central nervous system effects from radiation exposure during spaceflight central nervous system effects from radiation exposure during spaceflight travel outside the earth's protective atmosphere, magnetosphere, and gravitational field can harm human health, and understanding such harm is essential for successful manned spaceflight. potential effects on the central nervous system (cns) are particularly important. a vigorous ground-based cellular and animal model research program will help quantify the risk to the cns from space radiation exposure on future long distance space missions and promote the development of optimized countermeasures. possible acute and late risks to the cns from galactic cosmic rays (gcrs) and solar proton events (spes) are a documented concern for human exploration of the solar system. in the past, the risks to the cns of adults who were exposed to low to moderate doses of ionizing radiation (0 to 2 gy (gray) (gy = 100 rad)) have not been a major consideration. however, the heavy ion component of space radiation presents distinct biophysical challenges to cells and tissues as compared to the physical challenges that are presented by terrestrial forms of radiation. soon after the discovery of cosmic rays, the concern for cns risks originated with the prediction of the light flash phenomenon from single hze nuclei traversals of the retina; this phenomenon was confirmed by the apollo astronauts in 1970 and 1973. hze nuclei are capable of producing a column of heavily damaged cells, or a microlesion, along their path through tissues, thereby raising concern over serious impacts on the cns. in recent years, other concerns have arisen with the discovery of neurogenesis and its impact by hze nuclei, which have been observed in experimental models of the cns. human epidemiology is used as a basis for risk estimation for cancer, acute radiation risks, and cataracts. this approach is not viable for estimating cns risks from space radiation, however. at doses above a few gy, detrimental cns changes occur in humans who are treated with radiation (e.g., gamma rays and protons) for cancer. treatment doses of 50 gy are typical, which is well above the exposures in space even if a large spe were to occur. thus, of the four categories of space radiation risks (cancer, cns, degenerative, and acute radiation syndromes), the cns risk relies most extensively on experimental data with animals for its evidence base. understanding and mitigating cns risks requires a vigorous research program that will draw on the basic understanding that is gained from cellular and animal models, and on the development of approaches to extrapolate risks and the potential benefits of countermeasures for astronauts. several experimental studies, which use heavy ion beams simulating space radiation, provide constructive evidence of the cns risks from space radiation. first, exposure to hze nuclei at low doses (<50 cgy) significantly induces neurocognitive deficits, such as learning and behavioral changes as well as operant reactions in the mouse and rat. exposures to equal or higher doses of low-let radiation (e.g., gamma or x rays) do not show similar effects. the threshold of performance deficit following exposure to hze nuclei depends on both the physical characteristics of the particles, such as linear energy transfer (let), and the animal age at exposure. a performance deficit has been shown to occur at doses that are similar to the ones that will occur on a mars mission (<0.5 gy). the neurocognitive deficits with the dopaminergic nervous system are similar to aging and appear to be unique to space radiation. second, exposure to hze disrupts neurogenesis in mice at low doses (<1 gy), showing a significant dose-related reduction of new neurons and oligodendrocytes in the subgranular zone (sgz) of the hippocampal dentate gyrus. third, reactive oxygen species (ros) in neuronal precursor cells arise following exposure to hze nuclei and protons at low dose, and can persist for several months. antioxidants and anti-inflammatory agents can possibly reduce these changes. fourth, neuroinflammation arises from the cns following exposure to hze nuclei and protons. in addition, age-related genetic changes increase the sensitivity of the cns to radiation. research with animal models that are irradiated with hze nuclei has shown that important changes to the cns occur with the dose levels that are of concern to nasa. however, the significance of these results on the morbidity to astronauts has not been elucidated. one model of late tissue effects suggests that significant effects will occur at lower doses, but with increased latency. it is to be noted that the studies that have been conducted to date have been carried out with relatively small numbers of animals (<10 per dose group); therefore, testing of dose threshold effects at lower doses (< 0.5 gy) has not been carried out sufficiently at this time. as the problem of extrapolating space radiation effects in animals to humans will be a challenge for space radiation research, such research could become limited by the population size that is used in animal studies. furthermore, the role of dose protraction has not been studied to date. an approach to extrapolate existing observations to possible cognitive changes, performance degradation, or late cns effects in astronauts has not been discovered. new approaches in systems biology offer an exciting tool to tackle this challenge. recently, eight gaps were identified for projecting cns risks. research on new approaches to risk assessment may be needed to provide the necessary data and knowledge to develop risk projection models of the cns from space radiation. acute and late radiation damage to the central nervous system (cns) may lead to changes in motor function and behavior or neurological disorders. radiation and synergistic effects of radiation with other space flight factors may affect neural tissues, which in turn may lead to changes in function or behavior. data specific to the spaceflight environment must be compiled to quantify the magnitude of this risk. if this is identified as a risk of high enough magnitude then appropriate protection strategies should be employed.— human research program requirements document, hrp-47052, rev. c, dated jan 2009. introduction both gcrs and spes are of concern for cns risks. the major gcrs are composed of protons, α-particles, and particles of hze nuclei with a broad energy spectra ranging from a few tens to above 10,000 mev/u. in interplanetary space, gcr organ dose and dose-equivalent of more than 0.2 gy or 0.6 sv per year, respectively, are expected. the high energies of gcrs allow them to penetrate to hundreds of centimeters of any material, thus precluding radiation shielding as a plausible mitigation measure to gcr risks on the cns. for spes, the possibility exists for an absorbed dose of over 1 gy from an spe if crew members are in a thinly shielded spacecraft or performing a spacewalk. the energies of spes, although substantial (tens to hundreds of mev), do not preclude radiation shielding as a potential countermeasure. however, the costs of shielding may be high to protect against the largest events. the fluence of charged particles hitting the brain of an astronaut has been estimated several times in the past. one estimate is that during a 3-year mission to mars at solar minimum (assuming the 1972 spectrum of gcr), 20 million out of 43 million hippocampus cells and 230 thousand out of 1.3 million thalamus cell nuclei will be directly hit by one or more particles with charge z> 15. these numbers do not include the additional cell hits by energetic electrons (delta rays) that are produced along the track of hze nuclei or correlated cellular damage. the contributions of delta rays from gcr and correlated cellular damage increase the number of damaged cells two- to three-fold from estimates of the primary track alone and present the possibility of heterogeneously damaged regions, respectively. the importance of such additional damage is poorly understood. at this time, the possible detrimental effects to an astronaut's cns from the hze component of gcr have yet to be identified. this is largely due to the lack of a human epidemiological basis with which to estimate risks and the relatively small number of published experimental studies with animals. rbe factors are combined with human data to estimate cancer risks for low-let radiation exposure. since this approach is not possible for cns risks, new approaches to risk estimation will be needed. thus, biological research is required to establish risk levels and risk projection models and, if the risk levels are found to be significant, to design countermeasures. description of central nervous system risks of concern to nasa acute and late cns risks from space radiation are of concern for exploration missions to the moon or mars. acute cns risks include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. late cns risks are possible neurological disorders such as alzheimer's disease, dementia, or premature aging. the effect of the protracted exposure of the cns to the low dose-rate (< 50 mgy h–1) of proton, hze particles, and neutrons of the relevant energies for doses up to 2 gy is of concern. current nasa permissible exposure limits pels for short-term and career astronaut exposure to space radiation have been approved by the nasa chief health and medical officer. the pels set requirements and standards for mission design and crew selection as recommended in nasa-std-3001, volume 1. nasa has used dose limits for cancer risks and the non-cancer risks to the bfos, skin, and lens since 1970. for exploration mission planning, preliminary dose limits for the cns risks are based largely on experimental results with animal models. further research is needed to validate and quantify these risks, however, and to refine the values for dose limits. the cns pels, which correspond to the doses at the region of the brain called the hippocampus, are set for time periods of 30 days or 1 year, or for a career with values of 500, 1,000, and 1,500 mgy-eq, respectively. although the unit mgy-eq is used, the rbe for cns effects is largely unknown; therefore, the use of the quality factor function for cancer risk estimates is advocated. for particles with charge z>10, an addition pel requirement limits the physical dose (mgy) for 1 year and the career to 100 and 250 mgy, respectively. nasa uses computerized anatomical geometry models to estimate the body self-shielding at the hippocampus. evidence review of human data evidence of the effects of terrestrial forms of ionizing radiation on the cns has been documented from radiotherapy patients, although the dose is higher for these patients than would be experienced by astronauts in the space environment. cns behavioral changes such as chronic fatigue and depression occur in patients who are undergoing irradiation for cancer therapy. neurocognitive effects, especially in children, are observed at lower radiation doses. a recent review on intelligence and the academic achievement of children after treatment for brain tumors indicates that radiation exposure is related to a decline in intelligence and academic achievement, including low intelligence quotient (iq) scores, verbal abilities, and performance iq; academic achievement in reading, spelling, and mathematics; and attention functioning. mental retardation was observed in the children of the atomic-bomb survivors in japan who were exposed to radiation prenatally at moderate doses (<2 gy) at 8 to 15 weeks post-conception, but not at earlier or later prenatal times. radiotherapy for the treatment of several tumors with protons and other charged particle beams provides ancillary data for considering radiation effects for the cns. ncrp report no. 153 notes charge particle usage “for treatment of pituitary tumors, hormone-responsive metastatic mammary carcinoma, brain tumors, and intracranial arteriovenous malformations and other cerebrovascular diseases.” in these studies are found associations with neurological complications such as impairments in cognitive functioning, language acquisition, visual spatial ability, and memory and executive functioning, as well as changes in social behaviors. similar effects did not appear in patients who were treated with chemotherapy. in all of these examples, the patients were treated with extremely high doses that were below the threshold for necrosis. since cognitive functioning and memory are closely associated with the cerebral white volume of the prefrontal/frontal lobe and cingulate gyrus, defects in neurogenesis may play a critical role in neurocognitive problems in irradiated patients. review of space flight issues the first proposal concerning the effect of space radiation on the cns was made by cornelius tobias in his 1952 description of