Obstructive sleep apnea and attention deficits: A systematic review of magnetic resonance imaging biomarkers and neuropsychological assessments

Abstract Background and objective Obstructive sleep apnea (OSA) is a common sleep disorder that causes intermittent hypoxia and sleep fragmentation, leading to attention impairment and other cognitive deficits. Magnetic resonance imaging (MRI) is a powerful modality that can reveal the structural and functional brain alterations associated with attention impairment in OSA patients. The objective of this systematic review is to identify and synthesize the evidence on MRI biomarkers and neuropsychological assessments of attention deficits in OSA patients. Methods We searched the Scopus and PubMed databases for studies that used MRI to measure biomarkers related to attention alteration in OSA patients and reported qualitative and quantitative data on the association between MRI biomarkers and attention outcomes. We also included studies that found an association between neuropsychological assessments and MRI findings in OSA patients with attention deficits. Results We included 19 studies that met our inclusion criteria and extracted the relevant data from each study. We categorized the studies into three groups based on the MRI modality and the cognitive domain they used: structural and diffusion tensor imaging MRI findings, functional, perfusion, and metabolic MRI findings, and neuropsychological assessment findings. Conclusions We found that OSA is associated with structural, functional, and metabolic brain alterations in multiple regions and networks that are involved in attention processing. Treatment with continuous positive airway pressure can partially reverse some of the brain changes and improve cognitive function in some domains and in some studies. This review suggests that MRI techniques and neuropsychological assessments can be useful tools for monitoring the progression and response to treatment of OSA patients.


INTRODUCTION
Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by recurrent episodes of upper airway collapse during sleep, leading to intermittent hypoxia and sleep fragmentation (Bhuniya et al., 2022;Carvalho et al., 2023;Ji et al., 2022;Lal et al., 2021;Martins & Conde, 2021;Slowik et al., 2023).It affects millions of people worldwide (Benjafield et al., 2019;Lyons et al., 2020).OSA affects 33% of men and 16% of women in the adult population and is associated with an increased risk of cardiovascular, metabolic, and neurocognitive complications (Abbasi et al., 2021;Barletta et al., 2019;Lal et al., 2022;Liu et al., 2020;Wang et al., 2022).Among the neurocognitive consequences of OSA, attention impairment is one of the most frequently reported and disabling symptoms, impacting the quality of life and daily functioning of OSA patients (Angelelli et al., 2020;Bilyukov et al., 2018;Bucks et al., 2013;Krysta et al., 2017).Attention is a complex cognitive function that encompasses multiple processes and involves various brain regions.Attention impairment in OSA patients can affect different types of attention (Angelelli et al., 2020;Krysta et al., 2017;Simões et al., 2018).
The standard therapy for OSA is continuous positive airway pressure (CPAP), which delivers pressurized air through a mask to keep the airway open during sleep (Cao et al., 2017;Spicuzza et al., 2015).
These regions are part of a network that supports attention control and allocation (Ayalon et al., 2009;Canessa et al., 2011).Furthermore, advanced MRI techniques can also show the potential recovery of brain structure and function after CPAP treatment (Chen et al., 2017;Xiong et al., 2017).In total, the objective of this systematic review is to identify and synthesize the evidence on MRI biomarkers and neuropsychological assessments of attention deficits in OSA patients.

Search strategy
The systematic review selection process is summarized in the reporting in systematic reviews and meta-analyses(PRISMA) flow diagram guidelines (Figure 1) (Page et al., 2021).We conducted a comprehensive search of the Scopus and PubMed databases in all field formats to identify relevant studies.We used a combination of free-text and controlled vocabulary terms related to OSA, MRI, and attention impairment, disorder, loss, and deficit.The search was limited to studies published in English and included articles published up to June 2023.

Study selection
All reviewers independently assessed the eligibility of the retrieved studies based on the inclusion and exclusion criteria.Studies that met the following criteria were included: (1) Participants were adults diagnosed with OSA according to established criteria (ages more than 16-year old and definitive diagnosis with PSG device); (2) MRI was used to measure biomarkers related to attention alteration in OSA patients; (3) the studies reported qualitative and quantitative data on the association between neuropsychological assessments and MRI findings in OSA patients with attention deficits; (4) the studies were published in English.We excluded studies that (1) used other imaging modalities besides MRI; (2) measured biomarkers unrelated to attention impairment; (3) did not report qualitative and quantitative data on the association between MRI biomarkers and attention outcomes; or (4) were reviews, meta-analyses, case reports, editorials, letters, or conference abstracts.

Data extraction and quality assessment
One reviewer (M.M.) independently extracted the following data from each included study using a standardized form: study characteristics (first author and year, design, sample size, inclusion, and exclusion criteria), participant characteristics (age, sex, body mass index, apnea-hypopnea index (AHI), and neuropsychological assessments), MRI characteristics (field strength, coil, and imaging techniques), and main findings.Any discrepancies were resolved through discussion with other reviewers.Two reviewers (S.M. and S.Gh.) independently assessed the quality of the included studies using the Cochrane Risk of Bias tool for randomized controlled trials (Higgins et al., 2011) and the Newcastle-Ottawa Scale for observational studies (Lo et al., 2014).

Analysis of global population
In addition to the literature review, we conducted an analysis of the global representation and population diversity of the included studies on OSA, MRI measures, and neuropsychological assessments.The first author's country of origin was recorded for each study.Frequencies were calculated to quantify the contribution of different countries and regions to the overall literature.This allowed the assessment of geographical patterns in study locations and the identification of over-or underrepresentation of particular global patient populations.

Overview of the included studies
The search strategy yielded 954 studies from the electronic databases.
Of these, 694 records were excluded for various reasons (see Figure 1 F I G U R E 2 Main magnetic resonance imaging (MRI) techniques and neuropsychological assessments using the included studies.
for details).After the first screening, 260 studies were screened by title and abstract, and 63 of them were excluded.After an assessment of eligibility, 177 records were excluded because they did not meet the eligibility criteria.Finally, 19 studies were included in the systematic review.The studies were published between 2007 and 2022.The participant characteristics and study methodologies are summarized in Table 1.
Various MRI techniques and neuropsychological assessments were employed to investigate the relationship between OSA and attention deficits.These techniques included T1-weighted imaging (T1-w), T2-weighted imaging (T2-w), T2-fluid attenuated inversion recovery (T2-FLAIR), MRS, DTI, fMRI, resting-state fMRI (rs-fMRI), and others (Figure 2).Thirteen of the 20 studies employed structural MRI to examine brain alterations in OSA patients, including T1-w, T2-w, FLAIR, and DTI.Five of the 19 studies employed task-based fMRI, or rs-fMRI, to assess changes in brain function and FC in OSA patients.One study used MRS (Tonon et al., 2007), whereas another study employed the PWI technique (dynamic susceptibility contrast (DSC) method) (Yan et al., 2021).
The studies used a wide array of assessments to evaluate attention, vigilance, working memory, executive functions, and episodic memory.

Structural MRI findings
GMV reduction has been found in the frontal, temporal, and parietooccipital cortices, the hippocampus, the basal ganglia, the thalamus, and the cerebellum, mostly in the right hemisphere (Canessa et al., 2011;Lin et al., 2016;Torelli et al., 2011;Yaouhi et al., 2009).A couple of studies (Chokesuwattanaskul et al., 2021;Joo et al., 2013) discovered dorsolateral prefrontal cortex atrophy or cortical thinning in the inferior parietal lobule and superior parietal gyrus.These alterations have been linked to attention deficits and other cognitive impairments.In some cases, treatment with CPAP has been shown to improve GMV and cognitive function (Canessa et al., 2011;Rosenzweig et al., 2016) although the extent of improvement can depend on treatment compliance (Castronovo et al., 2014).
DTI findings have revealed reduced fractional anisotropy (FA) and higher mean (MD) and radial diffusivity (RD) in various brain regions, such as the corpus callosum (CC), prefrontal cortex, and premotor and supplementary motor cortex (SMC), which are associated with impaired prospective memory and sustained attention in OSA patients (Zhang et al., 2019).In the study comparing OSA patients to HCs, studies have discovered abnormalities in the integrity of the WM or fiber damage in the anterior CC, anterior cingulate gyrus, and frontoparietal network (Castronovo et al., 2014;Ramos et al., 2021;Zhang et al., 2019).Specifically, DTI biomarkers indicated higher RD in the prefrontal cortex, as well as lower FA and higher MD and RD in the premotor and supplementary motor cortex.A noteworthy association was observed between reduced anterior CC integrity and impaired prospective memory and sustained attention in OSA patients.Additionally, OSA was found to negatively impact cognition and WM integrity over a 4-year span (Lee et al., 2022).
Both incident and persistent OSA were linked to decrements in attention, visual processing, and visual memory (Lee et al., 2022).
These cognitive declines were associated with changes in FA of WM regions.Furthermore, reductions in cognition, mood, and sleepiness corresponded with decreased WM fiber integrity (FA and MD) across multiple brain areas in pretreatment OSA patients (Castronovo et al., 2014).After 3 months of CPAP intervention, only limited changes in WM were observed.In contrast, after 12 months of CPAP treatment, compliant patients exhibited improvements in WM integrity.These WM changes posttreatment were positively correlated with enhanced attention and executive functioning, emphasizing the importance of CPAP compliance for achieving favorable outcomes (Canessa et al., 2011).

Functional and metabolic MRI findings
Some studies revealed lower or altered FC in many resting-state networks (RSNs), including the default mode network (DMN) (Chang et al., 2020;He et al., 2022;Prilipko et al., 2012), dorsal attention network (DAN) (He et al., 2022), ventral attention network (VAN) (He et al., 2022), and salience network (SN) (He et al., 2022).The cingulate cortex, prefrontal cortex, middle frontal gyrus (MFG), inferior frontal gyrus (IFG), and middle and superior temporal regions are common among these networks.Some studies also discovered that when cognitive activities, such as working memory, attention, and mismatch processing, were performed, the ACC, MFG, and IFG were less active, in contrast right anterior prefrontal gyrus increased activity (He et al., 2022;Zhang et al., 2011).In another fMRI study, Prilipko et al. (2012), found that OSA patients had less deactivation in the DMN and TPN.Treatment with CPAP has been shown to modulate cerebral activation and deactivation patterns, leading to improved behavioral performance (Prilipko et al., 2012).
In OSA patients, abnormal FCs of the ventral anterior insula, dorsal anterior insula, and posterior insula were seen in several brain regions (Kong et al., 2021).Some studies have reported associations between FC and OSA severity indices, such as the AHI (Chang et al., 2020), ODI (Chang et al., 2020;Chokesuwattanaskul et al., 2021), and SaO 2 (Chang et al., 2020).OSA patients had substantially lower FC in the attentionrelated networks, such as the bilateral posterior cingulate gyri of the DMN, the right MFG of the DAN, and the left superior temporal gyrus (STG) of the VAN (He et al., 2022).OSA patients also had higher FC in the right superior frontal gyrus of the SN (He et al., 2022).
In regards to other perfusion and metabolic techniques, one study using DSC has shown reduced global and regional CBF and cerebral blood volume (CBV) in a variety of cortical and deep regions associated with the DMN and attention networks, primarily in bilateral parietal and prefrontal cortices (Yan et al., 2021).These reductions have been linked to intermittent hypoxia and sleep fragmentation (Yan et al., 2021).Another study used MRS to measure cortical Nacetylaspartate (NAA), creatine, and choline (Cho) concentrations and discovered that baseline cortical NAA concentration was significantly lower in OSA patients.After 6 months of CPAP treatment, no changes were detected (Tonon et al., 2007).Finally, one multimodal neuroimaging found that OSA patients had a decrease in brain metabolism that was more restricted than GM density changes and involved regions, such as the precuneus, the cingulate gyrus, and the parietooccipital cortex, as well as the prefrontal cortex (Yaouhi et al., 2009).
However, not all studies have reported improvements in cognitive performance following treatment (Tonon et al., 2007).Moreover, the extent of cognitive recovery may be influenced by some factor such as treatment compliance (Castronovo et al., 2014).

DISCUSSION
The present study aimed to review the MRI and neuropsychological characteristics and findings in attention deficits of OSA.This review provides an updated and comprehensive overview of the recent advances in MRI techniques and neuropsychological assessments that have been applied to OSA research.According to the systematic review, OSA has significant effects on brain structure and function, which could lead to attention deficits (Figure 4).
One of the main findings of this review is that OSA is associated with structural alterations in several brain regions that are involved in attention processing.The majority of the studies that used structural MRI reported reduced GMV or cortical thickness in multiple brain regions in OSA patients, especially in the frontal (Canessa et al., 2011;Chokesuwattanaskul et al., 2021;Joo et al., 2013;Yaouhi et al., 2009), temporal, and parietal lobes, as well as the hippocampus (Canessa et al., 2011;Lin et al., 2016;Yaouhi et al., 2009), thalamus (Yaouhi et al., 2009), caudate, and insula (Canessa et al., 2011;Chokesuwattanaskul et al., 2021;Joo et al., 2013;Lin et al., 2016;Prilipko et al., 2012;Torelli et al., 2011).These structural deficits were associated with cognitive impairments such as attentional disorder (Canessa et al., 2011;Joo et al., 2013;Lin et al., 2016;Torelli et al., 2011), which are commonly impaired in OSA patients.The GMV or cortical thickness reductions were also associated with OSA severity indices, such as AHI, ODI, SaO 2 , arousal index, and Epworth sleepiness scale.Some studies also found higher GMV or cortical thickness in some regions, such as the cerebellum, precuneus, ACC, and PFG, which can reflect compensatory mechanisms or recovery from edema after treatment (Canessa et al., 2011;Lin et al., 2016).Canessa et al. (2011) showed after treatment, significant improvements in attention were observed, which paralleled GMV increases in hippocampal and frontal structures (Canessa et al., 2011).Treatment with CPAP was shown to partially reverse some of the GMV or cortical thickness changes and improve cognitive function in some studies (Canessa et al., 2011;Castronovo et al., 2014).Cognitive (such as attentional disorder) and structural deficits in OSA can be secondary to sleep deprivation and repetitive nocturnal intermittent hypoxemia (Yan et al., 2021).These findings are in line with Lin et al. (2016), who showed after treatment, improvements in attention and executive-functioning paralleled GMV increases in hippocampal and frontal structures (Lin et al., 2016).
Furthermore, preoperatively, patients presented with worse cognitive function,and worse polysomnography scores associated with higher insular GMV (Lin et al., 2016).
The studies that used DTI reported reduced WM integrity or fiber density in several brain areas in OSA patients, mainly in the CC, prefrontal cortex, premotor cortex, SMC, and cingulum (Castronovo et al., 2014;Chokesuwattanaskul et al., 2021;Lee et al., 2022;Zhang et al., 2019).These regions are important for interhemispheric communication, motor control, and attention regulation (Boussaoud, 2001;Simon et al., 2002).The WM integrity or fiber density reductions were also correlated with OSA severity indices and cognitive performance measures, such as prospective memory and sustained attention (Koo et al., 2023;Mullins et al., 2020).Furthermore, CPAP treatment was found to improve WM integrity or fiber density in some regions and enhance attention and executive function in some studies that were approved by previous studies (Lajoie et al., 2020;Salsone et al., 2021).
Attention is supported by multiple brain networks that interact dynamically depending on the task demands and environmental context (Denkova et al., 2019;Kao et al., 2020;Parks & Madden, 2013;Zhou et al., 2023).These networks include the DAN, which mediates top-down control of attention; the VAN, which mediates bottomup detection of salient stimuli; the DMN, which mediates internally oriented attention; and the SN (Yousaf et al., 2017), which mediates switching between external and internal attention (Corbetta & Shulman, 2002;Dragomir & Omurtag, 2020;Menon & Uddin, 2010;Su et al., 2021).These networks are responsible for maintaining internal mental states, orienting attention to external stimuli, detecting salient events, and switching between other networks (Lindsay, 2020).The abnormal RSNs were associated with worse performance on neuropsychological tests (Benito-León et al., 2015;He et al., 2022).Besides, Kong et al. (2021) reported abnormal insular connectivity related to emotion, cognition, and sensorimotor function, which correlated with sleep and cognitive variables.These findings suggest that OSA imapirs attention and other higher order functions by disrupting FC within and between RSNs (Ayalon et al., 2009;Zhang et al., 2013).The FC or activation changes were also related to OSA severity indices and cognitive performance measures, such as global cognitive function, attention span, working memory, response time, and error rate (Ayalon et al., 2009;Park et al., 2021).
CPAP treatment was shown to modulate FC or activation in some regions and improve behavioral performance in some studies, but not in others.These inconsistent results may be due to different fMRI paradigms, analysis methods, or baseline characteristics (Khazaie et al., 2017;Li et al., 2022;Long et al., 2023;Prilipko et al., 2012;Prilipko et al., 2014;Sun et al., 2023).Moreover, OSA triggers compensatory or adaptive responses in the brain, such as increased activation or F I G U R E 4 Main magnetic resonance imaging (MRI) biomarker alterations and neuropsychological assessments in obstructive sleep apnea (OSA) patients.
deactivation in specific regions or networks, increased connectivity or plasticity in others, or higher brain volume or metabolism in some areas.These responses reflect an attempt to maintain cognitive function or cope with OSA's adverse effects (Chou et al., 2019;Tahmasian et al., 2016).
The DSC and MRS studies provide insight into the neural mechanisms underlying the attention deficits in OSA (Tonon et al., 2007;Wallin et al., 2018;Yan et al., 2021).Reduced CBF and CBV were observed in the DMN and DAN, including the bilateral parietal and prefrontal cortices.These regions are critical for sustained attention and attention allocation (Chang et al., 2020;Orosz et al., 2012;Schneider et al., 2022;Zhang et al., 2018).The hypoperfusion in these attention networks could contribute to the impaired attention and vigilance commonly reported in OSA patients (Faria et al., 2021;Legault et al., 2021).The reduced CBF and CBV were also associated with OSA severity measures like lower minimum SpO 2 and sleep fragmentation, suggesting that the neural abnormalities are related to the physiological impacts of OSA (L'Heureux et al., 2021;Macey, 2015).
In addition, OSA patients exhibited lower NAA concentrations in the cortical regions at baseline compared to HCs (Tonon et al., 2007).NAA is a marker of neuronal integrity and function (Chen et al., 2022;Kalra, 2019;Moffett et al., 2007).The lower NAA levels indicate neuronal dysfunction or loss, which could underlie the attention and cognitive impairments (Benarroch, 2008;Schuff et al., 2006).The reduced NAA concentrations were also correlated with worse sleepiness and oxygen desaturation in OSA, highlighting their clinical relevance (Kainulainen et al., 2019;Meliante et al., 2023;Wali et al., 2020).Despite significant improvements in EDS, sleep fragmentation, and oxygen saturation following CPAP treatment, the cortical perfusion, NAA concentrations, and cognitive functions did not normalize after 6 months of CPAP therapy in some studies.The persistent neural abnormalities may explain the residual attention and cognitive deficits even after CPAP treatment in some OSA patients (Liu et al., 2020;Xiong et al., 2017).
To sum up, the structural, functional, and

CONCLUSIONS
This review provides an updated and comprehensive summary of the MRI biomarkers and neuropsychological assessments of attention deficits in patients with OSA.We found that OSA is associated with structural and functional brain alterations in multiple regions and networks that are involved in attention processing, such as the frontal, temporal, and parietal lobes, the hippocampus, the thalamus, the insula, the CC, the ACC, the middle and inferior frontal gyri, the posterior cingulate cortex, and the STG.These brain changes are also correlated with OSA severity indices and cognitive performance measures, such as global cognitive function, attention span, working memory, response time, and error rate.Treatment with CPAP can partially reverse some of the brain changes and improve cognitive function in some domains and in some studies, but not in others.The inconsistent results may be due to methodological differences or confounding factors.

F
I G U R E 1 PRISMA flow diagram of the study selection process.

F
Geographic distribution of the countries and regions included in the systematic review of magnetic resonance imaging (MRI) biomarkers and neuropsychological assessments for obstructive sleep apnea (OSA) and attention deficits.The color gradient shows the proportion of articles from each country.with impaired cognitive performance in these domains, as well as global cognitive function, mood, and sleepiness.The cognitive impairments are correlated with the severity of OSA, as measured by polysomnography parameters, such as AHI, oxygen desaturation index (ODI), nadir oxygen saturation (SaO 2 ), and arousal index.In our analysis of global population diversity and heterogeneity in OSA and attention research involving MRI and neuropsychological assessments, we discovered a geographical distribution pattern (Figure 3).Out of the 19 articles included in our study, the majority of the contributions came from the United States (n = 5), China (n = 4), and Italy (n = 3), collectively accounting for 63% of the articles.Furthermore, East and Southeast Asian countries, such as China, South Korea (n = 2), Taiwan (n = 2), and Thailand (n = 1), exhibited the highest participation rate across continents, with a 47% share (9 out of 19 articles).Lastly, European countries, including Italy, France (n = 1), and the United Kingdom (n = 1), were responsible for 26% of the research (5 out of 19 articles).Notably, countries from the African continent, Oceania, Southwest Asia and the Middle East, Eastern Europe, and South America were not represented in the patient populations included in this study.Considering these findings, we recommend that future research efforts focus on increasing population heterogeneity by encouraging diagnostic interventions related to MRI and neuropsychological assessments in underrepresented regions.Such an approach will enhance the generalizability of subsequent review studies and provide a more comprehensive understanding of OSA's global impact.Additionally, conducting further investigations across diverse populations and countries will shed light on previously undiscovered aspects of the condition.
metabolic neuroimaging evidence converges to indicate that OSA affects multiple brain networks subserving attention, particularly front-parietal systems.The diffuse patterns of GM atrophy, WM disruption, hypoperfusion, and altered connectivity suggest OSA has a systemic impact on brain structure and function.Notably, the attention networks most strongly implicated-the DAN, VAN, and SN-play key roles in top-down atten-tional control, bottom-up stimulus detection, and switching between internal versus external attention.This aligns with the attentional deficits frequently reported in OSA.The involvement of both dorsal and ventral frontoparietal circuits points to OSA disrupting both goal-directed and stimulus-driven attention.Another key finding is that while some studies show recovery in brain structure/function and cognition following CPAP treatment, others show persistent deficits.This suggests individual variability in the reversibility of brain changes, which may depend on factors like OSA severity, neural compensatory capacity, and treatment compliance.Clinically, a subset of patients may require more aggressive management to fully reverse attention deficits.to take into account certain limitations.The utilization of various MRI techniques and neuropsychological tests in different studies can result in differences in the ability to detect changes in the brain and cognitive functions.To mitigate these inconsistencies, it would be helpful to standardize the protocols for structural, functional, and metabolic MRI, as well as cognitive assessment batteries that are specifically designed for patients with OSA.Larger sample sizes, especially for follow-up studies, are needed to confirm preliminary findings on the effects of OSA treatment.Future research should control for these potential confounds, which could also influence brain structure, function, and cognition.Another limitation is the paucity of longitudinal studies investigating structural brain changes and cognitive decline over time in OSA.Most studies employed cross-sectional rather than longitudinal designs.Further high-quality longitudinal research is critically needed to delineate progressive brain and cognitive changes in OSA and tease apart the effects of the disease process from potential confounds.Long-term follow-up of OSA patients and the employment of machine learning techniques are vital to facilitate the detection of complex patterns in multimodal imaging and cognitive decline with early diagnosis and treatment.