Obstructive Sleep Apnea (OSA) is a sleep-related respiratory disorder characterized by recurrent collapse of the upper airway during sleep (McNicholas and Pevernagie, 2022). This condition often leads to intermittent hypoxia, cytokine activation, dysmetabolism, nocturnal blood pressure surges, and sleep fragmentation (Kapur et al., 2017), which are commonly considered contributors to neurocognitive dysfunction associated with OSA (He et al., 2024; Vanek et al., 2020). There is an extensive body of research indicating that OSA is associated with a broad range of neurocognitive impairments, with the most prevalent reports focusing on memory and new learning, as well as attention and executive function (Bucks et al., 2013).

Continuous positive airway pressure (CPAP), which is regarded as the first line therapy for OSA, can improve hypoxia in OSA patients, reduce sleep fragmentation, and reverse sympathetic nerve excitation (Patil et al., 2019), but there is controversy regarding whether CPAP can improve cognitive dysfunction caused by OSA (Bucks et al., 2013). The existence of complex pathologies especially high loop gain maybe a reason for the failure due to impairment in both effectiveness and adherence (Ni and Thomas, 2023; Cheng et al., 2024). It is also plausible that pathological respiratory chemoreflex activation and the resulting heightened sympathetic activation and other pleotrophic effects such as oxidative stress, inflammatory response, and neuronal damage (Lv et al., 2023) may influence development of neurocognitive dysfunction, and response to treatment.

High loop gain within the respiratory system, a hallmark of unstable respiratory control, typically occurs during non-rapid eye movement sleep (NREM) (Deacon and Catcheside, 2015). Research indicates that in patients with OSA, respiratory control is significantly less stable during NREM sleep compared to rapid eye movement sleep (REM). This instability may contribute to cognitive decline via enhancing sleep fragmentation (Joosten et al., 2021). Additionally, high loop gain is a marker of carotid body activation, which is often linked to increased sympathetic nerve drive and glucose dysmetabolism (Joyner et al., 2018; Sacramento et al., 2020). That nighttime sympathetic activation may be an important factor in impairing the neurocognitive functions of patients with OSA has been reported (Alomri et al., 2021).

As described in our previous work, narrow band elevated low frequency coupling (e-LFC_NB) measured by cardiopulmonary coupling sleep spectrograms is a biomarker indicating periodic breathing and central sleep apnea (Thomas et al., 2007), indicating high loop gain. Our previous study showed that e-LFC_NB was a strong predictor for blood pressure dropping after CPAP in OSA (Ni et al., 2024). However, whether it influences neurocognitive function improvement by CPAP is not known.

This study conducted a secondary analysis of the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Our hypothesis was that e-LFC_NB%, as a marker of unstable respiratory control and a sign of carotid body activation, could predict neurocognitive change with CPAP.

This study uncovered the following findings: (1) a positive correlation between e-LFC_NB% and short-term improvements in BSRT-SR among OSA patients after CPAP treatment; (2) a positive correlation between e-LFC_NB% and both short-term and long-term improvements in SWMT-OMD among OSA patients following CPAP treatment. These findings may help predict which individuals are likely to experience enhancements in neurocognitive function from OSA therapy, as indicated by the sequence: apnea with e-LFC_NB%/High Loop Gain → NREM instability/fragmentation + Sympathetic Activation + Hypoxia → Prefrontal/Hippocampal Dysfunction → Specific Cognitive Deficits → Reversal by CPAP.

The pathogenic mechanisms through which OSA impairs neurocognitive functions include: intermittent hypoxemia, cytokine activation, metabolic dysfunction, sleep deprivation, hypercapnia and sympathetic nervous system activation (Pollicina et al., 2021). As high loop gain sleep apnea is NREM-dominant, the predominance of respiratory events in NREM sleep may cause disproportionate sleep fragmentation, which is crucial in the development of neurocognitive function (Devita et al., 2019). NREM sleep enhances information encoding capacity and learning in neural networks through a complex interplay of slow oscillations, spindles, and sharp-wave ripples (Mizuseki and Miyawaki, 2017; Peyrache and Seibt, 2020; Salfi et al., 2020), and is at risk from sleep fragmentation. Even brief periods of NREM sleep can significantly boost and restore cognitive functions (Kharas et al., 2024) but substantial fragmentation is likely to adversely impact memoy and learning functions. Sleep fragmentation itself can impair metabolic function (Stamatakis and Punjabi, 2010). Chronic sleep fragmentation exposures in a murine model mimicking the fragmentation of sleep that characterizes patients with apnea elicits evidence of inflammation in brain regions and explicit memory impairments in mice (Puech et al., 2023). In this model, sleep fragmentation was also associated with increased BBB permeability, the magnitude of which was closely associated with cognitive functional loss (Puech et al., 2023). Apneas and intermittent hypoxia events experienced during NREM sleep can trigger the activation of the sympathetic nervous system, leading to endothelial dysfunction (Lambert et al., 2013; Swenson, 2020) and blood pressure surges (Narkiewicz et al., 1998; Peled et al., 1998). Moreover, hypoxic events themselves can cause direct damage to neurocognitive functions (He et al., 2024; Chokesuwattanaskul et al., 2021).

Previous studies have confirmed that e-LFC_NB% is associated with the severity of OSA, sleep stability, respiratory chemoreflex regulation, and intermittent hypoxia (Deacon and Catcheside, 2015; Ibrahim et al., 2010; Thomas et al., 2018). Hypoxic events stimulate the sympathetic nervous system, thus e-LFC_NB% is also a marker of carotid body activation (Joyner et al., 2018). However, we adjusted for apnea severity in our analysis. CPAP treatment can improve neurocognitive function by reversing the processes of chronic intermittent hypoxia and sympathetic nerve activation, as well as reducing sleep fragmentation and can even slightly increase the duration of sleep, improving neural structural adaptability, and facilitating neuronal repair (Ziegler et al., 2001; Sánchez et al., 2009). It was recently reported using the APPLES that a higher arousal threshold is associated with greater improvements in executive function following CPAP therapy (Zinchuk et al., 2025). That is a lower propensity for fragmentation was protective.

In this study, two primary outcome indicators reflecting neurocognitive functions were assessed. First, SWMT-OMD primarily evaluates individuals’ executive functions and frontal lobe functions, particularly abilities related to working memory, and is significantly associated with the prefrontal cortex. Second, BSRT-SR mainly assesses individuals’ learning and memory capabilities, specifically verbal learning and memory, and is related to the brain’s hippocampus and temporal cortex (Kushida et al., 2012; Pollicina et al., 2021). Studies have demonstrated that the SWMT is sensitive to subtle changes in executive function (Gevins et al., 2011), and improvements in SWMT-OMD reflect enhanced frontal lobe performance. Similarly, research has indicated that improvements in BSRT-SR scores (even by 4–6 points) are clinically significant in OSA populations (Beebe et al., 2003). In our study, the observed improvements (e.g., BSRT-SR > 12) substantially exceed these benchmarks, underscoring their functional relevance. While the hippocampus is more sensitive to hypoxia (Churilova et al., 2022), its ability to adapt to prolonged hypoxic exposure is greater than that of the prefrontal cortex, potentially providing compensatory mechanisms (Shaw et al., 2021). During NREM hypoxia, sympathetic activation leads to increased levels of norepinephrine, which impairs the prefrontal cortex’s ability to support higher-order cognitive functions, such as decision-making and working memory (Arnsten, 2009). This makes the prefrontal cortex particularly susceptible to impairment from sympathetic activation during sleep. As a biomarker of sympathetic nerve excitation and NREM-period hypoxia, e-LFC_NB% could plausibly predict improvements in neurocognitive function after treatment. For BSRT-SR, the relatively slow subsequent improvement of the hippocampus and its weaker correlation with sympathetic excitation and hypoxia compared to the prefrontal cortex may explain why it can only predict short-term effects. In addition, the inconsistency in the quality of the BSRT-SR assessment scales before and after treatment, as mentioned in previous studies (Kushida et al., 2012), may also account for the results of this study. Regarding the third neurocognitive function assessment indicator mentioned in this study: PFN-TOTL, which is primarily used to evaluate a patient’s attention and psychomotor functions, is associated with the function of the prefrontal cortex (Braver et al., 2009). However, the study results indicate that e-LFC_NB% does not effectively predict the degree of improvement in this indicator. This may be due to the sensitivity of the indicator to CPAP treatment being insufficient, rendering it a less effective marker for assessing neurocognitive function in patients with OSA (Kushida et al., 2012).

This analysis has several limitations that should be taken into account. Data loss occurred due to issues with signal quality and analysis. We were unable to assess the night-to-night stability of e-LFC_NB%. Maintaining consistent quality in the assessment scales for neurocognitive function indicators could provide clearer indications of treatment responses. We did not directly estimate the loop gain in the analyzed data. Additionally, the subjective nature of cognitive function assessments may have influenced the results, as factors such as age, education, and social function status can affect individuals’ self-reports of cognitive function. The complex relationship between cognitive function and brain structure/function, including the brain’s compensatory and repair mechanisms, adds to the uncertainty in accurately evaluating cognitive impairment. Future research should address these limitations by employing larger, more diverse samples, and longitudinal study designs to better understand the impact of LFC_NB% and other biomarkers on the improvement of neurocognitive function in OSA patients after CPAP treatment.

Assessing pathological activation of the respiratory chemoreflex may help identify a biomarker for predicting improvement in neurocognitive function following CPAP treatment.