Intracranial pressure and visual acuity: The final frontier?

Earth's gravitational force is a unique biophysical stress that has played an important role in shaping the mechanism(s) governing human cardiovascular control. When gravitational forces are substantially reduced (i.e. microgravity), body fluids redistribute towards the head and cause an elevation of intracranial pressure (ICP). Visits to the International Space Station result in a chronically elevated ICP that may contribute to the loss of visual acuity seen in astronauts once they return to Earth (Lawley et al. 2017). Long-term microgravity exposure has also been associated with bone demineralization, pre-syncope and kidney stones; however, visual deterioration is widely considered as the most significant physiological challenge for space travel. Short duration flights (∼3 days) are associated with reduced near sighted vision in ∼23% of astronauts, and this increases to ∼48% after 6 months of microgravity exposure (Demontis et al. 2017). The National Aeronautics and Space Administration (NASA) have invested into a multimillion dollar visual Space-flight Associated Neuro-ocular Syndrome (SANS) project to address this issue and, despite these efforts, microgravity-induced visual impairments are still not completely understood. One hypothesis suggests that the microgravity-related cephalad fluid shifts increases ICP disproportionately to intraocular pressure (IOP), creating an IOP–ICP pressure gradient (Fig. 1). SANS presents similar to idiopathic intracranial hypertension (IIH) with papilloedema, optic nerve sheath dilatation and flattening of the eye globe (Demontis et al. 2017); however, other symptoms, including a lack of chronic headache, pulse synchronous tinnitus and diplopia, are not present, suggesting that SANS has a distinct pathophysiology different from that of IIH. In addition to microgravity fluid redistribution, spaceflight is associated with mild hypercapnia caused by poor ambient ventilation. Hypercapnia, a potent vasodilator, causes increases in cerebral blood flow, and thus cerebral blood volume (Laurie et al. 2020), which may facilitate elevated ICP in microgravity. Humanity is on the verge of embarking on a ground-breaking achievement that will define the 21st Century. In a collaborative effort, NASA and SpaceX have released comprehensive details describing plans to conduct a manned mission to Mars within the next 5 years. For this reason, more research is needed to better understand the mechanism(s) of cerebral blood flow control and reactivity with respect to elucidating the pathophysiology of SANS and determining methods to prevent the condition. The recent study in the Journal of Physiology by Laurie et al. (2020) reported the effects of very mild hypercapnia (ambient air CO2 ∼4 mmHg) and simultaneous 6° head-down tilt bed rest (HDTBR) for 30 days with respect to simulating the conditions associated with spaceflight. To the credit of Laurie et al. (2020), they successfully enrolled 12 participants for this ambitious investigation. Arterialized blood gases, cerebrovascular reactivity and ventilatory reactivity to hypercapnia were measured at baseline, then on days 1, 9, 15 and 30 of bed rest, and again 6 and 13 days post-HDTBR. The HDTBR reverses the head-to-foot hydrostatic gradient and promotes cephalad directed fluid shifting, which is used as a model to simulate microgravity. Long-term HDTBR with mild hypercapnia did not change the cerebrovascular reactivity to carbon dioxide or the hypercapnia ventilatory response during or after HDTBR. Numerous components of their study deserve praise for contributing to the limited current body of literature. However, there are a few aspects of the study that warrant further discussion to improve the overall quality and impact of future experiments. First, Laurie et al. (2020) assessed during and post HDTBR by arterialized venous puncture from the index or middle finger. When a topical vasodilator and/or heat is applied to the finger, anastomoses in the skin are recruited and a large portion of arterial blood flow to bypasses the capillaries causing venous blood to closely approximate true arterial blood. However, because not all venous blood arrives by shunt, arterialized venous samples overestimate by an average of 1.2 ± 0.6 mmHg (Zavorsky et al. 2007). The cerebrovasculature has a high CO2 sensitivity (3–6% increase in blood flow per unit mmHg CO2) and therefore even small inaccuracies can have substantial impact on the interpretation of absolute cerebrovascular CO2 reactivity data (Willie et al. 2012). The meta-analysis does show relatively good agreement between arterial and arterialized over large range (∼15–80 mmHg) therefore, assuming the difference in arterial to arterialized venous remains consistent within subject for all trials, the cerebrovascular CO2 reactivity should not be affected. Second, Laurie et al. (2020) measured cerebrovascular reactivity using the middle cerebral artery (MCA) via transcranial doppler (TCD). Participants, in the HDTBR position, hyperventilated for 1 min to lower the partial pressure of end-tidal () to 20–25 mmHg before switching to a rebreathe bag with 100% O2 until target expiratory was achieved at 55–60 mmHg. To calculate cerebrovascular reactivity to , a four-parameter log function was used to quantify the MCA blood velocity– curve with a simple linear regression for the steepest slope. Several recent studies have highlighted that TCD may not be representative of true cerebral blood flow during conditions of moderate-to-severe hypo and hypercapnia. Furthermore, because cerebrovascular reactivity differs between hypocapnia and hypercapnia, Laurie et al. (2020) should have analysed cerebrovascular reactivity to using two separate linear regressions (i.e. hypo- and hypercapnia slopes) (Willie et al. 2012). Future work should also consider measuring cerebral blood flow using Duplex ultrasound and/or magnetic resonance imaging (MRI) for more accurate measures of cerebral blood flow. Lastly, the applicability of the investigation by Laurie et al. (2020) and other similar studies might not accurately represent the day-to-day physiological stressors endured by astronauts in long-term spaceflight. To maintain bone density and vascular health, astronauts engage in 2 h of exercise daily. Training has substantial effects on cerebral blood flow and cerebrovascular reactivity with short training interventions improving cerebrovascular health (Willie et al. 2012). Improvements in maximal oxygen uptake () positively correlate with increases in cerebrovascular reactivity. Bedrest causes a substantial decrease in by a loss of aerobic capacity of 0.9% per day over 30 days. In light of this information, strict HDTBR without some sort of adapted exercise may not capture the proper environmental conditions of spaceflight. To fully characterize the effects of microgravity on cerebrovascular reactivity, future long-term bed rest studies should consider incorporating similar exercise routines comparable to spaceflight requirements. Nonetheless, Laurie et al. (2020) have taken numerous leaps forward to properly emulate spaceflight by adding mild hypercapnia to HDTBR. Numerous studies have aspired to simulate microgravity through HDTBR or head-out dry immersion (HODI). The HODI has participants laying semi-supine in a neck deep pool of water; however, it can only be used for a maximum of 3 days. Hydrostatic pressure is exerted equally across the body to balance gravitational forces, thus simulating microgravity. Head-out dry immersion results in peripheral vasoconstriction and reduced vascular capacitance, shifting blood towards the heart and central circulation (Demontis et al. 2017). However, neither model (i.e. HDTBR and HODI) can perfectly simulate microgravity. Each methodology exerts different biophysical properties on the body resulting in different interstitial and plasma compartment re-distributions causing unique cardiovascular and neuroendocrine responses, as suggested by differences in pulmonary pressure, mean arterial pressure, plasma norepinephrine, renin–angiotensin–aldosterone-system, anti-diuretic hormone and endothelium proliferation (Demontis et al. 2017). These differences make comparisons of data between these models difficult. Although ‘true’ microgravity can be emulated during parabolic flight, this is limited to only ∼20 s and spaceflight related ocular changes develop over weeks. HDTBR appears to be the best method for modelling SANS because of its viability for use in long duration studies (Demontis et al. 2017) The mechanism(s) responsible for elevated ICP leading to impaired visual acuity still require further study. Previous work by Lawley et al. (2017) demonstrated that brief (∼20 s) parabolic air flight does not increase ICP and, conversely, may actually decrease it. These data indicate that the length of microgravity stimulus is of critical importance. Persistent changes in fluid redistribution are probably required to increase ICP and, although the changes in ICP appear to be mild with microgravity, the long-term effect of consistently elevated ICP could plausibly be the physiological culprit behind the visual degeneration. The investigation by Laurie et al. (2020) has provided crucial foundations for further illuminating this pathophysiological syndrome; however, more work is required to understand how long-term simulated microgravity alters ICP. Future investigations should consider non-invasive measures of assessing ICP, such as quantitative MRI for cerebrospinal fluid pulsatility, ophthalmic artery blood flow pulsatility and optic nerve sheath diameter. Furthermore, studies should reassess cerebrovascular reactivity using duplex ultrasound or MRI to quantify both the cerebral blood flow and diameter changes that may occur during prolonged HDTBR, aiming to better understand cerebrovascular haemodynamics during microgravity. Laurie et al. (2020) have performed an excellent and logistically impressive human study that has advanced our current knowledge on cerebrovascular control during simulated microgravity. This investigation has provided evidence that: (1) prolonged HDTBR does not adversely impact cerebrovascular reactivity and (2) mild hypercapnia during HDTBR does not cause metabolic acidosis but, conversely, causes metabolic alkalosis. Moving forward, this area of research needs to be expanded to reduce the long-term risks associated with spaceflight. None. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. No funding was received.

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