https://doi.org/10.5664/jcsm.

8320

S C I E N T I F I C I N V E S T I G AT I O N S

Long-term changes of stimulation intensities in hypoglossal nerve stimulation

Zhaojun Zhu, MD1; Benedikt Hofauer, MD2; Markus Wirth, MD1; Clemens Heiser1
1
Otorhinolaryngology/Head and Neck Surgery, Klinikum rechts der Isar, Technical University Munich, Germany; 2Otorhinolaryngology/Head and Neck Surgery,
University of Freiburg, Germany

Study Objectives: Hypoglossal nerve stimulation (HNS) is a novel therapy in the treatment of obstructive sleep apnea. Previous studies have focused on the
effectiveness of HNS, but there are no studies specifically investigating the long-term changes of the stimulation intensities in HNS. Increasing stimulation
intensity requirements have been reported in the past in other peripheral nerve stimulation therapies. The aim of this study was to investigate the development
of stimulation intensities over the observation period of 4 years.
Methods: All patients who were implanted with an HNS system since December 2013 and maintained a bipolar configuration over the observation period
were included. Sensation threshold (ST), functional threshold, the titrated stimulation intensity (SI), and the apnea-hypopnea index (AHI) were recorded.
Results: A total of 82 patients were enrolled (sex: 69 men, 13 women, age: 60 ± 11 years, body mass index: 29. 8 ± 4.0 kg/m2). Two months after surgery,
the median ST was 0.8 ± 0.5 V. During the observation period of 48 months, no significant change of ST was observed. The median ST was 1.0 ± 0.4 V
(P = 0.93) at 48 months. Similar results were found for functional threshold and the titrated stimulation intensity. There was a significant reduction of the
baseline median AHI when compared with the median AHI at 1, 12, 24, 36 and 48 months after surgery (P < 0.05).
Conclusions: The stimulation intensities in HNS show no significant changes over 4 years. Despite the constant stimulation intensity, AHI was significantly
reduced. This indicates that the stimulation threshold of the hypoglossal nerve does not change over time with this therapy.
Keywords: hypoglossal nerve stimulation, OSAS, stimulation intensity
Citation: Zhu Z, Hofauer B, Wirth M, Heiser C. Long-term changes of stimulation intensities in hypoglossal nerve stimulation. J Clin Sleep Med. 2020;16(10):
1775–1780.

BRIEF SUMMARY
Current Knowledge/Study Rationale: Previous studies have focused on the effectiveness of hypoglossal nerve stimulation, but so far there is no
study that investigates the development of stimulation parameters. The aim of this study was to investigate the long-term changes of stimulation intensities
of hypoglossal nerve stimulation.
Study Impact: So far, this is the first study that analyzes the development of stimulation intensities of hypoglossal nerve stimulation over the observation
period of 4 years. Our study also shows that there are no sex differences in stimulation parameters.

INTRODUCTION ADHERE (Adherence and Outcome of Upper Airway Stimu-

Obstructive sleep apnea (OSA) is a subset of sleep-disordered
breathing that is characterized by recurrent episodes of up-
per airway narrowing and closure resulting in apneas and
hypopneas.1 OSA has been shown to lead to excessive daytime
sleepiness, increased likelihood of errors and accidents, and
be associated with behavioral, cognitive, and cardiovascular
morbidities.2,3 Therefore, successful treatment is important.
Positive airway pressure (PAP) is the standard treatment for
patients with moderate to severe OSA, but suboptimal adher-
ence is a limiting factor of PAP therapy effectiveness.4
Selective hypoglossal nerve stimulation (sHNS) is an emerg-
ing treatment option for OSA. The uniqueness of this therapy
lies in the fact that sHNS does not alter the anatomy of the upper
airway. In the past, prospective multicenter trials such as
the STAR (Stimulation Therapy for Apnea Reduction) trial
have already shown the effectiveness of sHNS.5 More recently,
the long-term safety and effectiveness was evaluated by the
lation for OSA International Registry) registry.6 The sHNS
system (Inspire Medical Systems, Maple Grove, MN) consists
of a stimulation lead with a cuff electrode that is placed around
branches of the hypoglossal nerve, an implantable pulse gen-
erator, and a respiratory sensing lead, resulting in a unilateral
stimulation of the hypoglossal nerve.7 By including only the
medial branches of the hypoglossal nerve, a selective stimu-
lation is achieved for the genioglossus, geniohyoid, and the
intrinsic tongue muscles. This results in unrestricted protrusion
of a stiffened tongue, which dilates the airway.7,8 Stimulation
parameters can be adjusted and titrated individually. These
parameters include the electrode configuration and the stimu-
lation amplitude. The most common electrode configuration is
the bipolar setting “+-+”.9 When the stimulation device is first
activated, the sensation threshold (ST) and the functional
threshold (FT) are determined. ST is the intensity at which the
patient perceives the stimulation, while FT represents the
stimulation intensity at which tongue protrusion over the lower

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Z Zhu, B Hofauer, M Wirth, et al.
teeth is first observed. The patient then begins a customization
phase of therapy to allow for acclimatization to different am-
plitudes of stimulation. The history of modern peripheral nerve
stimulation goes back to Wall and Sweet in 1967,10 who de-
scribed pain relief following brief electrical stimulation. Since
then, peripheral electrical stimulation has been used in various
medical specialties, eg, phrenic nerve stimulation for dia-
phragmatic palsy, stimulation of the extremities in patients
with spinal cord injury, and transcutaneous nerve stimulation
for neuropathic pain.11 In the past, some studies reported of
postsurgical fibrosis, especially perilead fibrosis, which in-
creases resistance, resulting in higher stimulation intensity
requirements.12 So far there are no studies that show long-term
changes of the stimulation intensity in sHNS. The aim of this
study was to investigate whether there is a significant change
in stimulation parameters during HNS therapy over the ob-
servation period of 4 years.
METHODS
Patient selection
For this study, all patients with moderate to severe OSA (apnea-
hypoxia index [AHI] between 15 and 65 events/h) and with a
body mass index (BMI) lower than 35 kg/m2 who received
an implant for sHNS since December 2013 and maintained
a bipolar configuration over the observation period were en-
rolled. Preoperative screening included in-lab polysomnography
(PSG) according to the American Academy of Sleep Medicine
guidelines from 2012, clinical examination and drug-induced
sleep endoscopy (DISE) to rule out complete concentric col-
lapse at the level of the soft palate. Patients were excluded
if pronounced anatomical abnormalities preventing the effec-
tive use of sHNS were identified during clinical examina-
tion (eg, enlarged tonsils). Informed consent was obtained for
each patient.
Upper airway stimulation system and
electrode configuration
Qualified patients underwent surgical implantation of the sHNS
system (Inspire II Upper Airway Stimulation System, Inspire
Medical Systems, Maple Grove, MN) as previously described.13
Proper functioning of the complete system was ascertained
intraoperatively prior to wound closure. One month after im-
plantation (M1), the stimulation system was activated with the
standard settings (bipolar electrode configuration “+-+,” pulse
width 90 µs, frequency 33 Hz). After several weeks of accli-
matization, a polysomnography with therapy optimization was
done for appropriate voltage titration and sensing settings. For
consistent comparison of the stimulation intensities, only patients
who maintained a bipolar configuration over the observation
period of 48 months were included. In general, the electrodes
can be configured to provide either monopolar or bipolar
stimulation. The three electrodes embedded in the stimulation cuff
and the implantable pulse generator (IPG) can be configured as
anode (+), cathode (−), or inactive (off ). This leads to 2 possible
bipolar configurations (“+-+”; “−+−”) and 3 monopolar con-
figuration options (“—,” “off-off,” and “-off-”). The most
Journal of Clinical Sleep Medicine, Vol. 16, No. 10
Changes of stimulation intensities in HNS
commonly used configuration is the bipolar configuration
“+-+”.9 In this configuration the stimulation current loop is only
inside the stimulation cuff, resulting in a high current loop that is
restricted to the perilead area, avoiding stimulation of adjacent
nerves. In the monopolar configuration, the IPG functions as the
anode, which causes a wider electrical field with a stimulation
current loop between the cuff and the IPG.
Follow-up
Follow-up visits were scheduled at months (M) 1, 2, 6, 12, 24,
36, and 48. At M1 the ST, FT, and SI were collected via telemetry.
Over the acclimatization period, patients were instructed to
increase stimulation strength gradually from the initially
programmed amplitude. Baseline ST, FT, and SI at M2 were
compared to corresponding voltage thresholds at follow-up
visits M12, M24, M36, and M48. Furthermore, the baseline
AHI before sHNS implantation and the AHI at follow-up visits
were recorded. Two months after surgery (M2) a therapy op-
timization of the stimulation during an in-lab PSG was per-
formed. The SI was titrated according to the AHI and patient’s
comfort. The aim was to reach the lowest AHI possible, pref-
erably lower than 10 events/h. Patients could modify the ti-
trated SI at home at a certain range, which was adjusted during
their sleep lab visit (usually ± 0.4 V) according to their needs
(sleep quality, self-reported effectiveness). For M12, M24,
M36, and M48, a home sleep test (HST) was performed at the
titrated SI that the patient was using as a home therapy level. The
PSG and HST were performed according to the American
Academy of Sleep Medicine guidelines from 2012. The same
scoring criteria for apneas and hypopneas were used for all
sleep studies: The alternative definition was used to score
a hypopnea as a reduction of airflow by > 30% for at least
10 seconds with a corresponding oxygen desaturation of ≥ 4%.
Apneas were scored based on a ≥ 90% reduction in airflow for
at least 10 seconds.
Statistical analysis
Data sets were tested for normality, then the appropriate sta-
tistical tests were performed based on the distribution of the
data. Results were summarized as means ± standard deviation.
Statistical analysis is done by Wilcoxon test and Mann-Whitney
U test for nonparametric statistics and Student’s t test for ap-
proximately normally distributed data. Paired tests were used
for comparing paired observations within individuals. For
comparing the ST, FT, and SI, only 56 data pairs were ana-
lyzed for M12, and 26, 10, 4 data pairs were analyzed for M24,
M36, and M48 respectively. Because M1 data are not repre-
sentative for the actual stimulation parameters, paired t tests
were used to calculate statistical significance between M2 and
M12, M24, M36, and M48. The alpha-level of significance
was set at 0.05 (2-tailed). Analyses were performed using SPSS
version 22.0 statistical software (SPSS Inc., Chicago, IL).
RESULTS
A total number of 82 patients were enrolled. Table 1 shows
the demographic and baseline characteristics. For statistical
1776 October 15, 2020
Z Zhu, B Hofauer, M Wirth, et al. Changes of stimulation intensities in HNS

Table 1—Patients’ baseline characteristics. Table 2—Median values of sensation threshold, functional
Parameter (Median ± SD)
threshold, and stimulation intensity (in volts) paired up at
Number 82
each follow-up.
Age, y 60 ± 11 Stimulation parameter in V ST FT SI
Sex (male/female) 69/13 0.8 ± 0.47 1.4 ± 0.51 1.8 ± 0.55
Body mass-index, kg/m2 29.8 ± 4.0 M2 vs M12 (n = 56) vs vs vs
Apnea-hypopnea index, events/h 31.4 ± 13.1 0.95 ± 0.42 1.6 ± 0.53* 1.9 ± 0.53
0.7 ± 0.44 1.4 ± 0.48 1.7 ± 0.60
Median values and standard deviation (SD) including the range of age,
M2 vs M24 (n = 26) vs vs vs
sex, body mass index, and baseline apnea-hypopnea index.
0.8 ± 0.33 1.5 ± 0.51 1.9 ± 0.53
0.8 ± 0.35 1.6 ± 0.39 2.0 ± 0.43
Figure 1—Development of median values of sensation
M2 vs M36 (n = 10) vs vs vs
threshold, functional threshold and stimulation intensity (in
0.95 ± 0.44 1.7 ± 0.51 2.0 ± 0.47
volts) of all patients with a bipolar electrode configuration
1.1 ± 0.45 1.7 ± 0.37 2.0 ± 0.17
over the observation period of 48 months.
M2 vs M48 (n = 4) vs vs vs
1.0 ± 0.39 1.9 ± 0.56 2.1 ± 0.36

Statistical analysis was performed for each follow-up group with M2 by

using paired t tests. *P < 0.05. FT = functional threshold, SI = stimulation
intensity, ST = sensation threshold.

Figure 2—Boxplot with maximum and minimum values

showing median AHI reduction over 48 months.

analysis, data for 82, 56, 26, 10, and 4 patients were available
at M2, M12, M24, M36, and M48, respectively. Two months
(M2) after device implantation, which included 1 month of
acclimatization the median ST was 0.8 ± 0.5 V. The median ST
did not change significantly at M48 (1.0 ± 0.4 V, P = 0.93)
(Figure 1). The median FT at M2 was 1.4 ± 0.5 V and showed no
significant difference compared with M48 (1.9 ± 0.6, P = 0.18).
Similar results were observed for the titrated SI. The SI was 1.8 ±
0.6 V at M2 and did not change significantly over the period
of time. At M48, the SI was 2.1 ± 0.4 V (P = 0.68). To have a
better comparison, paired sets of data were analyzed for each
follow-up (Table 2). Table 2 shows M2 data for each follow-up
group separately. Except for the FT at M12, there was no
significant difference for ST, FT, and SI at any other follow-up Median baseline apnea-hypopnea index (AHI) was compared with AHI
compared with M2. The AHI reduction was also analyzed. The values at 2 months after treatment (M2), M12, M24, M36, and M48 and
analyzed AHI values represent the entire night value. There was significant difference is marked with *P < 0.05.
a significant reduction of the baseline median AHI compared
with the median AHI at M2 (n = 82), M12 (n = 56), M24 (n = 26),
M36 (n = 10), and M48 (n = 4) (P < 0.05) (Figure 2). difference was found for baseline AHI (P = 0.27; P = 0.29) or
To further investigate influences on the stimulation param- for baseline BMI of those groups (P = 0.15; P = 0.74).
eters, the study group was divided by sex and age, with an older
patient being defined by age > 65 years. Our results show a
significant difference of the FT between younger and older DISCUSSION
patients for the follow-up visits M2, M12, and M24 (Table 3).
Statistical significance for further follow-ups was not analyzed Previous studies focused on the effectiveness, safety, and ad-
due to small sample sizes and missing data. Baseline AHI and herence of sHNS,14–16 but so far there is no study that inves-
baseline BMI were compared between male and female patients tigates the development of stimulation parameters. In other
and older and younger patients, respectively. No significant peripheral nerve stimulation therapies there have been reports of

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Z Zhu, B Hofauer, M Wirth, et al.
Table 3—Median values of sensation threshold, functional threshold, and stimulation intensity (in volts) of different patient groups.
Patient group/in V ST at M2 ST at M12 ST at M24
Female patients (n = 13) 0.8 ± 0.51 0.8 ± 0.28 1.0 ± 0.35
Male patients (n = 69) 0.8 ± 0.47 0.9 ± 0.44 0.8 ± 0.51
Patients < 65 y (n = 56) 0.8 ± 0.44 0.9 ± 0.40 0.8 ± 0.29
Patients ≥ 65 y (n = 26) 0.9 ± 0.54 1.1 ± 0.46 1.0 ± 0.34
No significant difference between female and male patients was observed for ST, FT and SI. Older patients (≥ 65 y) showed a significantly higher FT than
younger patients (< 65 y). *P < 0.05. FT = functional threshold, SI = stimulation intensity, ST = sensation threshold.
perineural fibrosis after implantation of the stimulation lead,
which resulted in higher stimulation intensities over time.12
Since sHNS is a novel stimulation therapy, it is essential to
analyze the long-term changes of stimulation intensity.
Sometimes it is necessary to change the electrode config-
uration during advanced titration of sHNS therapy to opti-
mize tongue motion and outcome for the patient. Although the
majority of patients only require 1 titration night, some patients
need a second titration to further optimize and individualize
therapy. During this second in-lab PSG (advanced titration),
testing of specific electrode configurations, stimulation tim-
ing, and impulse settings are performed. Different electrode
configurations can lead to varying nerve stimulation and
muscle activation, resulting in variable tongue movements.17
In monopolar stimulation, the stimulation intensity is lower
than in the bipolar configuration, which makes it difficult to
compare the development of stimulation intensities in patients
with changing configurations over time. Since this study is a
first approach to investigate the long-time development of
stimulation intensities, only bipolar stimulation intensities
were analyzed.
Our study shows that there is no significant increase of
stimulation parameters over 48 months. The ST, FT, and SI stay
almost constant over the observed time period. The SI was
initially titrated during in-patient polysomnography, with the
aim of reaching the lowest possible AHI. The SI is the stimu-
lation intensity, which lead to the lowest AHI during the titration
night. The SI might either have changed during time if the
patient modified it (eg, due to increasing sleepiness) or by the
physician due to results of the follow-up home sleep test or
patient´s symptoms. The FT was always above the ST, whereas
the installed SI was slightly above the FT. In Figure 1, it appears
that the FT increases insignificantly between the follow-ups
M24 and M48, but this may be due to the few data points that are
available. Of 10 patients, 6 actually showed a decreasing ten-
dency when comparing the FT at M24, M36, and M48, whereas
4 patients had a higher FT in the subsequent follow-ups. Similar
results were observed for ST and SI. When comparing paired
data of M2 and M12 for FT, a significant increase is shown
(Table 2). For future studies, more data samples over a longer
period are necessary to interpret the results for the increasing
tendency of FT. Recent investigations published by Strollo
et al18 showed comparable findings. The prospective multi-
center study analyzes the durability of the sHNS treatment effect
at 18 months and shows a significant AHI reduction and stable
Journal of Clinical Sleep Medicine, Vol. 16, No. 10
Changes of stimulation intensities in HNS
FT at M2 FT at M12 FT at M24 SI at M2 SI at M12 SI at M24
1.6 ± 0.25 1.6 ± 0.53 1.8 ± 0.44 2.0 ± 0.49 1.9 ± 0.46 2.2 ± 0.50
1.3 ± 0.51 1.6 ± 0.52 1.4 ± 0.51 1.7 ± 0.53 1.8 ± 0.53 1.7 ± 0.49
1.2 ± 0.51 1.4 ± 0.51 1.2 ± 0.46 1.7 ± 0.49 1.8 ± 0.45 1.7 ± 0.49
1.6 ± 0.53* 1.8 ± 0.49* 1.8 ± 0.48* 1.9 ± 0.66 2.0 ± 0.61 2.1 ± 0.47
values for the FT over time. When comparing the ST of the
follow-ups at M12 and M18, a significant reduction of the ST
was found.18 This was also mentioned by another study, which
described the 5-year outcome of sHNS therapy. Apparently,
ST, FT, and subdiscomfort thresholds decreased over time,
although data were not shown.19
To further differentiate and study possible effects of age and
sex on stimulation parameters, the study group was subdivided.
Since sex differences in electrical stimulation threshold has
been a well-studied issue in other electrical stimulations, we
investigated whether these differences could be also found for
sHNS. Previous studies reported that women show a lower
sensory threshold than men and have a significantly higher
functional threshold in surface electrical stimulation of skeletal
muscle.20 However, we found no significant difference when
comparing stimulation parameters of the male group with the
female group. This could be due to the fact that sHNS is a
direct nerve stimulation instead of a surface electrical stimu-
lation. Nevertheless some of the patients do also sense the
stimulation during sHNS. There are previously published re-
sults of patient-reported outcomes of sHNS, showing that
49% of patients sense the stimulation during the night. How-
ever, with more time and use of the therapy, fewer patients
found the sensation disruptive.21 Although not fully understood,
this phenomenon has been observed already with neuromus-
cular electrical stimulation. Improved tolerance and condi-
tioning were reported after repeated sessions of stimulation.22
Interestingly, our data show a significantly higher FT for pa-
tients older than 64 years compared with the younger group,
whereas the SI did not differ significantly. This leads to the
conclusion that the motor threshold of the tongue increases with
age. This was already observed by other groups previously.23
However, it seems that once the motor threshold is reached, the
muscle response of the tongue in older patients is comparable
with the muscle response of the younger patients, explaining the
insignificant difference of the SI. In addition, our previous study
also underlines this fact by showing an equally effective AHI
reduction in both older and younger patients.24
In concordance with previous studies, the AHI was reduced
significantly, and although the SI remained constant over the
time, the AHI still continued to decrease.15 This implies that
the stimulation threshold of the hypoglossal nerve remains
the same. Although cuff electrodes have been reported to have
higher risks for perineural fibrosis,12 our data do not support
this hypothesis. The consistent SI indicates that there is no
1778 October 15, 2020
Z Zhu, B Hofauer, M Wirth, et al.
increasing impedance that may be expected if perineural fibrosis
had occurred.
A possible disadvantage of this study is the fact that the ST
and FT are subjective parameters that depend on the patient’s
and investigator’s perspective. Another limitation that needs to
be noted is the generalizability of this data, as we only included
patients that maintained a bipolar configuration “+-+” for their
stimulation treatment. For further studies, some methods need
to be developed to compare all possible configurations. It also
needs to be pointed out that AHI was collected by different
methods (PSG and HST). The baseline AHI and the titration of
the therapy at month 2 were done by PSG, and HST was per-
formed during the later follow-up. This conforms to the best
clinical practice. Only patients who show an AHI > 10 events/h
in the HST get an additional PSG. To reduce possible errors
made by the automated scoring system, all HSTs were scored
manually by experienced technologists, and the same definition
for apnea and hypopnea were applied. However, due to the lack
of an EEG-signal during the HST, no information on the sleep
stages were available, which might influence the evaluation of
sleep-related breathing disorders to a certain degree.
In conclusion, this study shows that there is no significant
change of stimulation intensities in sHNS over 4 years, once
again confirming the safety of sHNS therapy and arguing
against the theory of the development of perineural fibrosis.
Similar to previous results, the AHI was reduced significantly.
There were no significant differences of stimulation parameters
between female and male patients. Older patients show a sig-
nificantly higher FT, suggesting possible age-related changes of
the motor threshold of the tongue muscle.
ABBREVIATIONS
AHI, apnea-hypopnea index
BMI, body mass index
DISE, drug-induced sleep endoscopy
FT, functional threshold
HNS, hypoglossal nerve stimulation
HST, home sleep test
IPG, implantable pulse generator
M1, 1 month after surgery
M2, 2 months after surgery
M12, 12 months after surgery
M24, 24 months after surgery
M36, 36 months after surgery
M48, 48 months after surgery
OSA, obstructive sleep apnea
PSG, polysomnography
sHNS, selective hypoglossal nerve stimulation
SI, titrated stimulation intensity
ST, sensation threshold
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SUBMISSION & CORRESPONDENCE INFORMATION DISCLOSURE STATEMENT

Submitted for publication April 24, 2019 All authors have seen and approved this manuscript. Work for this study was performed at
Submitted in final revised form December 9, 2019 the Otorhinolaryngology, Head and Neck Surgery Department of the Klinikum rechts der
Accepted for publication December 10, 2019 Isar, Technical University Munich in Germany. Benedikt Hofauer and Markus Wirth
Address correspondence to: Zhaojun Zhu, Otorhinolaryngology/Head and Neck received compensation for travel costs and congress fees from Inspire Medical Systems.
Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675 Clemens Heiser is a study investigator and received honoraria, travel, and research
Munich, Germany; Email: yaya.zhu@gmx.de support from Inspire Medical Systems. Zhaojun Zhu reports no conflicts of interest.

Journal of Clinical Sleep Medicine, Vol. 16, No. 10 1780 October 15, 2020