channel properties, particularly the Kþ
channels, in patients with FM.
Methods
Patients with FM were prospectively enrolled from Wan
Fang Hospital, Taipei Medical University, Taipei, Taiwan.
The diagnosis of FM was determined based on the modified
American College of Rheumatology (ACR) diagnostic criteria
proposed in 2011. Patients with comorbid rheumatological
disorders were not excluded from the study according to
the 2016 revised criteria.24
The widespread pain index
(WPI) score, symptoms severity (SS) scale score, pain scale
score (PS) by numerical rating, FM score (FS) (the sum of
WPI and SS scores), and the revised fibromyalgia impact
questionnaire (FIQ) score were obtained from each patient.
The FIQ score consisting of 21 items across the three do-
mains of function (9 items), overall impact (2 items), and
symptoms (10 items).25
All patients were either newly diagnosed or had no
current medical treatment at the time of assessment. After
enrollment, each patient underwent a neurological exam-
ination, a conventional nerve conduction study, and basic
blood chemistry tests. Patients with comorbid diffuse or
focal peripheral neuropathy (including carpal tunnel syn-
drome, polyneuropathy, etc.), alcohol abuse, uremia, or
other factors that may confound nerve excitability testing
(such as hypokalemia, hyperkalemia, etc.) were excluded
from the study. Control data were obtained from age- and
gender-matched healthy control (HC) subjects, who did not
have diabetes, renal disease, known neurological or pain
disorders, or any abnormal neurological examination find-
ings. All subjects gave informed consent to the procedures,
and the study was approved by the Joint Institution Review
Board of Taipei Medical University.
Nerve excitability tests
Nerve excitability studies were performed on the median
nerve. With stimulation at the wrist, the compound muscle
action potentials (CMAP) was recorded from the abductor
pollicis brevis muscle, and antidromic compound sensory
nerve action potentials (SNAP) was recorded from the index
finger, as per previously described protocols.26,27
The skin
temperature was monitored at the site of stimulation and
was maintained above 32
C. The sequences of stimulation
and recording were executed by QTRAC software (Institute
of Neurology, London, UK), with stimulating current applied
using an isolated linear bipolar constant-current stimulator
(DS5; Digitimer). Indirect information about the axonal
membrane and ion channel properties was collected
through the measurement of multiple nerve excitability
parameters produced by applying different condition-test
protocols, as described below.23,27e30
H.-W. Teng, J. Tani, T.-S. Chang et al.
1612

3. First, a stimuluseresponse curve was generated using
1 ms unconditioned stimuli. The target response was
automatically set at the curve’s steepest point (approxi-
mately 40% of the maximal response). The changes in the
threshold of stimulus current (mA) required to produce the
target response were tracked. The protocol of other tests
incorporated the following measures: (1) strengthedura-
tion relationship, with the rheobase (mA) representing the
minimal current amplitude required to produce an action
potential when the stimulus is infinite prolonged, and the
strengtheduration time constant (SDTC) (msec), both
estimated by Weiss’ equation from the measurements of
thresholds using test stimuli of 0.2, 0.4, 0.6, 0.8 and 1.0 ms
duration; (2) threshold electrotonus, using subthreshold
100-ms polarizing currents in both depolarizing (TEd; þ40%)
and hyperpolarizing (TEh; 40%) directions to alter a dif-
ference in potential across the internodal membrane; (3)
the currentethreshold (I/V) relationship, assessed by
measuring the change in threshold at the end of 200-ms
polarizing currents, the strength of which was altered in
10% steps from 150% (depolarizing) to 210% (hyper-
polarizing) of the control threshold; and (4) recovery cycle
using a supramaximal conditioning stimulus followed by
tracking the thresholds at various inter-stimulus intervals
from 2 to 200 ms. The recovery cycle consists of a relative
refractory period (RRP), a superexcitable period, and a late
subexcitable period. RRP was measured as the time of the
first intercept on the x-axis of the recovery cycle curve.
Superexcitability was measured as the maximal threshold
reduction and subexcitability as the maximal threshold in-
crease after an inter-stimulus interval of 10 ms.23,26,27
Statistical analysis
Categorical data were summarized as counts and percent-
ages, and continuous measures were summarized as means
and standard deviations. Because the sample size of both
FM and HC cohorts were less than 30, nonparametric
ManneWhitney U test was used for the nerve excitability
profile comparisons between these two cohorts. Pearson
correlation and univariate regression were applied for
examining the correlation of the symptom-related indices
and the interested nerve excitability profiles. The signifi-
cance level is P 0.05. All statistical analysis was per-
formed with the packaged software SPSS version 19.0 for
Windows (SPSS Inc., Chicago, U.S.A.).
Computer modeling of sensory axon excitability
The present study adopts a mathematical model for the
nerve excitability test of a myelinated human axon to
Figure 1 The flowchart of this study. WPI Z Widespread pain index; SS Z symptom severity.
Journal of the Formosan Medical Association 120 (2021) 1611e1619
1613

4. clarify the underlying pathophysiology of sensory axon in
FM. This computer modeling of the sensory axon was per-
formed using the MEMFIT program (version 2019/01/26).31
The discrepancy between computer-generated simulated
model and clinical excitability testing results was calcu-
lated by the weighted sum of the squares of the error
terms: [(xm xn)/sn]2
, where xm is the simulated threshold
from the simulated model, xn is the mean value from the
data of nerve excitability test, and sn is the standard de-
viation of the values. The weighting of model optimization
was the same for all thresholds of the same type and equal
for a thresholdecharge relationship, threshold electrot-
onus, I/V relationship, and recovery cycle. The optimiza-
tion of the model was done by an iterative least-squares
procedure to minimize the discrepancy. The present study
also created a computer-generated sensory axon model
based on HC data, to gain pathophysiologic insights of FM.
Results
Clinical profiles of patients with FM
Twenty-five patients were recruited in this study and had
provided informed consent. Three patients were excluded
because of coexisted peripheral neuropathy, while two
were excluded because of diabetes. The study flowchart
and clinical information of the excreted participants were
shown in Fig. 1. Table 1 shows the demographics of the
remaining twenty patients with FM (mean age 55.9 12.35
years; 19 females). Common comorbidities included
depression and anxiety, as Table 1 listed. Patients’ nerve
excitability profile was compared with twenty-two age and
sex-matched HC subjects (mean age 56.2 11.7 years,
P Z 0.93; 20 females, P Z 0.96). The mean WPI, SS, PS
scores and the FS of patients with FM at diagnosis were
9.95 3.65, 8.45 2.74, 7.75 1.04, and 18.3 5.1,
respectively. The mean FIQ scores were 46.07 19.6.
Sensory and motor nerve excitability profiles
The results of sensory nerve excitability profiles between
FM patients and HC are shown in Fig. 2. Stimulus current for
50% SNAP and rheobase current in the sensory axons tended
to be lower in the FM cohort (2.30 0.87 mA in vs.
2.80 1.01 mA in HC, Table 2), but this difference fell just
short of statistical significance. There was no significant
difference in the peak response of SNAP and SDTC between
FM and HC cohorts (Fig. 2AeB).
In threshold electrotonus, there were no significant
changes in the threshold reduction between FM and HC
during either depolarizing or hyperpolarizing conditioning-
current stimulation, except for a slightly increased TEh
overshoot (20.13 5.12 for FM, 17.2 4.39 for HC,
P Z 0.059) in the FM cohort (Fig. 2C), which was close to be
statistically significant. In the sensory recovery cycle, the
superexcitability (25.66 11.85% for FM, 19.9 5.28%
for HC) was significantly greater in the FM cohort
(P Z 0.029) than in the HC cohort (Fig. 2D). The subexcit-
ability (13.29 4.65% for FM, 11.4 2.84% for HC) was also
greater in the FM group, which approached the borderline
of significance (P Z 0.082). No significant change in
refractoriness at 2.5 ms (19.99 18.65% for FM,
18.5 16.2% for HC, P Z 0.314) was noted.
The indices of the motor nerves excitability test, as
shown in Table 2, showed no difference between FM and HC
in all parameters.
Table 1 Clinical profile of 20 patients with fibromyalgia.
Patient Age Sex TP GP WPI SS PS FS FIQ Major comorbidities
01 45 F 12 Y 15 10 8 25 N/A None
02 59 F 6 Y 15 7 7 22 37 Sicca syndrome, depression
03 65 F 15 Y 7 8 8 15 31.3 Depression, anxiety
04 51 F 7 Y 9 9 6 18 59 Depression, anxiety
05 70 F 9 Y 6 9 9 15 69 Depression, anxiety
06 50 F 4 N 7 9 6 16 50 Depression, anxiety, insomnia
07 45 F 10 Y 8 6 8 14 N/A Postpartum depression
08 45 F 7 Y 7 9 7 16 42.5 None
09 59 F 3 Y 13 5 7 18 59 Depression, anxiety
10 66 F 18 Y 17 10 6 27 21 Depression, anxiety, urinary symptoms
11 54 F 8 N/A 7 8 8 15 7 None
12 79 F 14 Y 15 12 9 27 81 Depression, anxiety, insomnia
13 65 F 16 Y 10 7 8 17 50 Reflux esophagitis, positive ANA
14 44 F 16 Y 15 12 9 27 73.5 Depression, migraine
15 61 F 9 Y 6 10 7 16 39.2 Osteoporosis, anxiety
16 50 F 4 Y 9 12 9 21 36.2 Anxiety
17 32 F 9 Y 9 9 9 18 65.2 Depression, reflux esophagitis
18 47 F 14 Y 10 11 9 21 50.8 Hepatitis B, positive RF
19 53 F 14 Y 12 5 8 17 23 Depression, migraine
20 69 M 5 Y 10 9 7 19 34.5 Reflux esophagitis, dyslipidemia
TP, number of tender points; GP, generalized pain; WPI, widespread pain index; SS, symptoms severity; PS, pain score; FS, fibromyalgia
score; FIQ, fibromyalgia impact questionnaire; Y, criteria met; N, criteria not met; F, female; M, male; N/A, data not available; ANA,
antinuclear antibody; RF, rheumatic factor; BMS, burning mouth syndrome; TMD, temporomandibular joint disorder.
H.-W. Teng, J. Tani, T.-S. Chang et al.
1614

5. The correlation between clinical profiles and the
nerve excitability profile
All the measured nerve excitability parameters were not
correlated significantly with any of the clinical disease
severity scales obtained in this study, except for a signifi-
cant correlation between increased subexcitability
(r Z 0.534, P Z 0.022) with lower FIQ (Fig. 3) in univar-
iate regression.
Computer modeling of the sensory axonal
excitability
Through computer modeling of the sensory axon, the pre-
sent study found that increase in.
BarretteBarrett conductance (from 33.9 to 38.7 nS)
causes the highest reduction in discrepancy by 25.18%,32
while increase of both nodal and internodal pump cur-
rents (from 0 to 0.0063 nA) causes the second highest
reduction in discrepancy by 24.69%. Reduction of leak
conductance (from 1.6 to 0.39 nS) causes the third highest
reduction in discrepancy by 21.36% (See Supplementary
data). By increasing the HC group’s BarretteBarrett
conductance to 38.7 nS in the computer-generated sen-
sory axon model, the present study generated a simulated
recovery cycle with increased superexcitability, similar to
the recovery cycle observed in the FM patients (Fig. 4).
Discussion
Distinct sensory axonal properties in FM
In the present study, neither the stimulus threshold nor
peak response in the stimuluseresponse curve significantly
changed in patients with FM in this study. These findings of
FM are different from other peripheral neuropathic with
pain syndromes, which mostly showed a shift to the right of
the stimuluseresponse curve or reduced amplitude of the
Figure 2 The excitability properties of sensory axons waveforms presented as mean SEM for the patients with fibromyalgia
(filled circles, n Z 20) and healthy controls (empty circles, n Z 22). Increased superexcitability (%) is significant differences
between FM and HC. (*P 0.05). (A) Absolute stimuluseresponse (SR) relations indicated by plotting half-maximal CMAP amplitude
v stimulus for the half-maximal response (logelog coordinates); (B) Strengtheduration time constant (SDTC). (C) Threshold
electrotonus (TE) for 100 ms sub-threshold conditioning depolarizes/hyperpolarizes currents (40%) of the threshold current.
Upward is depolarizing conditioning current, and downward is hyperpolarizing conditioning current. (D) Recovery cycle (RC): paired
supramaximal stimulus with a different interstimulus interval (ms).
Journal of the Formosan Medical Association 120 (2021) 1611e1619
1615

6. maximal response even in the early stage.25e30,33
This
might suggest that the sodium pump activation was not
affected in patients with FM.
The main finding in the present study was that sensory
superexcitability of the recovery cycle was increased in
patients with FM. Although the increased superexcitability
could be caused by the hyperpolarization of the axons, the
other nerve excitability parameters in the study were not
compatible with a hyperpolarized membrane state.23,34
Superexcitability is determined by the conductance of
paranodal fast Kþ
channels. Enhanced opening of paranodal
fast Kþ
channels, which is often observed in demyelinating
nerves with more exposed paranodal fast Kþ
channels from
under the myelin, reduces the resistance of juxta-node and
short-circuits the afterpotential, subsequently reducing
superexcitability and its period.35,36
On the contrary,
reduced conductance of the fast Kþ
channels could
contribute to increased superexcitability. On the other
hand, changes in subexcitability might be related to altered
nodal and internodal slow Kþ
channels. Taken together,
altered superexcitability and subexcitability suggested
changes in Kþ
channel function (Fig. 4).
In addition, increased sensory TEh overshoot was noted
in the threshold electrotonus of the FM cohort. Threshold
eletrotonus could provide valuable information on nodal
and internodal properties, such as slow Kþ
conductance,
inward rectifier, and myelin thickness.29
The slightly
increased TEh overshoot also supports the hypothesis that
there is indeed instability of Kþ
channels in the FM cohort.
Possible abnormal KD
conductance in the FM
cohort
Similar nerve excitability findings in the previous study of
neuromyotonia syndrome, in which the pathogenic auto-
antibodies were thought to act against fast Kþ
channels,
revealed increased overshoots and late subexcitability and
indicated that slow potassium conductance was increased
in the motor axon.37
Furthermore, other studies have
Table 2 Comparison of sensory and motor nerve excitability indices recorded from the median nerves between patients with
fibromyalgia and healthy control subjects.
Nerve excitability indices Sensory Motor
FM HC P-value FM HC P-value
Stimuluseresponse curve
Peak response (mV) 43.6 17.63 43.75 14.35 0.980 7.97 1.71 7.70 1.68 0.871
Current for 50% CMAP/SNAP (mA) 2.30 0.87 2.80 1.01 0.131 2.68 1.01 3.15 1.35 0.344
Strengtheduration property
Rheobase (mA) 0.99 0.46 1.25 0.59 0.166 1.75 0.71 1.98 0.83 0.465
SDTC (ms) 0.61 0.15 0.56 0.13 0.442 0.47 0.10 0.53 0.09 0.213
Recovery cycle
RRP (ms) 3.29 0.46 3.30 0.49 0.861 3.23 0.33 3.24 0.58 0.249
Refractoriness at 2.5 ms (%) 19.99 18.65 18.5 16.2 0.314 35.29 25.01 35.0 31.9 0.387
Superexcitability (%) 25.66 11.85 19.9 5.28 0.029* 27.05 7.22 26.5 6.38 0.685
Subexcitability (%) 13.29 4.65 11.4 2.84 0.082 13.71 4.10 13.2 3.83 0.552
Threshold electrotonus
TEd (peak) (%) 63.31 11.20 61.09 3.35 0.762 70.25 5.12 70.3 4.47 0.465
TEd (10e20 ms) (%) 63.47 10.21 61.61 3.99 0.669 69.35 5.68 70.1 4.76 0.185
TEd (90e100 ms) (%) 54.85 9.56 53.3 5.35 0.724 47.20 5.52 47.9 4.74 0.330
S2 accommodation (%) 8.47 5.53 7.82 4.89 0.724 23.04 3.20 22.4 3.39 0.935
TEd (undershoot) (%) 24.48 4.75 22.6 3.97 0.252 19.72 5.13 20.0 3.86 0.914
TEh (90e100 ms) (%) 145 25.87 143 17.0 0.940 120 20.21 121 18.7 0.358
TEh (overshoot) (%) 20.13 5.12 17.2 4.39 0.059 15.53 4.45 16.8 4.63 0.552
Currentevoltage relationship
Resting I/V slope 0.50 0.10 0.49 0.08 0.510 0.54 0.08 0.54 0.08 0.638
Data were summarized in mean standard deviation. FM, patients with fibromyalgia; HC, healthy control subjects.*P 0.05.
Figure 3 Univariate regression study of subexcitability (%)
and the FIQ score.
H.-W. Teng, J. Tani, T.-S. Chang et al.
1616

7. reported that the increased superexcitability, subexcit-
ability, and TEh overshoot, were also recognized in the
motor axons of patients with another fast Kþ
channel dis-
order, episodic ataxia type 1.29,38
These studies indicated
that the dysfunction of fast Kþ
channels might cause the
upregulation of slow potassium conductance secondarily,
based on the findings of concurrently increased subexcit-
ability and TEh overshoot.36,37
Interestingly, we found the
increased subexcitability is correlated to the lower FIQ
scores in FM cohort. We are curious whether the compen-
satory activity of slow Kþ
channels might have a role in
attenuating symptoms in FM patients. In summary, results
from the present study are compatible with paranodal fast
Kþ
channel dysfunction and a subtle increase in slow Kþ
channel conductance.
The computer modeling of sensory axons in the present
study suggested increased BarretteBarrett conductance.
BarretteBarrett conductance is an internodal leak
pathway from internodal periaxonal space to the extra-
cellular fluid via either myelin sheath or the paranodal
seals. Previous studies have not found evidence of prom-
inent myelin abnormalities in FM, and increased
BarretteBarrett conductance may reflect dysfunction in
the paranodal region, which is compatible with fast Kþ
channel dysfunction.
The association of KD
channel hypofunction and
the generation of pain
Previous nerve excitability studies have shown that neuro-
pathic pain could be attributed to the enhanced excit-
ability of the injured nerves resulting from altered
membrane ion channel function.39,40
While most of the
current researches are focused on the depolarizing ion
channels, studies on Kþ
channels, which also have pivotal
roles in the control and axonal excitability, are relatively
scarce in this field. As early as in the 1980s, studies have
shown that Kþ
channel blockers enhance spontaneous ac-
tivity in the peripheral nerves of rats, and they also lead to
paresthesia in human.19,41
The conductance of Kþ
channels
repolarizes the neuronal membrane, limits the generation
of action potential and its firing rate, and thus inhibit nerve
excitability. On the contrary, Kþ
channel blockers exert the
opposite effect. As Kþ
channels are also distributed on
nociceptive neuronal membrane, it should not be surprising
that a downregulated Kþ
channel conductance may cause
hypersensitivity to pain. With more evidence, it has been
postulated that reduced Kþ
channel function in the noci-
ceptive pathway might be responsible for many types of
pain.19,21
The hypothesis was supported by a study con-
ducted by a previous study, which showed that chronic pain
was reported in 50% of patients with autoantibodies against
voltage-gated Kþ
channels, which was five times more
frequent than those without these autoantibodies.20
Furthermore, some nociceptive medications are also re-
ported to mediate their analgesic effect, at least in part,
by opening of the Kþ
channels.21
Conclusions
The present study demonstrates that distinguishing axonal
excitability properties, implying reduced fast Kþ
channel
conductance in the peripheral sensory nerves, is observed
in patients with FM. Further biochemical or molecular
biological investigations should be undertaken to elucidate
the role of nociceptive axonal Kþ
channels in the patho-
physiology of FM, and whether this represents an opportu-
nity for novel therapeutic approaches.
Figure 4 Illustration of the peripheral mechanism of fibromyalgia (FM). In addition to being a central nervous system pain dis-
order, peripheral nerve dysfunction might contribute to FM’s clinical symptoms. The recovery cycle plotting of the FM cohort (filled
circles) vs. HC cohort (empty circles) in the left column is similar to the computer-generated graph with reduced paranodal fast Kþ
conductance (red line) vs. HC cohort (black empty circles) in the right column.
Journal of the Formosan Medical Association 120 (2021) 1611e1619
1617

8. Declaration of competing interest
The authors have no conflicts of interest relevant to this
article.
Acknowledgment
C. S.-Y. Lin was supported by grants from Sydney Medical
School Foundation, Faculty of Medicine Health, Sydney
University, Sydney, Australia. H.-W. Teng was supported by
grant from Wan Fang Hospital, Taipei Medical University
(105-wf-eva-03), J. Tani was supported by grant from Wan
Fang Hospital, Taipei Medical University (110-phd-02), Y.-C.
Lin was supported by grant from Wan Fang Hospital, Taipei
Medical University (109-wf-eva-22), and J.-Y. Sung was
supported by grants from the Ministry of Science and
Technology, Taiwan, ROC (104-2314-B-038-012-MY3) and
Wan Fang Hospital, Taipei Medical University (109-swf-eva-
06).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jfma.2021.02.003.
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