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 ventral tegmental area (VTA)—associated with OSA in our previous study were used as seeds. Functional connectivity values of the two brainstem nuclei (LC and LDTg) significantly differed among the three groups. The connectivity of the LC with the precuneus was stronger in OSA patients than in controls regardless of the concomitant LAT. The connectivity between the 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.
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) 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.
Axial views of differences in voxelwise functional connectivity between the LC and the cortex or LDTg and the cortex when comparing patients with OSA-LAT vs. OSA + LAT vs. healthy controls. (A) Statistical maps of the regions where functional connectivity with the LC significantly differed among the three groups. (B) Statistical maps of the regions where connectivity with the LDTg significantly differed among the three groups (cluster-level p