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Neurological changes in outer space
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.253647
Keywords: Neurology and microgravity, neurology and space travel, space medicine
Today, when there is an acute shortage of neurologists and neurosurgeons in India,[1] it may sound blasphemous and preposterous to discuss neurological changes that could occur in outer space. However, confirmation by the Indian Space Research Organization (ISRO)[2] that three Indians will spend 5–7 days in outer space in December 2021 makes it necessary that we be future ready and understand the neurological changes that may occur, due to microgravity and radiation exposure. In an earlier publication,[3] the author demonstrated that telemedicine has made distance meaningless. In fact, Geography has become History. Space exploration has captured our imagination and advanced human knowledge for nearly 60 years.[4] From 1961 to June 2018, a total of 561 individuals from more than 40 countries have been to outer space, on over 1230 spaceflights, and with a total of 46,947 person-days in space. During spaceflights, 17 nonfatal yet severe medical emergencies have been documented.[5] Several private organizations have announced plans to commence space tourism.[6] When billionaire and private citizen Yusaku Maezawa takes his planned trip around the Moon on a SpaceX Big Falcon Rocket in 2023, several health issues will need to be addressed. A trip to Mars, of course, will be an extraordinary challenge to the human body. Huge amounts of time, money, and effort are being invested in such a mission; therefore, an astronaut being grounded, or a mission being aborted due to ill-health will be unacceptable. Space tourists are less likely to be “super healthy,” as is expected of astronauts. It is, therefore, imperative that neuroscientists have a better understanding of the neurological changes that have occurred and might happen again when travelling beyond Earth's gravity. The space environment has factors such as weightlessness, electromagnetic fields, and radiation that may influence the function and structure of the central nervous system (CNS). Physiological changes are known to occur during and after long-term spaceflights, including neurovestibular disturbances, cephalic fluid shifts, cardiopulmonary pressure modifications, alterations in sensory perception and proprioception, psychological disturbances, and cognitive changes. Animal studies have shown altered plasticity of the neural cytoarchitecture, decreased neuronal metabolism in the hypothalamus, and changes in neurotransmitter concentrations. Recent progress in the ability to study brain morphology, cerebral metabolism, and neurochemistry in vivo in the human brain with positron emission tomography, single photon emission computed tomography, and next-generation magnetic resonance imaging (MRI) should provide the opportunity of investigating alterations that occur in the central nervous system (CNS) due to spaceflights.[7] Vazquez [8] pointed out that future missions to space would involve long-term travel beyond the magnetic field of the Earth, subjecting astronauts to radiation hazards posed by solar flares and galactic cosmic rays, altered gravitational fields, and physiological stress. Although the short-term effects of microgravity on neural control have been studied during low earth orbit missions, the consequences of prolonged microgravity and space radiation exposure have not been addressed sufficiently at the molecular, cellular, and tissue levels. Buckey et al.,[9] observed from Mir missions data that bone loss continues in space, despite an aggressive countermeasure program. The average bone mass losses were shown to be 0.35% per month; however, some load bearing areas lost >1% per month. A 1% loss rate, if it continued unabated for 30 months, could produce osteoporosis. van Ombergen et al.,[10] have expressed that microgravity, confinement, isolation, and immobilization must be endured during space missions. The exact impact of spaceflight on the human CNS remains to be determined, but preliminary spaceflight studies have shown an involvement of the cerebellum, cortical sensorimotor, somatosensory areas, and vestibular pathways. Extending this knowledge is crucial, particularly in view of the long-duration interplanetary missions and space tourism. This could also be relevant for patients with neurodegenerative or vestibular disorders, as well as for the elderly population, coping with multisensory deficit syndromes, immobilization, and inactivity. The pharmacokinetics and pharmacodynamics of usage of drugs acting on the nervous system have not yet been studied. Medications are administered under the assumption that they act in a similar way as on earth. Decreased drug and formulation stability in space could also influence the efficacy and safety of medications.[11] Together with present-day suboptimal technology, exposure to microgravity and cosmic rays raises health concerns about deep-space exploration missions. These physical factors affect the cardiopulmonary system, whose gravity-dependence is pronounced.[12] Cucinotta [13] considered that space programs to the Moon and Mars would result in increased exposure to space radiation. The biological effects of extended exposure to high-energy heavy ions on the nervous system are not yet understood. However, experimental studies suggest that there could be a risk of developing cancer. Experts are focusing on an increased understanding of the oncogenic potential of galactic cosmic rays. Neurophysiological changes The acute and chronic effects of hypobaric exposure on the brain have been evaluated.[14] These include decompression sickness, which may progress to severe neurological or pulmonary symptomatology. The brain (confusion, memory loss, visual changes, diplopia, scotomas, headache, seizures, vertigo, unconsciousness), spinal cord (dysesthesias, paresthesias, constriction and pain around the chest or abdomen, ascending paralysis, bowel and bladder incontinence), and peripheral nerves (fasciculations and paresthesias) can all be affected by a hypobaric exposure during space travel. Demertzi et al.,[15] have documented the occurrence of cortical reorganization in an astronaut's brain after a long-duration spaceflight. Differences were found in functional connectivity between the motor cortex and cerebellum in the resting state. Changes in the supplementary motor areas were observed during a motor imagery task. These results highlight the underlying neural basis for the observed physiological deconditioning due to the spaceflight.
The microgravity of space appears to affect every single organ and body system in different intensities and manner, both during short- and long-term missions. Kohn et al.,[16] noted the importance of understanding the impact of decreased gravity on the nervous system, which will be essential for ensuring the success of human survival in the hypogravity environments of Mars and the Moon. Persistent modulation in the sensory and motor systems and the resulting structural loss of muscle and bone mass have been reported. This is in addition to the recalibration of sensory perception, vestibular, and proprioceptive functions, changes in muscle synergies and coordination, decline of muscle force, as well as changes in posture control, locomotion, and functional mobility. These adaptations are of clinical relevance. Russomano et al.,[17] have pointed out that the application of lower body negative pressure partially reverses the headward shift of blood and body fluids occurring in microgravity. This contributes to the reduction of cardiovascular deconditioning and has been applied as a countermeasure during space flights. Fujii et al.,[18] emphasize that a better understanding of the mechanisms by which microgravity adversely affects the nervous system will lead to more effective treatments. Several neurologic alterations, including ataxia, postural disturbances, perceptual illusions, neuromuscular weakness, fatigue, and ocular changes, have been attributed to the effects of microgravity. They play an important role in maintaining the health of the astronaut and in re-adaptation to the terrestrial environment. Murthy et al.,[19] have discussed the effects of increased intracranial pressure (ICP) in humans during simulated microgravity.
Spaceflight-induced intracranial hypertension is now accepted as a distinct clinical phenomenon. The underlying physiological mechanisms leading to this are still poorly understood.[20] Spaceflight-induced visual pathology is thought to be a manifestation of increased ICP because of its similar presentation in cases of known increased ICP on Earth. Increased ICP by lumbar puncture has also been documented in symptomatic astronauts upon return to Earth. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood–brain barrier breakdown, and disruption to the cerebrospinal fluid (CSF) flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown. The other contributory factors include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. The effects of microgravity on the brain have received attention in relation to a syndrome involving optic disc edema and elevated ICP in astronauts returning from the International Space Station. NASA coined the phrase “Visual Impairment and Intracranial Pressure [VIIP] syndrome” to describe this constellation of signs and symptoms,[21] and it has been more recently renamed as Spaceflight Associated Neuro-ocular Syndrome (SANS). Understanding SANS has become a high priority for NASA in view of future long-duration missions. It is imperative to identify biomarkers for SANS risk prediction. Wostyn and Devyn [22] hypothesize that the response of optic nerve sheath to alterations in ICP may be a potential predictive biomarker for optic disc edema in astronauts. In a “letter to the editor,”[23] the same authors emphasize that the response of the optic nerve sheath to the rise in ICP during extended microgravity exposure may help to determine whether or not an astronaut is susceptible to developing ophthalmic changes of SANS. SANS has been identified as a health issue occurring in astronauts who have stayed in microgravity for at least 6 months.[24],[25] This syndrome was first reported in 2005, when a refractive change in visual acuity (mainly hyperopia) was detected after a long-duration space mission. This finding was further confirmed through evaluations conducted by means of a series of questionnaires applied to astronauts who took part in long spaceflight missions on the International Space Station (ISS).[26] Very little is known regarding the risk factors and pathophysiological mechanisms involved in SANS. The current consensus within the spaceflight community is that visual changes and eye alterations (papilledema, posterior globe flattening, hyperopic shift, choroidal folds) are a consequence of raised ICP resulting in optic nerve sheath distension [Figure 1]. This increase in optic nerve sheath diameter can readily be measured using a simple, noninvasive, and low-cost ophthalmic procedure, resulting in an easy way to diagnose this medical condition.[27] A recent study demonstrated a strong relationship between the body weight and the subsequent development of ocular changes in space.[28] Wostyn and Devyn [29] concur with the postulated theory that the “Ocular Glymphatic System” may also play a key role in the development of optic disc edema in astronauts. Vision changes after spaceflights have also been suggested as being related to alterations in folate- and vitamin B12-dependent one-carbon metabolism.[30] Publications on the effect of microgravity on ocular structures and visual function include specific reference to intraocular pressure and retinal vascular changes.[31],[32],[33],[34],[35] [Figure 1] shows the image of postflight optic disc swelling.[36]
Lawley et al.,[37] have reiterated that raised ICP is considered the most critical medical problem identified in the past decade of manned spaceflight missions. Astronauts often develop impaired vision, with a presentation that resembles syndromes of elevated ICP on the earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theories, Lawley observed that microgravity reduces the central venous pressure and ICP. However, ICP is not reduced to the levels observed in the 90° seated upright posture on Earth. Thus, the ICP over 24 h in microgravity is slightly above that observed on Earth, which may explain the remodeling of the eye in astronauts. The authors postulate that the human brain is protected by the daily circadian cycles. Studies [38],[39] have reviewed a spectrum of ocular and cerebral responses to extended microgravity exposure. A retrospective review of published observational, longitudinal examination of neuro-ophthalmic findings in astronauts after undergoing a long-duration spaceflight revealed that after 6 months of spaceflight, seven astronauts had ophthalmic findings consisting of optic disc edema in five, globe flattening in five, choroidal folds in five, cotton-wool spots in three, nerve fiber layer thickening detected by optical coherence tomography in six, and decreased near vision in six. Five of seven astronauts with near-vision complaints had a hyperopic shift. These five astronauts showed globe flattening on magnetic resonance imaging (MRI). Six lumbar punctures performed 8–57 days post-mission documented opening pressures varying from 18 to 28.5 cm H2O. The 300 postflight questionnaires documented that approximately 29 and 60% of astronauts on short-duration and long-duration missions, respectively, experienced a degradation in distant and near-visual acuity.[38] Kramer et al.,[40],[41] have documented magnetic resonance-derived cerebrospinal fluid (CSF) hydrodynamics as a marker and a risk factor for intracranial hypertension in astronauts exposed to microgravity. From a detailed study of 14 astronauts, the authors concluded that the increased postflight CSF production rate, with positive flattening, is compatible with the hypothesis of microgravity-induced intracranial hypertension. This infers a downregulation in CSF production in a microgravity environment, which is upregulated upon return to normal gravity. Increased postflight CSF maximum systolic velocity in astronauts with negative flattening suggests an increased craniospinal compliance and a potential negative risk factor for microgravity-induced intracranial hypertension. Space headache: A new secondary headache Vein et al.,[42] are of the opinion that headaches are a common, but rarely voiced, complaint during spaceflights. This is usually attributed as being a part of space motion sickness (SMS), whose clinical features and etiology have been discussed elsewhere.[43],[44] Using a specifically designed questionnaire based on the International Classification of Headache Disorders, second edition (ICHD-II) criteria, the authors propose to classify space headache as a separate entity among the secondary headaches, attributed to disorders of homeostasis. Of the 16 male and one female astronaut who participated in the survey, 12 (71%) reported as having experienced at least one headache episode while in space, whereas they had not suffered from headache when on Earth. There were, in total, 21 space headache episodes of moderate to severe intensity in 71% of the sample population. In two (12%) astronauts, the headache and associated symptoms matched the ICHD-II criteria for migraine, and in three astronauts (18%) for tension-type headache. In 12 (71%) astronauts, the headache was nonspecific. The majority of headache episodes (76%) were not associated with symptoms of SMS. Spaceflight appears to trigger headaches without other SMS symptoms in otherwise “super-healthy” male subjects. Wilson et al.,[45] propose that the headache of high altitude and microgravity is similar to the clinical syndromes of cerebral venous hypertension. Neurovestibular system The neurovestibular system is responsible for providing information regarding direction and degree of inertial and gravitational forces. Such information is essential to maintain equilibrium and spatial orientation. During the spaceflight, the gravitational force stops acting, resulting in a variety of clinical symptoms, including SMS. The symptoms include postural illusions, sensations of rotation, nystagmus, dizziness, vertigo, salivation, epigastric discomfort, vomiting, apathy, lethargy, sleepiness, fatigue, weakness, headache (especially frontal), as well as decrease in muscular coordination and performance.[46] National Aeronautics and Space Administration (NASA) has identified a potential risk of spatial disorientation, motion sickness, and reduced performance in astronauts during re-entry and landing of the proposed Orion crew vehicle. Angular accelerations of the crew vehicle during re-entry were simulated. The group that was given autogenic-feedback training exercises had significantly reduced clinical problems.[47] Investigations of basic vestibular physiology and reflex changes following exposure to microgravity have important implications for the diagnosis and treatment of vestibular disorders on Earth.[48] Researches [49],[50] have dealt with various aspects of extra-terrestrial vestibular physiology, including vestibular ataxia following shuttle flights, effects of microgravity on otolith-mediated sensorimotor control of posture, vestibulo-spinal response modification, as determined with the H-reflex during the Spacelab-1 flight, and the influence of long-duration spaceflight on postural control during self-generated perturbations and postural equilibrium following exposure to weightlessness. MRI changes following space travel Hasan,[51] in a retrospective analysis of 10 healthy astronauts, demonstrated the utility of multimodal quantitative magnetic resonance imaging (qMRI) with diffusion tensor imaging-based customized brain templates, to examine the structural attributes of various CNS compartments. Statistically significant positive features were observed, suggestive of structural neuroplasticity, associated with the professional activities of astronauts, and compensatory neurogenesis that counterweighs the expected normative volume loss with age. White matter hyperintensities (WMH) have also been linked to cortical and subcortical functions, particularly executive function, processing speed, and overall cognition along with motor/gait function.[52] MRI changes of brain structure following spaceflights have been studied,[53] including the brains of those 18 astronauts before and after long-duration missions involving stays on the international space station (ISS), and the brains of 16 astronauts before and after short-duration missions from the Space Shuttle Program. Pre- and postflight MRI cine clips derived from the high-resolution three-dimensional (3D) images of 12 astronauts after long-duration flights, and six astronauts after short-duration flights were examined to assess the extent of narrowing of CSF spaces and the displacement of brain structures. Preflight and postflight ventricular volumes were compared by means of an automated analysis of T1 weighted MRIs. The main prespecified analyses focused on the changes in volume of the central sulcus and the CSF spaces at the vertex, and vertical displacement of the brain. Narrowing of the central sulcus occurred in 17 of 18 astronauts after long-duration flights (mean flight time, 164.8 days) and in three of 16 astronauts after short-duration flights (mean flight time, 13.6 days). Cine clips from a subgroup of astronauts showed an upward shift of the brain after all long-duration flights (12 astronauts) but not after short-duration flights (six astronauts). Narrowing of CSF spaces at the vertex occurred in 12 astronauts after all long-duration flights and in one of six astronauts after a short-duration flight. Three astronauts in the long-duration group had optic disc edema, and all three had narrowing of the central sulcus. The cine clip available for one of the astronauts showed an upward shift of the brain. WMHs on MRI images of astronaut brains have been a matter of great discussion.[54],[55] Lower neurocognitive functions in U2 pilots with WMHs have been reported.[56] Back pain Astronauts have a 53–68% increased risk of experiencing moderate to severe low back pain (LBP) and a fourfold increased risk of developing herniated intervertebral discs (IVDs) during microgravity exposure and within one-year postflight. Atrophy and reduced motor control of the lumbar multifidus (LM) and transversus abdominis (TrA) muscles resulting from periods of deconditioning are linked to nonspecific LBP and spinal injury risk in both postflight astronauts and general populations.[57] The European Space Agency reported [58] LBP in 12 out of 20 astronauts during spaceflight. The report highlighted the importance of maintaining spinal movements, as end range flexion and extension exercises were anecdotally noted to ease pain during spaceflight. A relationship was also highlighted between LBP and atrophy of deep spinal muscles, particularly LM, during bed rest studies [Figure 2]. Wing et al.,[59] reported that 53–68% of astronauts experienced moderate to severe back pain when in space. On landing after a shuttle mission, a US astronaut reported severe LBP, which was later linked with a herniated nucleus pulposus at the L4-L5 intervertebral disc (IVD) level and required surgical intervention. Johnston et al.,[60] also reported that astronauts have a more than fourfold increased risk of herniated disc pulposus within the first year following spaceflight, compared with controls. Sayson and Hargens [61] suggest that this back pain and disc injury could be caused by a range of factors linked to spinal lengthening and reduced loading. A review by Belavy et al.,[62] supports this, suggesting the increased lumbar IVD herniation risk in the astronaut population was most likely caused by long-term disc tissue deconditioning resulting from swelling of the discs due to unloading during spaceflight. Lumbopelvic adaptations to microgravity include adoption of a flexed posture [Figure 2], spinal lengthening, increased IVD height and disc deconditioning, altered spinal curvatures and atrophy of the lumbopelvic musculature. On the ISS, astronauts take part in up to 2.5 h of exercise each day including running, cycling and strength training. These countermeasure exercise programs are known to be relatively successful at preventing bone loss and loss of muscle mass in some regions of the body. Many astronauts experience LBP, and there is a fourfold increase in the incidence of IVD injury on their return to Earth as compared with their non-astronaut peers. It is known that the spine lengthens, normal posture is lost, IVDs change their morphology, LM and TrA muscles atrophy, and a flexor-extensor lumbo-pelvic muscle imbalance occurs during spaceflight. Harrison et al.,[63] recently studied seven ISS astronauts who underwent pre- and postflight ultrasound examinations that included measurement of the anterior disc height and anterior intervertebral angles, with comparison of the pre- and postflight MRI images. In-flight ultrasound images were analyzed for changes in disc height and angle. Changes in anterior IVD angle (and an initial increase followed by a decrease) were observed in the lumbar and cervical spine during a long-duration mission. The cervical spine demonstrated a 0.5 cm loss of total disc height during in-flight assessments. In a provocative article titled, “From the international space station to the clinic,” Bailey et al.,[64] discuss how prolonged uploading may disrupt lumbar spine stability.
Although the mechanisms by which microgravity impairs the spine are unclear, developing in-flight countermeasures for maintaining the astronaut's spine health is necessary. As human spinal anatomy has adapted to an upright posture on the earth, observations of how spaceflight affects the spine could provide new and potentially important information on spine biomechanics that would benefit the population on the earth. In a prospective study, six NASA astronauts with a 6-month mission aboard the ISS had assessments of quantitative measures of lumbar spine anatomy and biomechanics before and after 6 months of microgravity exposure. The participants had a 3T MRI imaging and dynamic fluoroscopy of the lumbar spine at two time points: approximately 30 days before the launch (preflight), and one day following a 6-month spaceflight on the ISS. Supine lumbar lordosis decreased (flattened) by an average of 11%. The disc water content did not differ systematically from pre- to postflight. Recent work has shown an increased risk of cervical and lumbar IVD herniations in astronauts. Based on the literature review, the most likely cause for lumbar IVD herniations was swelling of the IVD during spaceflight. Postflight care, avoiding activities involving spinal flexion, followed by passive spinal loading during spaceflight and exercises to reduce IVD hyper-hydration postflight are recommended.
The relevance of Space Medicine in an emerging economy, particularly for neurology specialists may be questioned. Although it is unlikely that there will be immediate clinical applications for extraterrestrial neurology, knowledge of neurological changes due to microgravity and radiation will eventually offer additional insights into how the nervous system functions on Earth. We need to understand and accept that the future is always ahead of schedule. Who knows, perhaps one day some of the younger readers of this Indian journal may actually be evaluating a Vyomanaut or even a space tourist. Acknowledgements We are thankful to Ms. Lakshmi for secretarial assistance. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
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