This 1-year project assessed the likelihood of space radiation producing immediate and/or long-term functional changes in the CNS by measuring neurobehavioral function in rodents via animal tests analogous to "vigilance" tests in humans and relevant to astronaut mission performance effectiveness. Groups of animals were trained on the task, following which they received head-only radiation and were then re-tested immediately as well as periodically for up to 12 months post-exposure to assess potential long-term performance deficits. Results demonstrated that exposure to protons (150 MEV) in the range of 50–200 cGy can produce significant decrements in sustained attention and motor speed.

The psychomotor vigilance test (PVT) was originally developed as a human cognitive neurobehavioral assay for tracking the temporally dynamic changes in sustained attention, and has also been used to track changes in circadian rhythm. In humans the test requires responding to a small, bright-red-light stimulus (LED-digital counter) as soon as the stimulus appears, which stops the stimulus counter and displays the reaction time for each trial in milliseconds for a 1-sec period. Simple to perform, the PVT has only very minor learning effects, is widely used in human risk assessments in operational environments, and has been recently developed and adopted for use on the ISS for astronauts as a “self test” to provide performance feedback, detect changes in alertness, prevent errors, and manage fatigue from sleep loss, circadian disruption, and high workload requirements. A rodent version of the PVT, the rPVT, has been developed and demonstrated to track the same types of performance variables as the human PVT – i.e., general motor function and speed, fine motor control, inhibitory control (“impulsivity”), timing, selective attention, motivation, and basic sensory function. Five cohorts of 16 rats each (total N = 80) were trained on the rPVT, exported to BNL for head-only radiation exposure (0, 25, 50, 100, and 200 cGy protons @ 150 MeV/n), then returned to Johns Hopkins for follow-up testing.

For this project, an automated, computerized training and testing facility was developed for measuring long-term effects of radiation exposure on cognitive/behavioral functions involving vigilance and impulsivity in rodents at the Johns Hopkins Medical Institutions. Establishment of the test facility included 10 experimental testing chambers and associated equipment for assessing neurobehavioral function in rodents as well as for the daily automated, computerized training and testing of behavioral functions in test subjects. The facility supported both the exportation of groups of well-trained subjects to radiation exposure facilities such as Brookhaven National Laboratory (BNL) and the Department of Radiation Oncology of the Johns Hopkins Hospital, as well as the importation of radiation-exposed rodents from such facilities for detailed, long-term neurobehavioral risk assessments at our facility.

Results of the study demonstrated that the rPVT was readily learned by all rats and required as little as 5-7 days of training to acquire baseline performance levels. Validation data were also obtained to compare the performances on the PVT between humans and rodents; these data demonstrated that comparable performances were observed across species in terms of speed and distribution of response latencies, and the relative frequencies of performance lapses and errors of commission (i.e., premature responding). Following irradiation, performances in the rPVT were disrupted at exposure levels of 50, 100, and 200 cGy, showing a consistent, significant increase (i.e., slowing) in reaction times and increased lapses in responding, both indicative of a decrease in sustained attention. Additionally, premature responses showed consistent increases at the higher radiation levels. None of these changes were observed in the non-exposed control animals. Over this same time period, no significant changes were observed in discrimination accuracy, motivation (as indicated by trials completed), or food intake. Additional analyses also demonstrated a division within the exposure groups such that approximately 45-50% of exposed animals evidenced neurobehavioral deficits following radiation (“responders”), while the remainder of exposed animals were unaffected (“non-responders”). When analyzed separately, the responder groups showed distinct deficits in accuracy rates, lapses in attention, and in response speed, with these effects being independent of dose. That is, responder animals in the 25, 50, 100, and 200 cGy groups all evidenced similar degrees of disruption in sustained attention. Additionally, the changes in sustained attention were tracked over time for up to 1 year post-exposure and found to persist over this extended time period.

These results demonstrated the sensitivity of tests such as the rPVT for assessing the effects of head-only space radiation on cognitive neurobehavioral function. Exposure to protons at relatively low doses (e.g., 25 and 50 cGy) produced highly specific effects on vigilance that included impaired attention and motor function (i.e., slowed reaction times, increased lapses in attention, and increased premature responding). Such deficits could significantly impact routine performances in operational environments during lunar and Mars missions, and also negatively affect post-mission adjustment upon return to Earth. These findings support the likely continued success of the rodent model for studying the cognitive, neurobehavioral, and CNS risks associated with living in the space radiation environment while providing an innovative experimental platform for exploring the bases of individual vulnerability to radiation-induced impairments and evaluating potential prophylactics, countermeasures, and treatments.

This 1-year project is assessing the likelihood of space radiation producing immediate and/or long-term functional changes in the CNS by measuring neurobehavioral function in rodents via animal tests analogous to "vigilance" tests in humans and relevant to astronaut mission performance effectiveness. Groups of animals are trained on the task, following which they receive head-only radiation and then re-tested immediately as well as periodically for up to 12 months post-exposure to assess potential long-term performance deficits. To determine the likely mechanisms of damage to the CNS following radiation exposure, (e.g., radiation-induced changes in neurotransmitter system function), this research is also testing the hypothesis that, since monoamine neurotransmitter systems are implicated in vigilance and impulsivity, radiation-induced damage to monoamine neurotransmitter systems is responsible for the cognitive/behavioral impairment following exposure to space radiation.

During this one-year period, 80 rats have been trained on a rodent psychomotor vigilance task (rPVT), which is an animal analog of the Psychomotor Vigilance Task (PVT) used to study ‘vigilance’ in humans and validated to detect cognitive deficits caused by a variety of factors in space flight (e.g., sleep loss, sleep shifts, motion sickness). The rPVT task consists of a subject continuously monitoring and indicating the location of a brief visual target that occurs randomly in time. The task simultaneously assesses reaction time, vigilance, and impulsivity. Once trained on this task, all animals were exported to BNL for head-only radiation exposure and then returned to Johns Hopkins for follow-up testing. Radiation exposure doses consisted of 0, 25, 50, 100, and 200 cGy (5 dose levels) for protons (150 MeV/n). The zero-dose level represents non-exposed control animals (i.e., shipped to BNL, sedated and restrained for radiation exposure, but not actually radiated). Exposures of these 80 animals occurred on October 29-30, and the animals returned to Johns Hopkins approximately 1 week later and are just resuming their post-exposure testing runs. Results will be forthcoming as their psychomotor vigilance performances are tracked over the next 12 months.

Results from this first year of the project demonstrated the feasibility of establishing a computer-based, automated training and testing facility for assessing cognitive and behavioral function in the rodent model. Additional results indicate that rodents are readily trainable on cognitive/behavioral tasks that are also employed as standards for assessing normal human cognitive/behavioral function, and that the analog of a human psychomotor vigilance task can be employed with rodents to automatically assess neurobehavioral function on a daily basis. These findings support the likely continued success of the rodent model for studying the cognitive, neurobehavioral, and CNS risks associated with living in the space radiation environment.

To assess the likelihood of space radiation producing immediate and/or long-term functional changes in the CNS, neurobehavioral functions will be measured in rodents via animal tests analogous to the human CANTAB neuropsychological test battery and to "vigilance" tests in humans. Human neurobehavioral functions relevant to astronaut mission performance effectiveness will include assessments of general motor function and speed, vigilance, inhibitory control ("impulsivity"), timing, motivation, and basic sensory function. Groups of animals will be separately trained on each of these tasks, following which they will be exposed to radiation and then immediately re-tested as well as re-tested periodically for up to 18 months post-exposure to assess potential long-term performance deficits. To determine likely mechanisms of damage to the CNS following radiation exposure, pre-radiation and post-radiation pharmacologic assessments of the integrity of the relevant neurotransmitter systems will be conducted, as well as autoradiographic analyses of the integrity of different neurotransmitter systems.