**Respiratory Muscle Training Can Improve Cognition, Lung Function, and Diaphragmatic Thickness Fraction in Male and Non-Obese Patients with Chronic Obstructive Pulmonary Disease: A Prospective Study**

**Yuan-Yang Cheng 1,2,3 , Shih-Yi Lin 3,4 , Chiann-Yi Hsu <sup>5</sup> and Pin-Kuei Fu 2,6,7,8,\***


**Abstract:** Patients with chronic obstructive pulmonary disease (COPD) are frequently comorbid with mild cognitive impairment (MCI). Whether respiratory muscle training (RMT) is helpful for patients with COPD comorbid MCI remains unclear. Inspiratory muscle training (IMT) with or without expiratory muscle training (EMT) was performed. Patients were randomly assigned to the full training group (EMT + IMT) or the simple training group (IMT only). A total of 49 patients completed the eight-week course of RMT training. RMT significantly improved the maximal inspiratory pressure (MIP), the diaphragmatic thickness fraction and excursion, lung function, scores in the COPD assessment test (CAT), modified Medical Research Council (mMRC) scale scores, and MMSE. The between-group difference in the full training and single training group was not significant. Subgroup analysis classified by the forced expiratory volume in one second (FEV1) level of patients showed no significant differences in MIP, lung function, cognitive function, and walking distance. However, a significant increase in diaphragmatic thickness was found in patients with FEV1 ≥ 30%. We suggest that patients with COPD should start RMT earlier in their disease course to improve physical activity.

**Keywords:** COPD; respiratory muscle training; cognitive impairment; inspiratory muscle training; expiratory muscle training; FEV1; diaphragmatic thickness fraction

### **1. Introduction**

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation, which causes obstructed airflow from the lungs, resulting in muscle wasting and respiratory failure [1]. Currently, approximately 300 million people world-wide have COPD, contributing to approximately 64 million disability-adjusted life years [2]. In addition to smoking cessation, oxygen therapy, and long-acting bronchodilator therapy, comprehensive pulmonary rehabilitation programs involving aerobic exercise, cough technique education, and respiratory muscle training (RMT) are crucial in the management of COPD [3]. Inspiratory muscle training (IMT), the major method of RMT, can improve inspiratory muscle strength, exercise capacity, quality of life, and dyspnea [4]. Therefore, IMT has been recommended as a part of pulmonary rehabilitation programs for patients

**Citation:** Cheng, Y.-Y.; Lin, S.-Y.; Hsu, C.-Y.; Fu, P.-K. Respiratory Muscle Training Can Improve Cognition, Lung Function, and Diaphragmatic Thickness Fraction in Male and Non-Obese Patients with Chronic Obstructive Pulmonary Disease: A Prospective Study. *J. Pers. Med.* **2022**, *12*, 475. https://doi.org/ 10.3390/jpm12030475

Academic Editors: Ioannis Pantazopoulos and Ourania S. Kotsiou

Received: 9 February 2022 Accepted: 13 March 2022 Published: 16 March 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

with COPD [5,6]. Expiratory muscle training (EMT) can improve vital capacity and peak expiratory flow [7,8], which are also beneficial for cough function. In addition, the improvement in cough function is a vital part of pulmonary rehabilitation; therefore, RMT including IMT and EMT plays a critical role in the management of COPD [9].

Mild cognitive impairment (MCI) is defined based on the following four criteria [10]: (1) a change in cognition reported by the patient, caregiver, or clinician; (2) objective evidence of impairment in one or more cognitive domains, which typically includes memory; (3) preservation of independence in functional abilities; and (4) absence of dementia. Mini-Mental State Examination (MMSE) scores of 23–27 indicate MCI [11]. Many studies have revealed an association between COPD and MCI [12–15], and a dose–response relationship between the duration of COPD and the risk of MCI [13,14]. Furthermore, forced expiratory volume in one second (FEV1) is positively correlated with cognitive function throughout adulthood [16] because of the higher risk of neuronal injury in patients with chronic hypoxemia [17]. The chronic generalized inflammatory status of patients with COPD can affect MCI pathogenesis [18]. Although aerobic exercise can improve the cognitive function of patients with dementia [19–21], only one study has evaluated the effect of IMT on cognitive function [22]. Because FEV1 is associated with cognitive function, and RMT can improve FEV1 performance, RMT may improve cognitive function. However, whether RMT provides additional benefits for the cognitive function of patients with COPD whose MMSE scores are within the range of MCI remains unclear.

Because RMT is an important part of pulmonary rehabilitation, the aim of the current study investigated the improvement of cognition, lung function, clinical scores, and diaphragmatic muscle performance before and after the introduction of RMT in populations of COPD comorbid with mild cognitive impairment. In subgroup analysis, we want to compare the training efficacy between the full training group (EMT + IMT) and the single training group (IMT only) on cognition, lung function test, clinical scores, and diaphragmatic muscle performance. Finally, we will evaluate the RMT efficacy on patients with different severities of lung function impairment classified by the forced expiratory volume in one second (FEV1) level less than 30%.

#### **2. Materials and Methods**

#### *2.1. Participants*

Our study was a prospective study that was approved by the Institutional Review Board-I (107-A-09 Board Meeting) of Taichung Veterans General Hospital (protocol code: CF18259A; date of approval: 4 October 2018; clinical trial number: NCT04929990). Participants were recruited from the outpatient department of chest medicine in a tertiary referral center, and written informed consent was obtained from them or their authorized representatives before enrolment. Patients with the following criteria were enrolled: (1) a definitive diagnosis of COPD based on a FEV1/forced vital capacity (FVC) value of less than 0.7 at 10–15 min after short-acting beta-2 agonist (SABA) inhalation, and (2) an MMSE score between 23 and 27. The exclusion criteria were as follows: (1) being unable to follow RMT instructions or complete the questionnaires of our study due to cognitive impairment; (2) difficulty in completing cardiopulmonary exercise testing (CPET) or the 6 min walking test (6MWT) due to high-risk cardiopulmonary diseases or orthopedic conditions, such as critical aortic stenosis, early stage of post myocardial infarction, or lower limb amputation; (3) a diagnosis of lung cancer or a history of thoracoabdominal surgery; and (4) a body mass index (BMI) of ≥30.

#### *2.2. Protocol of Intervention*

After signing the informed consent form, the participants were assigned to the full RMT training group (EMT + IMT) or the single RMT training group (IMT only) through simple randomization (i.e., tossing a coin). Neither the participants nor the examiner were blinded. The patients enrolled into the current study performed both full RMT training or single RMT training using a threshold-type breathing trainer (Dofin DT11/14, Galemed, Taipei, Taiwan) at the hospital, and the RMT program included 30 breaths two times a day, 5 days a week, for a total of 8 weeks at home. IMT was performed after complete and slow air expiration, followed by quick and forceful air inspiration to overcome the threshold resistance of the device. By contrast, EMT was performed after complete and slow air inspiration, followed by quick and forceful air expiration. In the full RMT training group (IMT + EMT), before training, maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were measured using a digital pressure gauge (GB60, Jitto International, Taipei, Taiwan), and the best performance of the three trials was recorded. The procedure of MIP/MEP measurement resembled that of IMT/EMT training, except the breathing trainer was replaced with the digital pressure gauge. The initial intensity of training was set at 30% of MIP and MEP. The intensity was adjusted with the addition of 5% resistance each week, and a well-trained assistant contacted the participants telephonically to remind them to adjust the intensity every week.

In the simple RMT training group, only IMT was performed using the same type of Dofin DT11/14 breathing trainer. The initial resistance of the breathing trainer was set at 30% of MIP, and subsequent adjustments were made in accordance with the protocol of the experimental group. The participants were instructed to perform training for 30 breaths twice daily for 8 weeks at home, and they were also telephonically supervised by the same assistant every week.

#### *2.3. Parameter Measures*

Parameter measures in the current study were MMSE score; diaphragmatic thickness fraction and excursion examined through ultrasound; scores of the COPD assessment test (CAT) and modified Medical Research Council (mMRC) scale; percentage of predicted FVC, FEV1, FEV1/FVC, diffusing capacity of the lung for carbon monoxide (DLCO), and DLCO divided by alveolar volume (VA) examined using a pulmonary function test; dead space fraction (Vd/Vt) and minute ventilation to CO<sup>2</sup> output (VE/VCO2) slope examined using the cardiopulmonary exercise test (CPET); and distance walked and changes in oxygen saturation (SpO2) and perceived exertion (Borg scale) during six-minute walking test (6MWT). All these measures were assessed the day before the initiation of the RMT program and again 8 weeks later at the end of the program.

Diaphragmatic thickness fraction and excursion were measured using an ultrasound machine (Alpinion E-cube i7, who Medical Co., Ltd., Taipei, Taiwan). With the participant in the supine position, diaphragmatic thickness at the intercostal space between the 7th and 8th or the 8th and 9th ribs in the anterior axillary line was examined using a high-frequency ultrasound probe (10–15 MHz). The thickness of the diaphragmatic apposition zone was visualized below the intercostal muscles (Figure 1). The diaphragmatic thickness fraction was calculated as follows: (end-inspiration thickness—end-expiration thickness)/endexpiration thickness [23]. Diaphragmatic excursion was measured by placing a 2–6-MHz ultrasound probe at the right mid-clavicular line, and the amount of movement of the posterior edge of the liver was traced and measured using M mode ultra-sonography [24]. Limitations, such as the variations of probe tilting angle and the impact of the increased echogenicity of the liver, were considered in our study. The sonographic measurements were performed by one single examiner, which could reduce the inter-observer variability, and none of our participants' liver echogenicity was too high to clearly identify the posterior edge of liver.

CAT consists of eight questions, each scored from 0 to 5. mMRC only has one question, which is graded from 0 to 4. Both questionnaires are useful in discerning the respiratory difficulty encountered in daily life for patients with COPD, and in categorizing them for guiding treatment [25]. Regarding the assessment of dementia severity, the MMSE is one of the most widely adopted questionnaires in health care settings. The highest total score on the MMSE is 30, and a score of 23–27 indicates MCI [11], which was used in our study.

For patients with COPD, the pulmonary function test is crucial for grading disease severity, and predicting prognosis. In patients with FEV1/FVC < 0.7 [26], COPD severity

can be further categorized into four groups according to the extent to which FEV1 reaches the predicted level: <30%, 30–50%, 50–80%, and >80%. In addition to spirometry data, a diffusion study, including DLCO and DLCO/VA, was conducted using a pulmonary function measurement machine (Vmax Encore VS229, Carefusion Co., Ltd., San Diego, CA, USA). for guiding treatment [25]. Regarding the assessment of dementia severity, the MMSE is one of the most widely adopted questionnaires in health care settings. The highest total score on the MMSE is 30, and a score of 23–27 indicates MCI [11], which was used in our study.

*J. Pers. Med.* **2022**, *12*, x FOR PEER REVIEW 4 of 13

**Figure 1.** Participant recruitment flowchart: BMI: body mass index; CPET: cardiopulmonary exercise test; IMT: inspiratory muscle training; EMT: expiratory muscle training; 6MWT: six-minute walking test. **Figure 1.** Participant recruitment flowchart: BMI: body mass index; CPET: cardiopulmonary exercise test; IMT: inspiratory muscle training; EMT: expiratory muscle training; 6MWT: six-minute walking test.

For patients with COPD, the pulmonary function test is crucial for grading disease severity, and predicting prognosis. In patients with FEV1/FVC < 0.7 [26], COPD severity can be further categorized into four groups according to the extent to which FEV1 reaches the predicted level: <30%, 30–50%, 50–80%, and >80%. In addition to spirometry data, a diffusion study, including DLCO and DLCO/VA, was conducted using a pulmonary function measurement machine (Vmax Encore VS229, Carefusion Co., Ltd., San Diego, CA, USA). In patients with COPD, exercise performance and cardiopulmonary endurance frequently worsen as the disease progresses. Moreover, 6MWT involves walking as far as possible for 6 min, and is a common indicator of oxidative capacity in patients with cardiopulmonary diseases [27]. We established 6MWT distance by having our participants walk back and forth on a 30 m-long walkway with two cones placed at both ends, and we recorded changes in oxygen saturation and perceived exertion on the Borg scale during 6MWT. In addition, a cardiopulmonary exercise test can detect any gas exchange abnormalities during exercise in patients with COPD [28,29]. Patients with COPD have a higher In patients with COPD, exercise performance and cardiopulmonary endurance frequently worsen as the disease progresses. Moreover, 6MWT involves walking as far as possible for 6 min, and is a common indicator of oxidative capacity in patients with cardiopulmonary diseases [27]. We established 6MWT distance by having our participants walk back and forth on a 30 m-long walkway with two cones placed at both ends, and we recorded changes in oxygen saturation and perceived exertion on the Borg scale during 6MWT. In addition, a cardiopulmonary exercise test can detect any gas exchange abnormalities during exercise in patients with COPD [28,29]. Patients with COPD have a higher VE/VCO<sup>2</sup> slope [29] and Vd/Vt [28] during exercise. In this study, we measured these parameters during peak exercise. CPET was performed using an electro-magnetically braked cycle ergometer, and a mask was used to collect the partial pressure of O<sup>2</sup> and CO<sup>2</sup> simultaneously; a 10 W/min ramp protocol was used. All the testing procedures followed the guidelines of the American Heart Association [30].

#### VE/VCO2 slope [29] and Vd/Vt [28] during exercise. In this study, we measured these *2.4. Statistical Analysis*

parameters during peak exercise. CPET was performed using an electro-magnetically braked cycle ergometer, and a mask was used to collect the partial pressure of O2 and CO<sup>2</sup> simultaneously; a 10 W/min ramp protocol was used. All the testing procedures followed the guidelines of the American Heart Association [30]. *2.4. Statistical Analysis* SPSS 17.0 (IBM, Chicago, IL, USA) was used to perform the statistical analysis. Categorical variables were presented as frequency and percent, and analyzed using the chisquared test to determine significance. For nonparametric data distribution, differences between groups were assessed using the nonparametric Mann–Whitney U test or Wilcoxon signed ranks test. Results are presented as the mean and standard deviation (SD). To determine the sample size, we adopted G\*Power 3.1.9.7 (Heinrich-Heine-Universität Düsseldorf, Germany) to analyze improvements in the MMSE score after physical exercise SPSS 17.0 (IBM, Chicago, IL, USA) was used to perform the statistical analysis. Categorical variables were presented as frequency and percent, and analyzed using the chi-squared test to determine significance. For nonparametric data distribution, differences between groups were assessed using the nonparametric Mann–Whitney U test or Wilcoxon signed ranks test. Results are presented as the mean and standard deviation (SD). To determine the sample size, we adopted G\*Power 3.1.9.7 (Heinrich-Heine-Universität Düsseldorf, Germany) to analyze improvements in the MMSE score after physical exercise training, as described previously [21]. With a difference in the improvement of MMSE between 2.67 ± 1.88 and 0.2 ± 2.87 under the setting of α = 0.05 and power –1 − β) = 0.8, the effect size was 1.018, and at least 36 cases were deemed necessary to achieve sufficient statistical power. All tests were two-sided, with *p* < 0.05 considered significant.

#### **3. Results**

#### *3.1. Patients' Clinical and Demographic Characteristics*

From June 2019 to February 2021, a total of 70 patients were enrolled into the study, and 49 participants completed the 8-week course of the RMT program for the final analysis. Because there was only one female patient, the study also excluded her data to reduce the effect of gender difference. Table 1 presents a summary of the demographic characteristics, and clinical and physiological parameters of all participants. Among them, 29 and 20 participants were included in the full RMT training group (IMT + EMT) and the single training group (IMT only), respectively. Figure 1 presents the flowchart of participant recruitment and the case numbers in the subgroup of RMT training. Classified by the FEV1 level, 28.6% of participants were <30% (*n* = 14), and 71.4% of patients were ≥30% (*n* = 35).


**Table 1.** Demographic characteristics, and clinical and physiological parameters in patients with COPD enrolled into respiratory muscle training program (*n* = 48).

IMT, inspiratory muscle training; EMT, expiratory muscle training; CAT, chronic obstructive pulmonary disease assessment test; mMRC, modified Medical Research Council; 6MWT, 6-min walking test; Vd/Vt, dead space fraction; VE/VCO2, minute ventilation to CO<sup>2</sup> output; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; DLCO, diffusing capacity of the lung for carbon monoxide; VA, alveolar volume; MMSE, Mini-Mental State Examination.

#### *3.2. Differences between before and after RMT Program*

Before and after RMT were compared with respect to all parameters (Table 2). After RMT, patients exhibited significant improvements in FEV1 (%), CAT score, mMRC score, MMSE score, MIP (cmH2O), MEP (cmH2O), SpO<sup>2</sup> at rest (%), diaphragmatic thickness fraction, and diaphragmatic excursion (all *p* < 0.01). In addition, the Borg scale after 6MWT was significantly decreased after the RMT program (*p* = 0.016). No significant differences were observed in DLCO (%), 6MWT distance (m), and CPET test after RMT program (all *p* > 0.05).


**Table 2.** Comparison of the difference of parameters between before and after RMT program implementation.

CAT, chronic obstructive pulmonary disease assessment test; DLCO, diffusing capacity of the lung for carbon monoxide; EMT, expiratory muscle training; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; IMT, inspiratory muscle training; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; mMRC, modified Medical Research Council; MMSE, Mini-Mental State Examination; 6MWT, 6-min walking test; SpO2, oxygen saturation; Vd/Vt, dead space fraction; VE/VCO2, minute ventilation to CO<sup>2</sup> output; VA, alveolar volume; \* *p* < 0.05, \*\* *p* < 0.01.

#### *3.3. Differences between the Full RMT Training and Single RMT Training Group*

The characteristics of the full RMT training and single RMT training groups were compared (Table 3). After 8 weeks, both groups exhibited increases in lung function, MIP, diaphragmatic excursion, and thickness fraction (Figure 2). However, the between-group difference in the full training (IMT + EMT) and single training (IMT only) groups was not significant in all parameters listed in Table 3. *J. Pers. Med.* **2022**, *12*, x FOR PEER REVIEW 7 of 13

**Figure 2.** Ultrasonographic evaluation of diaphragm. (**A**) Diaphragmatic thickness was measured below the intercostal muscles between the ribs. +:Markers of the anterior and posterior edges of diaphragm. (**B**) Amount of diaphragmatic excursion was measured using the M mode to trace the movement of the posterior edge of liver. +:Markers of the posterior edge of liver during respiration. **Figure 2.** Ultrasonographic evaluation of diaphragm. (**A**) Diaphragmatic thickness was measured below the intercostal muscles between the ribs. +: Markers of the anterior and posterior edges of diaphragm. (**B**) Amount of diaphragmatic excursion was measured using the M mode to trace the movement of the posterior edge of liver. +: Markers of the posterior edge of liver during respiration.

(IMT + EMT) in patients with COPD after RMT program implementation.

**Table 3.** The differences between the single training group (IMT only) and the full training group

FVC (%) 83.11 ± 19.54 80.86 ± 19.20 0.722 FEV1 (%) 46.32 ± 16.93 41.43 ± 14.56 0.371 FEV1/FVC (%) 43.55 ± 18.88 40.24 ± 12.72 0.386 DLCO (%) 80.00 ± 27.95 72.29 ± 15.13 0.624 DLCO/VA 90.00 ± 28.66 83.36 ± 25.68 0.711

CAT score 7.75 ± 4.46 10.00 ± 6.91 0.396 mMRC score 1.20 ± 0.62 1.07 ± 0.72 0.667 MMSE 25.78 ± 5.47 26.14 ± 3.23 0.585 MIP (cmH2O) 75.25 ± 38.30 83.82 ± 37.69 0.714 MEP (cmH2O) 99.81 ± 34.57 ---

6MWT distance (m) 321.75 ± 73.09 351.92 ± 63.83 0.166 SpO<sup>2</sup> at rest (%) 95.95 ± 2.67 96.16 ± 3.45 0.289 Nadir SpO<sup>2</sup> in 6MWT 92.25 ± 4.89 92.72 ± 4.93 0.680 SpO<sup>2</sup> change in 6MWT 3.70 ± 3.15 3.44 ± 3.88 0.549 Borg scale at rest 0.95 ± 0.89 0.64 ± 0.95 0.160 Borg scale after 6MWT 2.30 ± 1.98 2.60 ± 1.80 0.523 Borg scale change in 6MWT 1.35 ± 1.63 1.96 ± 1.43 0.076

Diaphragmatic thickness fraction 50.74 ± 28.74 60.44 ± 27.55 0.098 Diaphragmatic excursion (cm) 4.00 ± 1.17 3.72 ± 1.40 0.523

*3.4. Differences of RMT Training Effect between FEV1 < 30% and FEV1 ≥ 30% among Patients* 

The subgroup analysis of the RMT training effect between different severities of FEV1 in patients with COPD was compared (Table 4). After 8 weeks, both groups exhibited increases in FVC (%), FEV1 (%), and the distance of 6MWT; and decreases in CAT

Vd/Vt 31.70 ± 8.52 33.96 ± 4.40 0.230 VE/VCO<sup>2</sup> slope 36.21 ± 5.75 36.75 ± 5.62 0.991

**IMT Only (***n* **= 20) IMT + EMT (***n* **= 28)** *p* **Value**

Clinical score

6MWT

Sonography evaluation

CPET

Mann–Whitney U test.

*with COPD*


**Table 3.** The differences between the single training group (IMT only) and the full training group (IMT + EMT) in patients with COPD after RMT program implementation. *J. Pers. Med.* **2022**, *12*, x FOR PEER REVIEW 8 of 13

*3.4. Differences of RMT Training Effect between FEV1 < 30% and FEV1* ≥ *30% among Patients with COPD* ΔBorg scale after 6MWT −0.71 ± 1.70 −0.69 ± 1.71 0.922 Sonography evaluation ΔDiaphragmatic thickness fraction −6.84 ± 56.35 26.84 ± 28.55 0.048 \*

The subgroup analysis of the RMT training effect between different severities of FEV1 in patients with COPD was compared (Table 4). After 8 weeks, both groups exhibited increases in FVC (%), FEV1 (%), and the distance of 6MWT; and decreases in CAT score, mMRC score, and Borg scale sore (Table 4). In addition, cognitive function in terms of the MMSE score improved in both groups. However, only diaphragmatic thickness fraction exhibited significant between-group differences in improvement (*p* = 0.044) (Figure 3). ΔDiaphragmatic excursion (cm) 1.09 ± 1.50 0.73 ± 1.14 0.734 CPET ΔVd/Vt 0.46 ± 5.92 0.02 ± 4.94 0.565 ΔVE/VCO2 slope −0.38 ± 3.71 −0.01 ± 5.18 0.678 Mann–Whitney U test. \* *p* < 0.05, Δ: value of parameter after training—value of parameter before training.

**Figure 3***.* Difference of diaphragmatic thickness fraction before and after RMT*.* \* *p* < 0.05. **4. Discussion Figure 3.** Difference of diaphragmatic thickness fraction before and after RMT. \* *<sup>p</sup>* < 0.05.


**Table 4.** Comparison of the RMT training effect between FEV1 < 30% and FEV1 ≥ 30% in patients with COPD.

Mann–Whitney U test. \* *p* < 0.05, ∆: value of parameter after training—value of parameter before training.

#### **4. Discussion**

This study yielded three major findings. First, the results of our study indicated that RMT, both in the full training group (IMT + EMT) and simple training group (only IMT), could significantly improve not only cognition, but also inspiratory strength, diaphragmatic performance, FEV1, and dyspnea scores in the patients with COPD comorbid with mild cognitive impairment. Second, we observed that even with a baseline FEV1 of <30%, benefits could be derived from RMT in terms of the outcome measures. Third, we found that patients with preserved lung function (FEV1 ≥ 30%) significantly increased in diaphragmatic thickness fraction after RMT training. The strength of current study is that it is the first to use not only clinical score and lung function test, but also apply both diaphragmatic ultrasonography and the cardiopulmonary exercise test to evaluate the effect of RMT. To the best of our knowledge, this is the first study to evaluate the different RMT training models and the impact of RMT in different severities of patients with COPD.

IMT was necessary in both full and simple RMT training groups in the current study, and the FEV1 was improved after RMT training. Several studies have demonstrated that IMT can elevate FEV1 [31–34] due to the improvement in trunk control, with more favorable respiratory biomechanics [35]. In addition, IMT can improve cognitive function, as reported in a previous study [22]. Many studies have demonstrated the relationship between hypoxemia and cognitive impairment [36,37]; however, we cannot conclude that the cognition improvement of our patients was due to the increase of resting SpO2. That is because the level of SpO<sup>2</sup> in our participants never reached the threshold level of hypoxemia. Since FEV1 level was positively correlated with cognitive function [16], we suggest that the cognition improvement of this cohort was due to the increase in FEV1 rather than the increase of resting SpO<sup>2</sup> after RMT implementation. However, the underlying mechanism requires further study.

Our study revealed that RMT implementation, both in the simple and full training group, improved not only cognition, and FEV1 and SpO<sup>2</sup> at rest, but also MIP, diaphragmatic thickness fraction, diaphragmatic excursion, and CAT and mMRC scores. The results

are consistent with those of previous studies [9,38,39]. Weiner et al. reported that dyspnea was alleviated in IMT-only and IMT + EMT groups, but not in the EMT-only group [38]. Weiner and McConnell concluded that no additional benefit was obtained by adding EMT to IMT [39]. Xu et al. revealed improved scores of mMRC, CAT, and St George's Respiratory Questionnaire in both IMT and IMT + EMT groups, with no significant between-group differences [9]. One important reason is that expiration is predominantly accomplished by elastic recoil instead of active muscle contraction, and therefore, the improvement of inspiratory capacity can also facilitate the performance of expiration. On the contrary, the improvement of expiratory strength may not be so practical in daily respiration, and thus, the indicators of life quality, such as CAT and mMRC scores, cannot be further improved through EMT. Our results also showed that the between-group difference in the full training (IMT + EMT) and single training (IMT only) groups was not significant in all parameters. In addition, our study further provided the image evidence of ultrasonography in diaphragmatic excursion and thickness fraction to support the viewpoint that IMT is the most important part of RMT.

In the current study, the VE/VCO<sup>2</sup> slope and Vd/Vt during peak exercise did not significantly change after the training program in either group. The VE/VCO<sup>2</sup> slope, also known as exercise ventilatory efficiency, is an essential prognostic factor in COPD. Vd/Vt, also called the dead space fraction, is considered a comprehensive marker of gas exchange in patients with COPD [40]. RMT cannot enhance ventilator efficiency, and the dead space fraction is probably because RMT can only improve respiratory muscle strength, and not alveolar function of gas exchange.

Most of the previous studies recruited patients with higher FEV1, as easy fatigue during training and poor compliance of training protocol are more common in patients with FEV1 < 30% [41–43]. However, the subgroup analysis of the current study revealed no significant between-group difference exhibited in patients with FEV1 < 30% and ≥30%. A study compared the effect of IMT between patients with baseline FEV1 < 50% and ≥50%, and revealed that patients with poor lung function (FEV1 < 50%) demonstrated significant improvement in the sensation of dyspnea after 3 weeks of respiratory training [44]. In our study, we found that the decreases of CAT score and mMRC score were larger in patients with FEV1 < 30%, although it did not reach the statistical difference, which may owe to the small case numbers in the FEV1 < 30% group. A recent meta-analysis demonstrated the benefit of IMT in improving COPD parameters; the authors reported that a shorter intervention time (≤4 weeks) improved MIP only, and a longer training period (6–8 weeks) also improved functional capacity, such as 6MWT distance [45]. Although the training period of our study was up to 8 weeks, no significant change was found in the 6MWT distance. One primary reason for this may be that our participants' MMSE scores were in the range of MCI, which may affect their ability to achieve full exertion during 6MWT. On the other hand, 6MWT distance reflects cardiopulmonary aerobic capacity, which could be improved only after aerobic exercise training theoretically. RMT, which is a form of strength training, can produce little effect on aerobic capacity. Therefore, inconsistent results were also mentioned in the past meta-analysis regarding the effect of RMT on 6MWT distance [45]. Further studies may be required to elucidate it.

A major strength of our study is that we incorporated the result of diaphragmatic ultrasonography to validate improvements in MIP and MEP. Furthermore, parameters including the VE/VCO<sup>2</sup> slope and Vd/Vt obtained in CPET were analyzed to determine the reason for the change. However, our study has some limitations. First, although the total number of participants was as per the required sample size for this study, only 14 patients had a baseline FEV1 < 30%, which may have been too few to achieve sufficient statistical power. The data of the improvement of diaphragmatic thickness fraction from two patients with FEV1 < 30% even became outliers. The data of the improvement of diaphragmatic thickness fraction from two patients with FEV1 < 30% even became outliers. Future studies should include more patients with COPD and a baseline FEV1 < 30% to validate our findings. Second, MMSE has limited sensitivity and specificity for diagnosing

MCI against healthy controls [46]. Our participants only had MCI according to MMSE scores, but they did not have a confirmed diagnosis of MCI. Third, our participants had MMSE scores suggestive of MCI, which may have affected their compliance with the RMT program at home, despite us having assigned an assistant to contact and encourage the participants every week via telephone. Finally, we excluded those with BMI ≥ 30 to improve the reliability of ultrasonographic results, and none of our participants were female. Therefore, our results may only be applicable to male and non-obese patients with COPD.

### **5. Conclusions**

Our study results revealed that the 8-week RMT program improved not only cognitive function, but also CAT score, mMRC score, and diaphragmatic thickness in male and non-obese patients with COPD comorbid mild cognitive impairment. In addition, we found that IMT is the most important part of RMT, as the combination of EMT with IMT was not superior to IMT alone. Furthermore, even patients with a baseline FEV1 of <30% derive benefits from RMT. Patients with preserved lung function (FEV1 ≥ 30%) significantly increased in diaphragmatic thickness fraction after RMT training. We suggest that patients with COPD should start to receive IMT earlier in their disease course to increase their respiratory strength, and thus, achieve a high quality of life.

**Author Contributions:** Conceptualization, Y.-Y.C., S.-Y.L., C.-Y.H. and P.-K.F.; data curation, Y.-Y.C. and P.-K.F.; formal analysis, Y.-Y.C. and C.-Y.H.; funding acquisition, P.-K.F.; investigation, Y.-Y.C. and P.-K.F.; writing—original draft, Y.-Y.C. and P.-K.F.; writing—review and editing, Y.-Y.C., S.-Y.L., C.-Y.H. and P.-K.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** The authors sincerely appreciate funding in part by the Department of Medical Research of Taichung Veterans General Hospital (TCVGH-1104401B) and the Ministry of Science and Technology (Taiwan) (MOST109-2410-H-075A-001-SSS; MOST 110-2410-H-075A-001& MOST-1102622H075A001) for the supporting of study manpower, materials, and the publication fees in the open access journal.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Taichung Veterans General Hospital (IRB number: CF18259A, date of approval, 4 October 2018; clinical trial number: NCT04929990).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the regulation of the Institutional Review Board of Taichung Veterans General Hospital in Taiwan.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**


### *Review* **Elements of Sleep Breathing and Sleep-Deprivation Physiology in the Context of Athletic Performance**

**Dimitra D. Papanikolaou <sup>1</sup> , Kyriaki Astara 1,2, George D. Vavougios 1,3 , Zoe Daniil <sup>1</sup> , Konstantinos I. Gourgoulianis <sup>1</sup> and Vasileios T. Stavrou 1,\***


**Abstract:** This review summarizes sleep deprivation, breathing regulation during sleep, and the outcomes of its destabilization. Breathing as an automatically regulated task consists of different basic anatomic and physiological parts. As the human body goes through the different stages of sleep, physiological changes in the breathing mechanism are present. Sleep disorders, such as obstructive sleep apnea-hypopnea syndrome, are often associated with sleep-disordered breathing and sleep deprivation. Hypoxia and hypercapnia coexist with lack of sleep and undermine multiple functions of the body (e.g., cardiovascular system, cognition, immunity). Among the general population, athletes suffer from these consequences more during their performance. This concept supports the beneficial restorative effects of a good sleeping pattern.

**Keywords:** sleep deprivation; exercise; cardiovascular; cognitive

**Citation:** Papanikolaou, D.D.; Astara, K.; Vavougios, G.D.; Daniil, Z.; Gourgoulianis, K.I.; Stavrou, V.T. Elements of Sleep Breathing and Sleep-Deprivation Physiology in the Context of Athletic Performance. *J. Pers. Med.* **2022**, *12*, 383. https:// doi.org/10.3390/jpm12030383

Academic Editor: Kentaro Inamura

Received: 28 January 2022 Accepted: 1 March 2022 Published: 2 March 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Sleep-Disordered Breathing Physiology**

#### *1.1. Respiratory Aspect*

The mechanism of breathing includes air flow through the passages of the respiratory system due to pressure gradients that are formed by contraction of the diaphragm and the thoracic muscles. Air flows from a region of higher pressure to a region of lower pressure. Respiration involves the interplay between three different pressures: the atmospheric, the interalveolar, and the intrapleural pressure. Inspiration is the active phase of respiration and the result of muscle contraction, and expiration is the passive phase in calm state. Regulation of respiratory system is subconscious and determines rhythmic rotation between inspiration and expiration and ventilation (breathing frequency and depth) [1].

Sleep state is associated with significant changes in respiratory physiology, including ventilatory responses to hypoxia and hypercapnia, upper airway, and intercostal muscle tone, and tidal volume and minute ventilation. These changes are further magnified in certain disease states, such as chronic obstructive pulmonary disease, restrictive respiratory disorders, neuromuscular conditions, and cardiac diseases [2]. Sleep-disordered breathing (SDB), which causes sleep deprivation and intermittent hypoxia, encompasses a broad spectrum of sleep-related breathing disorders, including obstructive sleep apnea (OSA), central sleep apnea (CSA), as well as sleep-related hypoventilation and hypoxemia. Relative hypotonia of respiratory muscles, body posture changes, and altered ventilatory control result in additional physiologic changes contributing to hypoventilation [3]. Hypercapnia, hypoxemia, and negative intrathoracic pressure swings lead to increased sympathetic response in order to maintain the normal air flow followed by hyperventilation.

#### *1.2. Neural Aspect*

Breathing is an automatic function and is regulated, according to the metabolic demands, by the autonomic nervous system (ANS) and, more specifically, by the respiratory center (RC), a central pattern generator (CPG) located in medulla oblongata along with the other vital reflexes. Cortical–medullary circuits furthermore guarantee that voluntary control of breathing is possible [4]. Upon loss of cortical functions without the loss of the medullary CPG, however, control is maintained by the latter.

#### *1.3. Input Sensors*

Wakefulness, non-rapid eye-movement sleep (NREM), and rapid eye-movement sleep (REM) sleep represent three distinct states during the sleep–wake cycle [5]. Breathing is maintained during sleep, but its regulation differs from wakefulness [6]. The progression through sleep stages is accompanied by a sequence of physiological changes based on chemoreceptor and baroreceptor reflexes [7]. Chemoreceptors are divided into peripheral and central. Chemoreflex input consist of peripheral (carotid and aortic bodies), which reflect the concentrations of arterial O2, and of central receptors, which are sensitive to CO<sup>2</sup> and H<sup>+</sup> changes in the CSF [8]. Consequently, the ventilatory feedback control system of the chemoreflex is vulnerable to rapid fluctuations of this input, similar to those that occur during NREM sleep [9].

Two additional respiratory control centers exist in the medulla: the vasomotor (VMC) that regulates blood pressure and the cardiac center (cardioinhibitory and cardioacceleratory centers) for the regulation of heart rate. The three centers are interconnected to function coordinately for the release not only of the chemoreflex but also for the baroreflex [10]. The baroreceptor reflex is activated when blood pressure is found increased by the baroreceptors in walls of carotid internal artery and of aorta and vasodilation occurs (inhibition of VMC) as well as decreased heart rate (stimulation of cardioinhibitory centers).

In sleep-disordered breathing, the circle of intermittent hypoxia–hypercapnia stimulates chemoreflex entirely, which in turn overstimulates SNS, attenuates baroreflex, and enhances hyperventilation after arousal [11]. Arousal occurs in order to increase the muscle tone and compensate for hypoventilation. Interestingly, the increased tone of SNS persists during daytime, too. As baroreflex is desensitized, the PNS is incapable of antagonizing the detrimental effects of SNS overstimulation, demonstrating mainly hypertension and tachycardia.

#### *1.4. Output Mediators*

The mutable environment of respiratory regulation during sleep affects multiple systems and structures: the ANS as well as lungs, chest wall, and upper airway [12]. During wakefulness and REM, sympathetic tone is dominant, whereas during NREM sleep, parasympathetic tone prevails to create a state of reduced activity [13]. Therefore, blood pressure and heart rate are reduced during NREM, whereas in REM sleep, the pulses of sympathetic activity induce tachycardia and relatively increase blood pressure [14].

During sleep, ventilation and functional residual capacity decrease slightly [15]. In stage I of NREM sleep, sufficient muscle tone is maintained, and frequent body posture changes occur. Respiratory pattern is more regular, while minute ventilation is progressively reduced, resulting in an increase of end-tidal carbon dioxide (ETCO2) compared to a waking state. During REM, respiratory pattern varies while ventilation further drops, accompanied by a slight reduction in oxygen saturation [16].

These fluctuations of arterial blood pressure, heart rate, and respiration occur in NREM and REM sleep and during transitions between sleep and arousal [17]; they may explain the sensitivity differences in hypoxia–hypercapnia, a major pathophysiologic element in sleepdisordered breathing [5]. Pulmonary stretch receptors work in coordination with central and peripheral chemoreceptors as the corresponding reflexes affect upper airway and respiratory pump muscles. The relationship is displayed in detail in Figure 1. A reduction in respiratory muscle tone occurs during NREM sleep but is more prominent during

REM [18], attenuating the occlusion pressure responses to both hypoxia and hypercapnia in REM sleep stage, a clinical phenomenon consistent with emerging even in normal people [19]. In this context, arousals emerge, fragmenting sleep architecture. A protective reflex is activated by local upper airway (UA) mechanoreceptors due to the negative pressure in the UA, preventing its collapse by enhancing activity of UA dilators [20]. This reflex re-establishes ventilation in an alternative-to-arousal manner.

**Figure 1.** All the reflexes that take part in the control of respiratory rate during sleep. As inspiration occurs, upper airway muscles are activated by the mechanoreceptors, resulting in a protective reflex that prevents occlusion of airflow without arousals. However, inspiratory activation may become insufficient in terms of timing and magnitude due to stronger activation of respiratory pump muscles that lead to inadequate compensation for the airway-collapsing effect of negative inspiratory pressure.

#### **2. Sleep Deprivation**

Sleep-disordered breathing is associated with sleep deprivation. This sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive decline in attention, memory, and decision making [21]. Sleep-disordered breathing is common among overweight and obese children. It is a risk factor for several health complications, including cardiovascular disease. Inflammatory processes leading to endothelial dysfunction are a possible mechanism linking SDB and cardiovascular disease [22,23].

### *2.1. Sleep Deprivation and CO<sup>2</sup> Retention*

Disordered breathing is commonly associated with hypercapnia, which is followed by sufficient CO<sup>2</sup> retention. This phenomenon leads to various impairments due to dangerous levels of hypercapnia. Acute responses to CO<sup>2</sup> affect breathing primarily via central chemoreceptors [24]. Retention of CO<sup>2</sup> not only contributes to chemoreflex via hypercapnia and acidosis but also serves as a powerful stimulus to increase respiration. Hypoxia potentiates the effects of CO2, resulting in a stronger ventilatory response. Through various mechanisms, retention of CO<sup>2</sup> can persist during daytime, too [25].

Carbon dioxide retention is related to oxidative stress and increased sympathetic activity with subsequent effects, such as hypertension. Recent evidence has now implicated a role for oxidative stress in sleep and sleep loss [26]. Oxidative stress is defined by increased oxygen reactive species (ROS) production and inability of the cell to alienate them. Prolonged wakefulness/sleep deprivation activates an adaptive stress pathway termed the unfolded protein response, which temporarily guards against the deleterious consequences of reactive oxygen species [24,26]. The elevated sympathetic response also triggers a generalized inflammatory cascade that is associated with the pathophysiology of multiple comorbidities, including insulin resistance, hypertension, diabetes, atherosclerosis, and metabolic syndrome [27]. Epidemiologic studies in adults and children and laboratory studies in young adults indicate that sleep deprivation may be associated with several relevant impairments: decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite (Table 1). Nevertheless, the current epidemic of obesity could be partly attenuated by better sleep regulation [28]. In healthy adults who are chronically sleep restricted, a simple, low-cost intervention, such as sleep extension, is feasible and is associated with improvements in fasting insulin sensitivity [29]. In the matter of inflammatory system, sleep loss triggers signaling pathways in the brain and periphery. The Toll-like receptor 4 (TLR4) activates inflammatory signaling cascades in response to endogenous and pathogen-associated ligands known to be elevated in association with sleep deprivation. TLR4 is therefore a possible mediator of some of the inflammationrelated effects of sleep loss [30]. Furthermore, total sleep loss produces significant increases in plasma levels of sTNF-alpha receptor I and IL-6, messengers that connect the nervous, endocrine, and immune systems [31].

**Table 1.** Responses and sleep deprivation.


ESS, Epworth Sleepiness Scale; F, female; fMRI, functional magnetic resonance imaging; M, male; *n*, number; N2, nitrogen; O2, oxygen; OSAHS, obstructive sleep apnea–hypopnea syndrome; OSAS, obstructive sleep apnea syndrome; PSG, polysomnography study; RW, rested wakefulness; TSD, total sleep deprivation.

#### *2.2. Sleep Deprivation and Exercise: Cognitive Implications*

A sleep-deprived brain fails to recuperate neurons, undermining cognitive performance. General cognitive assessment tests unveil the cognitive phenotype of SD, especially in attention and short-term memory, as they anatomically overlap [36,37]. Furthermore, SD, in the context of sleep apnea, affects learning and memory [38,39] (Table 1). Furthermore, other daytime consequences, such as excessive sleepiness and fatigue, coexist and interact with cognitive impairment [40]. These are linked with various effects on exercise, including athletic performance, reaction time, accuracy, strength and endurance [41]. Alertness, judgment, and decision making suffer due to SD, shifting motivational behaviors towards sleep-promoting goals [42,43].

Sleep deprivation of 30 to 72 h consecutively does not affect cardiovascular and respiratory responses to exercise of varying intensity or the aerobic and anaerobic performance capability of individuals. Muscle strength and electromechanical responses are also not affected. Time to exhaustion, however, is decreased by sleep deprivation [44]. Research indicates that some maximal physical efforts and gross motor performances can be maintained. Effects on cognitive function consist of slower and less accurate cognitive performance. Reduction in sleep quality and quantity could result in an autonomic nervous system imbalance, simulating symptoms of the overtraining syndrome [45]. The integrity of sleep architecture seems to determine subjective sleep quality and waking performance. The effects of insufficient sleep primarily concern subjective and objective sleepiness as well as attention, whereas performance on higher cognitive functions appears to be better preserved albeit at the cost of increased effort [46]. All in all, sleep deprivation induces a vulnerability in various domains of cognition, leading to overall suboptimal performance.

This vulnerability to cognitive impairment due to sleep deprivation is conjoined with mood disorders and particularly symptom severity [47]. Emotional information is misinterpreted, making sleep-deprived subjects prone to anxiety [48] and depressive symptoms [49] as well as altered reward-seeking and impulsive behaviors [50]. Stress is one of the main factors influencing sleep. Hyperarousal is a key component in all modern etiological models of insomnia disorder. Overactive neurobiological and psychological systems contribute to sleep onset disorders. Sleep reactivity is the degree to which stress disrupts sleep, manifesting as difficulty falling and staying asleep. Individuals with highly reactive sleep systems experience drastic deterioration of sleep when stressed, whereas those with low sleep reactivity proceed largely unperturbed during stress. Research points to genetics, family history of insomnia, gender, and environmental stress as factors that influence sleep reactivity. High sleep reactivity is also linked to risk of shift-work disorder, depression, and anxiety [51–53] (Figure 2).

**Figure 2.** Sleep deprivation on general population.

Exercise could improve to one extent cognitive performance. High-intensity resistance training has shown to enhance memory and critical thinking while ameliorating the symptomatology of mood disorders [54]. Concomitantly, aerobic exercise prevented further cognitive deterioration in cases of mild cognitive impairment [55]. The advancement in understanding and implementing exercise in patients with underlying pathology has supplemented training programs for professional athletes with techniques to reinforce cognitive performance along with athletic [56]. Due to the great variety of sports, there are different requirements that presuppose the existence of individualized programs. Therefore, future studies could focus on specific groups of athletes and highlight personalized programs centered on sleep hygiene.

#### *2.3. Sleep Deprivation and Exercise: Cardiovascular Implications—The Example of Sleep Apnea*

Recent epidemiological studies have revealed relationships between sleep deprivation and hypertension, coronary heart disease, and diabetes mellitus due to increased activity of sympathetic system [57,58]. Obstructive sleep apnea–hypopnoea syndrome (OSAHS) is associated with increased cardiovascular morbidity and mortality. Subjects with OSAHS and no known cardiovascular disease had increased arterial stiffness and impaired endothelial function compared to controls [34] (Table 1). A brief, mild hypercapnic exposure increases vascular resistance in the renal and segmental arteries [32]. Sleep-disordered breathing, short sleep time, and low sleep quality are frequently reported by patients with heart failure (HF). Sleep-disordered breathing, which includes OSA and CSA, is common in patients with HF and has been suggested to increase the morbidity and mortality in these patients. Both OSA and CSA are associated with increased sympathetic activation, vagal withdrawal, altered hemodynamic loading conditions, and hypoxemia [59].

There are several parameters that describe the mechanism that leads to increased risk of cardiovascular impairment. Sleep-disordered breathing, such as in OSA, activates the sympathetic system and contributes to systemic inflammation, metabolic dysregulation, vascular endothelial dysfunction, and uncoupling of myocardial workload [5,7]. Moreover, high blood pressure and increased heart rate combined with increased oxygen demand, accompanying hypertension and dyslipidemia, lead to variety of cardiovascular diseases, such as atherosclerosis and even heart failure [5,7]. Chronic sleep deprivation is associated with increased risk of cardiometabolic disease (Figure 2). Laboratory studies demonstrate that sleep deprivation causes impaired whole-body insulin sensitivity and glucose disposal. Evidence suggests that inadequate sleep also impairs adipose tissue insulin sensitivity and the NEFA rebound during intravenous glucose-tolerance tests [60]. In addition, muscle recovery is hindered when athletes are sleep deprived through inflammatory exacerbation [61].

In conclusion, potential mechanisms of influence on quality and quantity of sleep may allow scientists to positively influence sleep in athletes and maximize their performance and health [41]. Exercise itself may result in a fundamental therapeutic approach, as preliminary data have shown that it restabilizes sleep architecture and quality [62]. In fact, some novel therapeutic strategies have emerged related to inspiratory muscle training. Inspiratory muscle strength training (IMT) has shown promising results in managing both sleep apneas and arterial hypertension [63,64]. Assessing and training inspiratory strength in athletes could prove beneficial in counteracting the detrimental effects of the aforementioned sleep disturbances [65].

#### *2.4. Sleep Deprivation and Performance*

Sleep optimization via sleep extension has been shown to enhance athletic performance and provide increased benefits regarding aerobic function and metabolism [66]. Beneficial effects attributed to longer sleep periods have also been observed in basketball [67], handball [68], and rugby players [69], among others. Aside from general aspects of health and performance, sleep optimization has shown to improve specific aspects of the athlete's performance, i.e., serve accuracy in tennis and stroke performance in swimming [42], as well as cognitive aspects [70], with a high dependency on the quality of sleep and its architecture [71]. Notably, sleep extension may be achieved by supplementing sleep with fixed naps, shown to significantly diminish sleep inertia and promote overall better performance [72].

Conversely, diminished sleep may be detrimental not only performance-wise but as a contributor to training and performance-related injuries [73]. A study in elite female football athletes has shown that there is significant inter-individual variability, and hence, personalized approaches in promoting sleep health should be adopted [74]. The latter concept can be generalized in several sports and with expert recommendations clearly advocating a case-based approach to sleep optimization [75].

#### **3. Beneficial Sleep Effects**

Sleep, in particular slow-wave sleep, is a restorative state that enables recovery from prior wakefulness and fatigue by repairing processes and repleting energy [76]. Sleep has also been shown to have a restorative effect on the immune system and the endocrine system, facilitate the recovery of the nervous system and metabolic cost of the waking state, and play an integral role in learning, memory and synaptic plasticity, all of which can impact both athletic recovery and performance [77]. Adequate sleep duration and consistency with its internal organization, namely four to ix NREM/REM cycles, each lasting approximately 90 to 110 min [78], as well as quality may be important for preventing cardiovascular diseases in modern society [58]. Even midday, short-term breaks of napping have been proved to be as valuable as extending nighttime sleep [79], in particular when combined with exercise [80]. Wakefulness results in an oxidative burden, and sleep provides a protective mechanism against these harmful effects [26].

#### **4. Conclusions**

Optimal sleep extends its benefits to all systems, exerting its main effect on cognition and the cardiovascular and respiratory system. Adequate sleep quality and quantity consist of the two components crucial for the effective human function and restitution. Conversely, sleep deprivation undermines these effects with significant declines in cognitive tasks and hindered cardiovascular adaptability and responses. It is possible that an extension of sleep duration could prevent these detrimental effects and enhance its efficient role.

**Author Contributions:** D.D.P., K.A., G.D.V., Z.D., K.I.G. and V.T.S. conceived and designed the review and wrote and edited the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data are available after request.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

