Head down tilt (HDT) reduces intracranial perfusion and leads to jugular vein congestion (Marshall-Goebel et al., 2016; Kramer et al., 2017). Moreover, an increased intracranial pressure is a consequence of HDT (Lawley et al., 2017). Xie et al. (2013) have demonstrated that sleep, among other factors, is vital for cranial fluid exchange and metabolic clearance of by-products via the “glymphatic” system. Transport via the “glymphatic” system is also dependent on body position (Lee et al., 2015). Yet one of the major drivers for intracranial fluid regulation is respiration (Dreha-Kulaczewski et al., 2015; Delaidelli and Moiraghi, 2017). Body position, altered respiration and the accompanying changed intracranial fluid dynamics are likely to affect sleep at HDT.

Of note, HDT is also used as a ground-based model of spaceflight (Kakurin et al., 1976; Pavy-Le Traon et al., 2007). Fluid shifts in the direction of the head and venous congestion in particular are salient effects of both spaceflight and HDT.

Sleep is often disturbed in astronauts. Reduced sleep quality is frequently ascribed to the “multistressor environment” onboard the space station, comprising challenges by noise, workload, lighting, sleep shifting and hypercapnia. All these factors combined eventually result in deteriorated sleep quality and quantity. A daily sleep period of a sufficient time (8.5 h) is set during missions. However, astronauts reported an actual sleep duration of only about three quarters of the available sleeping time (Dinges et al., 2013). Sleep duration is further reduced during periods of circadian misalignment (Flynn-Evans et al., 2016). The shortened and disturbed sleep during shuttle flights and on the International Space Station (Dijk et al., 2001; Whitmire et al., 2009) is changed to an extent that has detrimental effects on cumulative sleep duration and performance in Earth-based studies (Van Dongen et al., 2004). Polysomnographic recordings showed altered sleep architecture with a reduction in deep sleep (Gundel et al., 1997; Dijk et al., 2001). This is in accordance with astronauts specifically complaining about impaired refreshment post-sleep (Dijk et al., 2001) as deep sleep is vital for recovery. The reduction in sleep duration also results in increased susceptibility to stress while physical exhaustion rises due to the impaired sleep quality (Dinges et al., 2013). All these factors combined ultimately result in a higher risk of misconception and errors. Additionally, sleep disturbance is a main reason for medication intake in space (Barger et al., 2014). The effects of these medications – for example sleepiness – can last for several hours. This, again, places the astronauts at higher risk during work periods. The described reasons for inefficient sleep and their possible impact on astronauts’ performance necessitate a better understanding of sleep during microgravity as well as during ground-based bed rest studies as a simulation of microgravity.

To the best of our knowledge, it had not been considered that alterations in intracranial fluid regulation, clearance of metabolites and sleep performance can impact each other negatively at −12° HDT. However, based on the alterations above, it seems quite possible. There are two studies reporting a reduction in deep sleep (stage 4 according to Rechtschaffen and Kales) as well as increased arousal frequency during experimental −6° HDT bed rest (Mizuno et al., 2005; Komada et al., 2006) that lasted for 3 days. Both studies used a counterbalanced design with the subjects staying in horizontal position at another session. Gkivogkli et al. (2016) assessed sleep parameters repeatedly during a 50 days −6° bed rest study. Subjects were randomly assigned to two groups. In contrast to the control group, the training group performed reactive sledge jumping three to four times a week. The preliminary results published in the abstract for the SAN2016 Meeting suggest an increase in N1 sleep stage, and a decrease in the total sleep time, N2, N3, and REM sleep stage in the control group between baseline and 21 days of −6° HDT. In the training group N1 and N3 sleep stage seem to increase, N2 sleep stage decreases, while duration REM sleep stage does not change on the 21st day of −6° HDT compared to baseline. Meck et al. (2009) reported that about half of their subjects complained about impaired sleeping, especially in the first week of their 90 day head down bed rest, but also before starting the bed rest. This is in accordance with results from a study conducted by DeRoshia and Greenleaf (1993). Subjects’ subjective sleep quality improved after finishing the 30 days −6° bed rest. However, HDT-effects in the last three bed rest studies were assessed longitudinally, and may thus have been confounded with effects of isolation or lack of exercise. Yet, evaluation of objective sleep parameters is not done in most studies.

Therefore, we decided to study the short-term effects of HDT on sleep using the current guidelines of the American Academy of Sleep Medicine (AASM). As our interest was based on postulated effects of intracranial fluid regulation upon metabolic clearance, we decided to limit the exposure to HDT to one night only. We hypothesized that HDT will negatively affect sleep performance. We deliberately used −12° HDT rather than −6° HDT as −12° HDT has shown to be more efficient when measuring possible correlation between intracranial fluid systems (Marshall-Goebel et al., 2016; Kramer et al., 2017).

A significant increase (P = 0.002, g = 1.078) of the percentage of light sleep (N1 + N2) of the total sleep time could be detected during −12° HDT (59.9% ± 7.2%) in comparison with 0° (50.9% ± 9.4%). The fraction increased in 10 out of the 11 subjects, the maximum rise being 21.6%. One of the subjects (0J) showed a slight decrease of the light sleep (-3.1%) during the −12° HDT night.

There was a significant decrease in percentage of slow wave sleep (N3) (P = 0.002, g = -0.898) from the 0° night (25.4% ± 6.4%) to the −12° HDT night (20.2% ± 5.2%). This decrease ranged between 1.4 and 12.7% in 10 subjects, while the amount of N3 remained the same (17.9%) in the last subject (0E) during both nights.

There was a significant decrease (P = 0.035, g = -0.634) in the percentage of REM sleep of the total sleep time when comparing the night in horizontal position (23.7% ± 6.3%) to −12° HDT (19.9% ± 5.7%). The extent of the decline varied between 1.5 and 9.7%. 2 Subjects (0J, 0N) showed an increase in the amount of REM sleep during −12° HDT (Figure 2).

The mean time period for each of the sleep stages can be seen in Table 2. There were no significant differences between 0° position and −12° HDT position.

Total sleep time was not significantly affected (P = 0.44) by −12° HDT (410.4 min ± 55 min vs. 422 min ± 79.1 min at 0°). There was no significant difference in sleep onset latency (P = 0.30). Both, maximum (110 min) and minimum (2.0 min) onset latency occurred during the night subjects stayed in horizontal posture. However, when excluding the subject with the maximum sleep onset latency, the latency is significantly prolonged at −12° HDT. We found no significant difference in the number of sleep state changes when comparing the two experimental conditions (−12°: 128.1 ± 37.3; 0°: 119 ± 33.2; P = 0.19).

The mean peripheral tissue oxygenation at finger level remained unchanged (94.5%) during both nights with standard variation only differing slightly (2.8% vs. 2.9%). The lowest basal oxygenation of 88% was measured during −12° HDT. There was no significant change in minimum oxygenation detectable (−12°: 85.9% ± 6.8%; 0°:83.6% ± 11%; P = 0.41). The percentage of the mean time with the peripheral tissue oxygenation being lower than 90% showed no significant difference (P = 0.95) (Table 3).

There was a significant decrease (P = 0.047, g = −0.968) in subjective sleep quality during the −12° HDT night (4.8 ± 1.5) when compared to the 0° night (6.1 ± 1.1). However, subjective sleep duration did not differ significantly between the experimental conditions (−12°: 5.3 ± 1.8 h; 0°: 6.4 ± 1.4 h; P = 0.10). The subjective feeling of refreshment showed no significant difference (P = 0.09) between the −12° HDT night (5.6 ± 1.8) and the night spend in horizontal position (6.3 ± 1.3) (Table 4).

In comparison to the baseline data collected during measurement block 1 of each campaign frontal tissue thickness did not differ significantly on the first (P = 0.077) and the second interventional day (P = 0.811) at −12° HDT (Table 5). Frontal tissue thickness of the left and right side were differing (P = 0.009). There was no difference between conditions over time (P = 0.116).

The maximum cross-sectional area of the internal jugular vein increased significantly at −12° HDT on interventional day 1 (1.46 cm² ± 0.66 cm², P = 0.004) and day 2 (−12° HDT: 1.41 cm² ± 0.66 cm², P = 0.002) when compared to the baseline data collection (0.87 cm² ± 0.54 cm²). No difference could be detected when comparing the left and right side (P = 0.161). The minimal cross-sectional area of the internal jugular vein was also significantly different between interventional condition (−12° HDT day1: 1.31 cm² ± 0.64 cm², day 2: 1.18 cm² ± 0.62 cm²) and baseline data (0.65 cm² ± 0.52 cm²) on both interventional days (P = 0.009, P < 0.001, respectively). It did not differ between both sides over time (P = 0.369). The variation of the cross-sectional area of the internal jugular vein was different when comparing both sides (P = 0.003). It did not differ significantly between both conditions (P = 0.686).

The maximum cross-sectional of the external jugular vein was not significantly different with condition over time (P = 0.415), between the HDT- and control group (P = 0.128) and between sides (P = 0.271). However, the minimal cross-sectional area of the external jugular vein did differ between the conditions over time (P = 0.001). There was no significant difference between both sides over time (P = 0.980).

The percentage of slow wave sleep (N3) and REM sleep significantly decreased during −12° HDT, thereby resulting in a compensating significant increase of light sleep (N1/2). The subjective sleep quality was significantly lower when sleeping in HDT. These results are consistent with recent findings (Mizuno et al., 2005; Komada et al., 2006).

Despite these changes in sleep, the respective percentages of the sleep stages still are within the normal range for young adults (Carskadon and Dement, 2005) – although at the ends. This might be due to the subjects’ ages ranging between 21 and 55 years. This and the fact that the number of sleep stage changes remained similar during both positions suggest normal sleep architecture. Mizuno et al. (2005) drew the same conclusion at −6° HDT.

Minimum and maximum cross-sectional area of the internal jugular vein increased significantly at −12° HDT. The minimum cross-sectional area of the external jugular vein was significantly larger at −12° HDT compared to horizontal posture. Both findings indicate venous congestion at −12° HDT.

Frontal skin tissue thickness did not increase significantly during both interventional days at −12° HDT.

We had hypothesized that HDT induced changes on cerebral hemodynamics (Marshall-Goebel et al., 2016) would affect metabolic clearance and sleep. These changes in sleep might influence the transport capability of the “glymphatic” as this transport predominantly takes place during sleep (Xie et al., 2013) resulting in a reciprocal relation.

Dreha-Kulaczewski et al. (2017) showed that venous flow is a major driver for cerebrospinal fluid (CSF) circulation with both systems having opposed flow directions. Therefore, venous congestion as assessed in our study most likely results in a decreased flow of CSF into the cranium. This might directly affect metabolic clearance via CSF circulation.

Although we were not able to analyze the data of the thoracic and abdominal belts, respiration is likely to be affected by HDT: Negative thoracic pressure during inspiration is a main driver for CSF circulation (Dreha-Kulaczewski et al., 2015) as it results in a venous flow out of the cranium. Thereby, CSF flows toward the cranium. Therefore, a potential underlying cause of the increased venous congestion we observed is a change in respiration.

Respiratory obstruction may play a role in sleeping at −12° HDT. Resistance in the upper airway is associated with the lung volume (Begle et al., 1990; Stanchina et al., 2003). During HDT, lung volume decreases due to the shift of abdominal organs toward the head. This possibly results in an increased airflow resistance. The data of the abdominal and thoracic belts could not be evaluated efficiently and no difference was detected for continuous measurements of peripheral oxygen saturation. Therefore, a definite conclusion cannot be drawn.

The resulting effects of the decrease in cranial perfusion (Marshall-Goebel et al., 2016) and increased venous congestion at HDT might be similar albeit not identical to those in chronic heart failure. Chronic heart failure has a strong correlation to the obstructive sleep apnea syndrome. Although the reason for this is multifactorial one cause is possibly the fluid increase in the pharynx (Bradley and Floras, 2003).

This might also be one cause for impaired sleeping at HDT. Due to this shift, fluid also accumulates in the upper airways. The subjects were young, healthy males and the obstruction might not be as severe as in patients suffering from chronic heart failure. Thus, the full disease pattern of obstructive sleep apnea syndrome is not displayed.

In patients suffering from chronic heart failure, the retention of CSF within the cranial cavity might be the cause for cognitive impairment similar to that of idiopathic intracranial hypertension patients (Caplan, 2006). Assumed pathophysiologies for idiopathic intracranial hypertension include an increased outflow resistance of CSF (McGeeney and Friedman, 2014). Additionally, sleep apnea syndrome is related to idiopathic intracranial hypertension (Biousse et al., 2012; McGeeney and Friedman, 2014). Yet, it remains unclear whether it may be one of the causes or the result of the disease. The interactions of arterial, venous and CSF systems described above in addition with respiratory changes might be a possible approach.

With regards to obstruction, the individual build has to be taken into account. Fat distribution is an important risk factor for obstructive sleep apnea syndrome (Horner et al., 1989; Shinohara et al., 1997). Yuan et al. could show a correlation between neck circumference and pharynx collapsibility (Yuan et al., 2013) in adolescents. All our subjects’ BMIs were within the normal range but minor influences of individual body fat distribution cannot be completely ruled out.

The change of sleep stages observed in our study could also be explained by a raised level of physiological stress hormones during HDT as Norepinephrine is one of the transmitters influencing REM sleep stage (McCarley and Hobson, 1975; Winokur et al., 2001). Although, Rai and Kaur (2011). found that said increase in stress hormones took place only after the first week of bed rest, subjects were only positioned at −6° HDT. −12° HDT might lead to a quicker response of the stress system.

Mood, especially an increase in depression, plays a major role during HDT bed rest studies (Styf et al., 2001; Pavy-Le Traon et al., 2007) – even though not always reaching clinically significant level (Liu et al., 2012). As depression and sleep influence each other mutually (Kaneita et al., 2006), this has to be taken into account. However, −12° HDT was applied for less than 24 h and depressive disorders were an exclusion criterion. Liu et al. found no significant changes in anxiety level at −6° HDT (Liu et al., 2012) rendering altered mood an unlikely confounder of sleep (Rosa et al., 1983).

Gundel et al. observed a change in circadian rhythm of astronauts (Gundel et al., 1997) assessed by measuring the body temperature. During bed rest studies these changes generally occur at a later time (Pavy-Le Traon et al., 2007). Therefore, this factor did most likely not affect sleep in our study.

Whereas the subjective feeling of refreshment and estimated sleep duration were not influenced by the body position, subjective sleep quality was significant lower at −12° HDT which might be explained by the significant reduction of slow wave sleep (N3). Both slow wave sleep and sleep efficiency affect subjective sleep quality (Keklund and Akerstedt, 1997). Yet, when comparing subjective with objective sleep quality the results remain inconsistent (Akerstedt et al., 1994).

One limitation of our study regarding sleep was the issue of sliding at −12° HDT. Despite applying several countermeasures, subjects still described wakening because of reaching the head-end of the bed. This impedes the distinction between the effects of HDT itself and those of the sliding on the sleep behavior. The issue of sliding might also have contributed to deterioration in subjective comfort.

The study was designed to diminish any impact of the first night effect. A recent finding indicates REM sleep might even be influenced up to four nights (Le Bon et al., 2001). This might have affected our measurements. However, the counterbalanced design of the study should have reduced the possible impact on sleep.

Before sleeping, two subjects were given painkillers. Although none of the subjects woke up due to pain, the general increase in back pain, stomach pain and headache during bed rest (Styf et al., 2001) might still have influenced their sleeping. Apart from that, several subjects described a feeling of distention in their upper abdomen during −12° HDT contributing to general discomfort. Ibuprofen could affect sleep (Murphy et al., 1994) via inhibition of prostaglandin synthesis and the consequential change in body temperature and melatonin synthesis (Murphy et al., 1996). Yet, these results could not be confirmed (Gengo, 2006).

As with every bed rest study, there remains the question to what extent results are valid for actual space missions. With the observations being generally applicable this comparison might still be impeded due to surrounding circumstances during spaceflight, such as noise and mission parameters (Monk et al., 1998; Mallis and DeRoshia, 2005).

Overall, we could confirm previous findings from bed rest studies regarding sleep stage changes and sleep architecture. We also hypothesized that interrelations between the cranial perfusion systems and metabolic clearance would be a possible explanation for the poorer sleep behavior at −12° HDT. All in all, a better understanding of sleep and its relation to the intracranial fluid system is not only relevant for future space missions but might also have implications for clinical medicine.

This study was carried out in accordance with recommendations of the Declaration of Helsinki in its latest version, Datenschutzgesetz (Data Protective Act), Medizinproduktgesetz (MPG) (Medical Device Law), and Medizinprodukte – Betreiber Verordnung (MPBetrV). The protocol was approved by the ethics committee of the regional medical board (Ärztekammer Nordrhein). All subjects gave written informed consent in accordance with the Declaration of Helsinki.

All authors contributed to the hypothesis development, study design, data acquisition, and manuscript finalization. Analysis of the IPCog study results were carried out by ALB, ZL, DG, BJ, JZ, and JR. PG and JR supervised the study. ALB wrote the first draft of the manuscript and designed the graphs.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.