ABSTRACT A low arousal threshold (LAT) is a pathophysiological trait of obstructive sleep apnea (OSA) that may be associated with brainstem ascending reticular activating system-cortical

functional connectivity changes. We evaluated resting-state connectivity between the brainstem nuclei and 105 cortical/subcortical regions in OSA patients with or without a LAT and healthy

controls. Twenty-five patients with moderate to severe OSA with an apnea–hypopnea index between 20 and 40/hr (15 with and 10 without a LAT) and 15 age- and sex-matched controls were

evaluated. Participants underwent functional magnetic resonance imaging after overnight polysomnography. Three brainstem nuclei—the locus coeruleus (LC), laterodorsal tegmental nucleus

LDTg and the posterior cingulate cortex was also stronger in OSA patients regardless of the LAT. Moreover, OSA patients without a LAT showed stronger LDTg-posterior cingulate cortex

connectivity than those with a LAT (post hoc _p_ = 0.013), and this connectivity strength was negatively correlated with the minimum oxygen saturation in OSA patients (r = − 0.463, _p_ = 

0.023). The LAT in OSA patients was associated with altered LDTg-posterior cingulate cortex connectivity. This result may suggested that cholinergic activity may play a role in the LAT in

OSA patients. SIMILAR CONTENT BEING VIEWED BY OTHERS ALTERED FUNCTIONAL CONNECTIVITY OF THE ASCENDING RETICULAR ACTIVATING SYSTEM IN OBSTRUCTIVE SLEEP APNEA Article Open access 30 May 2023

RESTING-STATE FUNCTIONAL MAGNETIC RESONANCE IMAGING OF HIGH ALTITUDE PATIENTS WITH OBSTRUCTIVE SLEEP APNOEA HYPOPNOEA SYNDROME Article Open access 23 September 2020 EFFECTS OF A SINGLE NIGHT

OF CONTINUOUS POSITIVE AIRWAY PRESSURE ON SPONTANEOUS BRAIN ACTIVITY IN SEVERE OBSTRUCTIVE SLEEP APNEA Article Open access 02 June 2023 INTRODUCTION Obstructive sleep apnea (OSA) is a

condition where the upper airway narrows or collapses during sleep. This can cause frequent arousals, sleep fragmentation, intermittent desaturation, and sympathetic activation1,2.

Anatomically, most OSA patients have a narrowed upper airway that results in increased negative pressure during inspiration3. Moreover, nonanatomical factors, such as low arousal threshold

(LAT), high loop gain, and poor upper airway muscle responsiveness, also contribute to the pathophysiology of OSA3,4. Arousal is associated with apnea termination and can play a protective

role in OSA4. However, frequent arousal from sleep is also linked to sympathetic activation and leads to cardiometabolic complications or memory disturbance observed in OSA patients5,6. The

arousal threshold is a measure of the respiratory effort level that triggers arousal during sleep. Arousal responses differ between OSA patients, and 30–50% of them have a LAT7. Those with a

LAT are prone to be easily aroused from sleep in response to relatively mild respiratory stimuli. The LAT can be identified noninvasively according to the following polysomnography results:

(apnea–hypopnea index (AHI) < 30/hr) + (minimum oxygen saturation > 82.5%) + (fraction of hypopnea > 58.3%). Each criterion is scored as 1, and a score of more than 2 indicates a

LAT in OSA patients8. OSA patients with a LAT (OSA + LAT) are less obese, older, more likely to be female, and more likely to have rapid eye movement sleep-predominant OSA than those without

a LAT (OSA-LAT)7,9,10. A LAT is associated with sleep discontinuity and poor compliance with PAP therapy9,11. Moreover, a LAT may be a therapeutic target in selected patients with OSA12.

However, no studies have evaluated neural substrates or possible pathomechanisms associated with a LAT in OSA patients. The ascending reticular activating system is a network of brainstem

nuclei that is connected with cortical and subcortical regions and is involved in arousal and vigilance13. Patients with OSA may have a neural arousal-associated pattern generator that

responds to an obstructive respiratory event14. We previously reported altered resting-state functional connectivity among three brainstem nuclei [the locus coeruleus (LC), laterodorsal

tegmental nucleus (LDTg), and ventral tegmental area (VTA)] and cortical/subcortical regions in patients with moderate to severe OSA compared to that in controls15. We hypothesized that the

LAT in OSA patients may be related to the altered brainstem nuclei-cortical/subcortical functional connectivity. Our aim was to assess resting-state functional connectivity between the three

preidentified brainstem nuclei and 105 cortical/subcortical regions in patients with moderate to severe OSA with or without a LAT compared to that in healthy controls. RESULTS PATIENT

CHARACTERISTICS Twenty-five patients with moderate to severe OSA [apnea–hypopnea index (AHI) between 20/hr and 40/hr] and fifteen age- and sex-matched controls without OSA were evaluated.

The mean participant age was 48 years old, and 34 (85.0%) were male, which was similar among the three groups. The Pittsburg Sleep Quality Index score was higher than that of the controls

only in the OSA+LAT group (post hoc _p_ = 0.005). The mean apnea, hypopnea, AHI, and minimum oxygen saturation in OSA patients were 8.6 ± 6.0/hr, 20.6 ± 5.9/hr, 29.2 ± 5.4/hr, and 81.0%,

respectively. OSA + LAT patients showed a lower apnea index (post hoc _p_ = 0.006) and higher minimum oxygen saturation than OSA-LAT patients (post hoc _p_ = 0.001). No significant

difference in sleep quality and daytime sleepiness was observed between the two groups (Table 1). DIFFERENCES IN BRAINSTEM NUCLEI–CORTEX CONNECTIVITY BETWEEN CONTROLS AND OSA PATIENTS

LC-precuneus and LDTg– posterior cingulate cortex functional connectivity differed among the three groups. Voxelwise functional connectivity t-maps of the LC and LDTg in the controls,

OSA-LAT, and OSA + LAT patients are presented in Supplementary Fig. S1. Controls exhibited negative connectivity between the LC and the precuneus and between the LC and the posterior

cingulate cortex. In contrast, OSA patients exhibited positive connectivity between the LC and the precuneus and the between the LC and the cingulate cortex regardless of the LAT. For LDTg,

controls exhibited negative connectivity with the right lateral occipital cortex and cingulate cortex. In contrast, OSA-LAT patients showed positive LDTg connectivity with the cingulate

cortex, and OSA + LAT patients showed positive LDTg connectivity with the precuneus regions. Compared with the controls, OSA patients showed stronger functional connectivity between the LC

and the precuneus regardless of the concomitant LAT (post hoc _p_ < 0.001). The connectivity between the LDTg and the posterior cingulate cortex was also stronger in OSA patients

regardless of the LAT (post hoc _p_ < 0.001). Moreover, the LDTg-posterior cingulate cortex connectivity was stronger in the OSA - LAT group than in the OSA+LAT group (post hoc _p_ = 

0.013) (Table 2, Supplementary Table 1, and Fig. 1). RELATIONSHIP WITH SLEEP PARAMETERS We next evaluated the correlation between the LDTg–posterior cingulate cortex connectivity and

parameters determining LAT (values of the AHI, hypopnea fraction, and minimum oxygen saturation) in OSA patients. No significant correlation was found after Bonferroni correction. We only

observed a trend towards negative correlations between functional connectivity strength between the LDTg and the posterior cingulate cortex and minimum oxygen saturation after controlling

for age as a covariate (r = − 0.463, _p_ = 0.023, Fig. 2). The correlation between the connectivity strength and hypopnea fraction (r = − 0.237, _p_ = 0.266), or AHI (r = 0.312, _p_ = 0.137)

were non-significant. Moreover, experimental correlation analysis of clinical and polysomnography parameters that differed between groups also showed no significant results. DISCUSSION We

compared the resting-state functional connectivity of three ascending reticular activating system nuclei associated with OSA (the LC, LDTg, and VTA) and cortical/subcortical areas between

OSA patients with or without a LAT and controls without OSA. As in our previous study15, LC and LDTg-cortical functional connectivity was enhanced in OSA patients. LC-precuneus cortex and

LDTg–PCC connectivity was stronger in OSA patients than in controls regardless of the LAT. The LDTg-PCC connectivity was stronger in the OSA-LAT group than in the OSA + LAT group and tended

to be negatively correlated with minimum saturation in OSA patients. Patients with OSA + LAT usually awake more frequently during sleep, which may lead to lower sleep quality16. Accordingly,

we found that only OSA + LAT, not OSA-LAT showed higher PSQI score thant the controls. However, because no significant difference in sleep questionnaire score was found between the OSA-LAT

and OSA + LAT, and our experimental correlation analysis showed no significant association, effect of sleep-related symptom on functional connectivity was considered to be limited.

LDTg-posterior cingulate cortex connectivity differed according to the LAT in OSA patients. Pertinently, cholinergic neurons from the LDTg are part of the ascending reticular activating

system, which is associated with arousal, and our results suggested that cholinergic activity may contribute to the concomitant LAT in OSA patients. The posterior cingulate cortex is also

known as a crucial structure associated with arousal, and its functional connectivity changes according to arousal or awareness status17. Posterior cingulate cortex activation may be

affected by cholinergic function because enhancing cholinergic activity through acetylcholine esterase inhibitors increases cerebral blood flow to the posterior cingulate cortex18. Among the

factors determining LAT, minimum oxygen saturation showed the strongest association with the LDTg-posterior cingulate cortex connectivity strength. OSA-LAT patients are often exposed to a

higher hypoxic burden than OSA + LAT patients because arousal may not occur even in situations of severe hypoxia. In healthy volunteers, sustained hypoxia delays the time to arousal and

increases the respiratory arousal threshold19. Hypoxic burden may affect LDTg-cortical connectivity. Hypoxia decreases the number of cholinergic neurons20 and acetylcholine synthesis in rat

brains21. Exposure to hypoxia also reduces cerebral blood flow to the posterior cingulate cortex22. Increased FC between LDTg and posterior cingulate cortex in OSA may be a compensatory

mechanism for hypoxic burden in patients with OSA, which can be more severe in OSA-LAT patients than in those with OSA + LAT. Our results may imply that cholinergic activity is associated

with OSA and the LAT. This suggested that modulating cholinergic function may be a therapeutic option that can improve OSA severity or the arousal threshold. Several studies have reported

the effect of the acetylcholine esterase inhibitor donepezil on OSA severity. A placebo-controlled randomized trial showed that 10 mg donepezil in Alzheimer's disease patients with OSA

improved AHI values and oxygen saturation23. Another study with nondemented participants reported improvement in AHI values, desaturation index values, and minimum oxygen saturation after

one month of donepezil use24. However, the effect was not consistent. One randomized double-blind crossover study did not find a significant reduction in the AHI, minimum oxygen saturation

or arousal threshold after donepezil administration for a single night25. Another randomized study also did not find changes in AHI values or minimum oxygen saturation after patients using

donepezil for 1 month26. Several limitations should be considered when interpreting the results of our study. This was a single-center study with a limited number of participants. To

minimize the effect of OSA severity on brainstem-cortical FC, we only evaluated patients with an AHI between 20 and 40/hr. Moreover, the demographics of our OSA + LAT patients differed from

those in prior studies. Therefore, caution is warranted when generalizing our results to other populations. Age was included as a covariate, but OSA disease duration couldn’t be due to

practical limitations. The LAT was not measured directly but was estimated using the polysomnography parameter, which is known to have high sensitivity and specificity8. Moreover, the

association between the LAT and LDTg- posterior cingulate cortex functional connectivity does not imply a causal relationship between the two. Further pharmacological or neuromodulation

studies will be needed to establish a causal relationship between the connectivity and LAT. CONCLUSIONS This study suggested that cholinergic LDTg– posterior cingulate cortex functional

connectivity is associated with the LAT in patients with moderate to severe OSA. Among the factors determining LAT, minimum oxygen saturation exhibited the strongest correlation with LDTg-

posterior cingulate cortex connectivity. Future studies with larger numbers of patients are needed to elucidate the clinical implications of LDTg- posterior cingulate cortex connectivity for

determining individualized treatment options in OSA patients. METHODS PARTICIPANTS We recruited 25 moderate to severe OSA patients with AHI between 20 and 40/hr (10 without LAT and 15 with

LAT) and 15 controls without OSA. We previously recruited 50 moderate to severe OSA patients and 20 controls without OSA to report that higher AHI values were associated with increased

ARAS-cortical FC15. Because one of the criteria for identifying LAT is AHI value < 30/hr8, we included only those with AHI between 20 and 40/hr to minimize the effect of the AHI on the

ARAS-cortical FC. Twenty of the patients from our previous study who met the criteria (7 without LAT and 13 with LAT) and 5 additional newly recruited patients (3 without LAT and 2 with LAT)

were included in this study. Fifteen age and gender-matched controls were selected from 20 healthy volunteers from our previous study15. For age matching, controls within ± 5 years of age

difference were selected. Individuals with structural abnormalities, other sleep or neurological diseases (e.g., stroke or neurodegenerative disease) were excluded. The participants first

completed sleep questionnaire and then underwent overnight-PSG in accordance with their habitual sleep time. The resting-state fMRI was completed early in the morning, 2–3 h after wake-up

time while awake. This study was approved by the Institutional Review Board of Kyung Hee University Hospital in Gangdong (IRB no: 2020-12-010), and written informed consent was obtained from

all participants. This study was performed in accordance to the Declaration of Helsinki. CLINICAL ASSESSMENT Subjective sleep symptoms were evaluated by sleep questionnaires prior to PSG.

The questionnaire included the Beck Depression Inventory (BDI)-II27, Epworth Sleepiness Scale (ESS)28, and Pittsburgh Sleep Quality Index (PSQI)29, which evaluate depression symptoms,

daytime sleepiness, and sleep quality, respectively. POLYSOMNOGRAPHY Overnight PSG was performed using Grass-Telefactor twin version 2.6 (West Warwick, RI, USA) and scored manually according

to the _American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep and Associated Events_, version 2.630. Arousal was defined as abrupt frequency shift on

electroencephalography channel for at least ≥ 3 s. Obstructive apnea was indicated as a decrease in airflow amplitude of ≥ 90% for at least ≥ 10 s along with evident respiratory effort.

Hypopnea was indicated as a decrease in airflow amplitude of ≥ 30% relative to baseline for at least ≥ 10 s, accompanied by either ≥ 3% oxygen desaturation or an arousal. The AHI was

calculated as the sum of apnea and hypopnea events per hour during sleep. IMAGE ACQUISITION AND PREPROCESSING MRI was performed the morning after polysomnography using a 3.0 Tesla MRI system

with a 32-channel encoding head coil (Ingenia, Philips Medical System, Best, the Netherlands) and acquired and analyzed as in our previous study15,31. The following parameters were used to

acquire resting-state fMRI data: repetition time (TR) = 2000 ms; echo time (TE) = 35 ms; field of view (FOV) = 220 × 220 mm; flip angle (FA) = 90°; acquisition voxel size = 3.3 × 3.3 × 3.3;

reconstructed voxel size = 1.7 × 1.7 × 3.3 mm3; echo-planar imaging (EPI) factor = 33; and number of slices = 34. Structural three-dimensional (3D) T1-weighted (T1W) images were acquired

with the following parameters: TR = 8.1 ms, TE = 3.7 ms, FA = 8°, FOV = 236 × 236 mm2, and voxel size = 1 × 1 × 1 mm3. Statistical Parametric Mapping (SPM) version 12 software (Wellcome

Department of Cognitive Neurology, London, UK) and the default preprocessing pipeline in the CONN-fMRI FC toolbox (https://www.nitrc.org/projects/conn) version 21a32 were used to process the

images after discarding the first five scans as was done in our previous study15,31. We applied default preprocessing pipeline in the CONN toolbox for preprocessing. Briefly, this included

realigning the images to the first volume, unwarping, and adjusting for slice acquisition timing (interleaved bottom-up order). Next, the functional images were co-registered with the

participants' structural data and spatially normalized to a standard MNI template space. To improve signal-to-noise ratio, we applied a spatial smoothing with 2-mm full-width

half-maximum (FWHM) isotropic Gaussian kernel. Additionally, a component-based noise correction technique (CompCor) was employed to regress out and correct for head motion, physiological

noise, and nuisance signals, including six motion parameters, signals from white matter, and cerebrospinal fluid (CSF) voxels. Finally, a band-pass filter (0.009–0.08 Hz) was applied and the

signal was linearly detrended. There was no significant difference in six motion realignment parameters (controls: 0.125 ± 0.057 vs. OSA-LAT: 0.145 ± 0.047 vs. OSA + LAT: 0.136 + 0.035, _p_

 = 0.577) or global signal change and framewise displacement (controls: 0.803 ± 0.048 vs. OSA-LAT: 0.779 ± 0.051 vs. OSA + LAT: 0.789 + 0.042, _p_ = 0.433). REGION OF INTEREST SEED REGION We

used three brainstem nuclei (LC, LDTg, VTA) identified in our previous study as region of interests. The brainstem nuclei were derived from the Harvard Ascending Arousal Network Atlas

provided by the Martinos Center for Biomedical Imaging (Charleston, Massachusetts, USA, https://www.nmr.mgh.harvard.edu/resources/aan-atlas)33. SEED-TO-VOXEL FUNCTIONAL CONNECTIVITY ANALYSIS

Seed-to-voxel analysis was performed to measure functional connectivity between each brainstem nucleus and 105 cortical/subcortical regions of the Harvard–Oxford atlas embedded in the CONN

toolbox34. Partial Pearson’s correlation analyses were performed to determine the temporal correlations between the blood oxygen level-dependent (BOLD) signals of each ARAS nucleus and other

voxels in the whole brain. Group differences in ARAS-cortical FC were evaluated using generalized linear model (GLM) one-way analysis of variance (ANOVA) adjusting for age. To identify

significant clusters, an uncorrected peak value threshold of a _p_ value < 0.001 and a familywise error (FWE)-corrected threshold of _p_ < 0.05 were applied. STATISTICAL ANALYSIS All

data are presented as the mean ± standard deviation. One-way ANOVA and post hoc Bonferroni correction were used to evaluate differences in demographics and clinical measures among the three

groups: OSA + LAT, OSA-LAT, and controls. A chi-square test was used to analyze the categorical data. Among all OSA patients, Pearson partial correlation coefficients were calculated to

assess the relationships between the aberrant brainstem-cortical functional connectivity and clinical variables determining LAT (AHI, Hypopnea fraction, and spO2 nadir) after adjusting for

age. The significance level was set to 0.05, and the level of significance was p ≤ 0.05/3 (0.017) for the post hoc analysis. All statistical comparisons were conducted using SPSS (Version

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National Research Foundation of Korea (NRF) (No. NRF-2020R1C1C1013160). AUTHOR INFORMATION Author notes * These authors contributed equally: Ki-Young Jung and Won Chul Shin. AUTHORS AND

AFFILIATIONS * Department of Neurology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, 892 Dongnam-Ro, Gangdong-Gu, Seoul, 05278, Republic of Korea

Jung-Ick Byun & Won Chul Shin * Department of Radiology, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Republic of Korea Geon-Ho Jahng, 

Chang-Woo Ryu & Soonchan Park * Department of Otorhinolaryngology, Head and Neck Surgery, Kyung Hee University College of Medicine, Seoul, Republic of Korea Kun Hee Lee * Department of

Oral and Maxillofacial Surgery, Kyung Hee University College of Dentistry, Kyung Hee University Dental Hospital at Gangdong, Seoul, Republic of Korea Sung Ok Hong * Department of Neurology,

Seoul National University Hospital, Neuroscience Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 110-744, Republic of Korea Ki-Young Jung

* Department of Medicine, AgeTech-service, Convergence Major, Kyung Hee University, Seoul, Republic of Korea Won Chul Shin Authors * Jung-Ick Byun View author publications You can also

search for this author inPubMed Google Scholar * Geon-Ho Jahng View author publications You can also search for this author inPubMed Google Scholar * Chang-Woo Ryu View author publications

You can also search for this author inPubMed Google Scholar * Soonchan Park View author publications You can also search for this author inPubMed Google Scholar * Kun Hee Lee View author

publications You can also search for this author inPubMed Google Scholar * Sung Ok Hong View author publications You can also search for this author inPubMed Google Scholar * Ki-Young Jung

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CONTRIBUTIONS J.-I.B.: conceptualization, formal analysis, funding acquisition, roles/writing—original draft; G.-H.J.: data curation, investigation, writing—review & editing; C.-W.R.:

data curation, supervision; S.P.: data curation, investigation; K.H.L.: data curation, investigation, S.O.H.: data curation, investigation, K.-Y.J.: supervision, writing—review &

editing, validation; W.C.S.: conceptualization, supervision, writing—review & editing. CORRESPONDING AUTHORS Correspondence to Ki-Young Jung or Won Chul Shin. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER'S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published

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http://creativecommons.org/licenses/by-nc-nd/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Byun, JI., Jahng, GH., Ryu, CW. _et al._ Low arousal threshold is associated

with altered functional connectivity of the ascending reticular activating system in patients with obstructive sleep apnea. _Sci Rep_ 14, 18482 (2024).

https://doi.org/10.1038/s41598-024-68394-8 Download citation * Received: 29 November 2023 * Accepted: 23 July 2024 * Published: 09 August 2024 * DOI:

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