The hypothesized intracranial pressure (ICP) increase in prolonged microgravity conditions is considered one of the main potential risks for the astronauts’ health. The risk of damage to the retina and to the optical nerve [1,2,3] is related to the development of the spaceflight-associated neuro-ocular syndrome (SANS), previously known as visual impairment and intracranial pressure (VIIP) syndrome. Lumbar puncture (LP) taken 12 to 60 days after return to Earth in four ISS astronauts [1, 2] demonstrated elevated LP opening pressure values (from 15.4 to 20.6 mmHg), but the ICP increase during spaceflight has not been demonstrated yet.

As the direct LP measure of ICP is an invasive method, reliable non-invasive indirect approaches are necessary to measure ICP on the International Space Station (ISS). One of the most promising methods is based on the variation of the otoacoustic emission (OAE) phase. The cochlear lymphatic fluids are in contact with the cerebrospinal fluids, so the increase of the pressure in the peripheral ear is a good proxy for the pressure of the intracranial fluid [4]. The increased pressure causes an increase of the middle ear reflectance [5], and as a direct consequence, the OAE phase increases. Avan et al. [6] presented a model in which the increased stiffness of the middle ear is parametrized by the decrease of the capacitive component of the impedance, mainly in the low frequency range.

In the present study, we will use OAE phase measurements to detect the astronauts’ ICP changes in microgravity during long-term missions on the ISS.

A reliable quantitative relation between the OAE phase variation and the ICP change comes from studies on pathological subjects in which controlled ICP was induced and invasively measured for ethically justified medical purposes. A linear relation between the OAE phase and the ICP variations has been proposed by Avan et al. [7], based on data by Büki et al. [8], obtained during neurosurgery:

$$\frac}=2.72 \ \text/\text$$

(1)

The results by Williams et al. [9] about the relation between DPOAE phase change and induced controlled ICP increase agree roughly with Eq. (1), suggesting also that the low-frequency (about 1 kHz) DPOAE phase may be relatively more sensitive to ICP changes. This observation agrees with the results obtained by Bershad et al. [10], who measured ICP and DPOAE changes (magnitude and phase) in 20 patients undergoing lumbar puncture. The OAE level change measurements require specifying the acquisition method and the stimulus calibration (if any) adopted in the study, because they are obviously sensitive to the actual stimulus level reaching the cochlea. The OAE level may change, as the phase, due to changes in both forward and backward middle ear transmission, but it could also be affected by changes in the working point or in the effectiveness of the cochlear amplifier.

The present study compares DPOAE phase measured in 0G on the ISS in a straight relaxed body posture to those measured pre-flight in the seated upright position. As most 0G ICP studies use a different baseline position (supine), it is necessary to discuss the effect of body posture on the ICP measurements, both direct and OAE-based. In free-falling reference frames as the ISS or an aircraft during parabolic flight, there is no preferred direction to define a horizontal or vertical body posture, but the curled or straight body posture could still make a difference.

In terrestrial gravity (1G), ICP is sensitive to the subject’s body posture, as demonstrated by several experiments, summarized in Table 1. Curled or straight body positions also yield different ICP values [11]. In the horizontal position, flexing the hips did not systematically change ICP, while flexing the neck increased ICP by 3.7 (with straightened hips) to 5.5 mmHg (with flexed hips). Focusing on the difference between seated and supine position, direct ICP measurements [11,12,13,14] found differences between 10 and 16 mmHg between seated and supine position.

ICP changes associated with postural changes in 1G have been detected also using OAE-based techniques. Büki et al. [17] found significant phase changes (on the order of 20–30°), going from vertical position to − 30° head-down-tilt (HDT). Voss et al. [5] found large DPOAE level and phase changes between vertical and − 45° HDT positions, in the 0.5–4 kHz frequency range. Using Eq. (1), Avan et al. [6] estimated an ICP increase by about 6 mmHg (15°) in 1G going from seated to supine position, and a larger one (7, 12 mmHg, 19°, 34°) from seated to HDT position at tilt angles of − 6° and − 20°. In the pre-flight and post-flight sessions of an ICP spaceflight experiment [14], the sensitivity of the TEOAE test to changes of the body tilt angle was demonstrated in 1G, finding a systematic and significant progressive phase increase going from seated to supine (17°) and to − 15° HDT position (39°). In a recent ground experiment [15] on 15 normal-hearing subjects, an identical twin of the instrument used in the present study on the ISS was used to detect phase changes associated with postural changes, measuring an average phase change of 17° between the seated and supine positions, which would correspond, according to Eq. (1), to about 6 mmHg of ICP increase in the supine position.

Interestingly, three 1G body-tilt experiments [7, 15, 16] measuring the OAE (either DPOAE or TEOAE) phase yielded similar average phase difference between seated and supine conditions (16–17°), which according to Eq. (1), would correspond to about 6 mmHg of ICP increment in the supine position. The comparison with direct ICP measurements (see Table 1) suggests that, in postural experiments, the OAE-based techniques could underestimate the actual ICP changes.

In a parabolic flight experiment, direct ICP measurements [14] on hematological patients demonstrated, during free-falling (0G) sections, an ICP decrease by about 4 mmHg, with respect to the baseline 1G supine position, much lower than that measured going from seated to supine position in 1G (of order 11 mmHg). A steady state 0G condition (such as that of ISS astronauts) would therefore imply an ICP level intermediate between the seated and supine 1G levels (and closer to the supine one). They concluded that the SANS risk for astronauts could be associated with the prolonged absence of the restoring effect of the low-ICP condition that one experiences every day in 1G while standing or seated, for almost two-thirds of each day.

The OAE-based method for the ICP estimate was also used to evaluate the transitory effect of short-term exposure to microgravity during parabolic flight sections [7]. Using Eq. (1), an average increase of the ICP relative to the 1G seated baseline of 11 mmHg (a 30° phase increase was measured) was estimated. The same authors had found a smaller ICP increase (6 mmHg, 15°) going from seated to supine position in 1G.

Taken together, these two parabolic flight studies would suggest that the OAE-based technique could be more sensitive to transitory 0G than to postural changes and that full equivalence between OAE-based estimates and direct ICP measurements is not guaranteed.

In a recent comprehensive study [16], using a wide set of indirect ICP indicators, the phase of Transient Evoked Otoacoustic Emissions (TEOAE) was recorded from the right ear of 13 astronauts during their long term missions on the ISS. On average, during spaceflight, a significant average phase decrease below the pre-flight supine value (− 19.7° on flight day FD45), and no significant change (+ 2.4°, compatible with a null result) with respect to the pre-flight seated value were found. It may be worth mentioning that, for the only one subject with a diagnosis of optical disc edema, the authors reported instead a very large increase of TEOAE phase during spaceflight (see their Fig. 2).