Investigation of the effects of head irradiation with gamma rays and protons on startle and pre-pulse inhibition behavior in mice.

With the increased international emphasis on manned space exploration, there is a growing need to understand the impact of the spaceflight environment on health and behavior. One particularly important aspect of this environment is low-dose radiation. In the present studies, we first characterized the γ- and proton-irradiation dose effect on acoustic startle and pre-pulse inhibition behaviors in mice exposed to 0-5 Gy brain-localized irradiation, and assessed these effects 2 days later. Subsequently, we used 2 Gy to assess the time course of γ- and proton-radiation effects on startle reactivity 0-8 days after exposure. Exposures targeted the brain to minimize the impact of peripheral inflammation-induced sickness behavior. The effects of radiation on startle were subtle and acute. Radiation reduced the startle response at 2 and 5 Gy. Following a 2-Gy exposure, the response reached a minimum at the 2-day point. Proton and γ-ray exposures did not differ in their impact on startle. We found there were no effects of radiation on pre-pulse inhibition of the startle response.

Assessing neurocognitive dysfunction in cranial radiotherapy: can cognitive event-related potentials help?

Cognitive changes are common sequelae of cancer and cancer treatment, particularly in patients receiving cranial radiotherapy (RT). These effects are typically assessed by subjective clinical examination or using objective neuropsychological tests. Biologically based neurophysiological methods have been increasingly applied to the study of cognitive processing in neuropsychiatric and neurological disorders and as objective measures of cognitive status for patients with dementia. These methods detect the activation of neural circuits that directly mediate cognitive function in the human brain and include metabolic and electrophysiology based techniques. Neuroimaging procedures such as 18FDG PET and more recently fMRI, which detect metabolic activation associated with cognitive processing, provide excellent spatial resolution and can be directly correlated with neuroradiological findings associated with cranial RT neurotoxicity. Clinical electrophysiology procedures such as cognitive event-related potentials (ERP), which detect the neuronal electrical activity associated with cognitive processing, offer excellent temporal resolution at low cost. Cognitive ERP techniques are already being used to assess severity and progression of cognitive dysfunction in patients with vascular and degenerative dementias, but have been largely overlooked in studies of radiation-related cognitive impairments. We review these various electrophysiological methods in the context of their relevance to assessing cranial RT effects on cognitive function, and provide recommendations for a neurophysiological approach to supplement current neuropsychological tests for RT cognitive impairments. This technology is well suited for clinical assessment of neurocognitive sequelae of cancer and should provide new insights into the mechanism of RT-related cognitive dysfunction.

Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study.

OBJECTIVES: Modafinil has recently been approved for the treatment of shift work sleep disorder, making it potentially available for shift-working emergency physicians. The authors' objectives were to determine whether modafinil improved cognitive performance of emergency physicians following overnight shifts and to record symptoms and subjective evaluations of the effect of modafinil on the participants. METHODS: This was a randomized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines. Participants were assigned to one of two study groups, with study sessions occurring at least seven weeks apart, and received either modafinil or placebo depending on their random allocation. Testing after night shifts included a coding task and an AX version of the Continuous Performance Task, both of which test cognitive function. Participants also completed visual analog scales for three subjective outcomes, and symptoms were elicited. RESULTS: Modafinil facilitated performance on long interstimulus-interval AX trials (F [1, 23] = 6.65, p = 0.1) and marginally reduced errors on AY trials in the Continuous Performance Task (F [1, 23] = 3.59, p = 0.07), suggesting facilitation of sustained attention, cognitive control, and working memory. Additionally, modafinil, compared with placebo, facilitated performance on the coding task at the first session. Subjective data from visual analog scales confirmed that modafinil increased perceived alertness during the simulated patient care sessions but worsened sleep onset when opportunities for sleep arose. CONCLUSIONS: Modafinil increased certain aspects of cognitive function and subjectively improved participants' ability to attend post-night-shift didactic sessions but made it more difficult for participants to fall asleep when opportunities for sleep arose.

HZE radiation and dopaminergic modification of startle and prepulse inhibition in mice.

C57BL/6 mice were exposed to 5 Gy (28)Si or (56)Fe particle radiation in order to explore the immediate or short-latency effect of exposure to high energy (HZE) particle radiation on dopaminergic modification of acoustic startle and prepulse inhibition. The radiation is representative of the type which would be encountered as galactic cosmic rays during long-duration space flight. The acoustic startle response was elicited with 120 dB white noise and prepulse inhibition of the startle response was produced with 79 dB and 86 dB stimuli presented with a 125 ms onset asynchrony. Startle reactivity was inhibited by (56)Fe radiation but not by (28)Si particles. Apomorphine (3 mg/kg) produced a general inhibition of startle reactivity while haloperidol (1 mg/kg) facilitated it. Apomorphine disrupted prepulse inhibition, but only in animals which were not exposed to radiation. Both (56)Fe and (28)Si radiation exposure attenuated the disruption of prepulse inhibition induced by apomorphine. In contrast, the facilitation of prepulse inhibition induced by haloperidol was not modified by radiation. These data are consistent with a short-latency disruption of dopaminergic systems by HZE particle radiation. We speculate that this disruption may occur as a restriction in the capacity of the dopaminergic system.

The effects of low-dose, high-LET radiation exposure on three models of behavior in C57BL/6 mice.

To investigate the behavioral consequences of exposure to whole-body irradiation such as might occur for astronauts during space flight, female C57BL/6 mice were exposed to 0, 0.1, 0.5 or 2 Gy accelerated iron ions (56Fe, Z = 26, beta = 0.9, LET = 148.2 keV/microm) of 1 GeV per nucleon using the Alternating Gradient Synchrotron at the Brookhaven National Laboratory. Animal testing began 2 weeks after exposure and continued for 8 weeks. Under these conditions, there were few significant effects of radiation on open-field, rotorod or acoustic startle activities at any of the times examined. The lack of radiation effects in these behavioral models appears to offer reassurance to NASA mission designers. These results suggest that there may be negligible effects of HZE radiation on many behaviors during a 2-8-week period immediately after radiation.

Behavioral consequences of radiation exposure to simulated space radiation in the C57BL/6 mouse: open field, rotorod, and acoustic startle.

Two experiments were carried out to investigate the consequences of exposure to proton radiation, such as might occur for astronauts during space flight. C57BL/6 mice were exposed, either with or without 15-g/cm2 aluminum shielding, to 0-, 3-, or 4-Gy proton irradiation mimicking features of a solar particle event. Irradiation produced transient direct deficits in open-field exploratory behavior and acoustic startle habituation. Rotorod performance at 18 rpm was impaired by exposure to proton radiation and was impaired at 26 rpm, but only for mice irradiated with shielding and at the 4-Gy dose. Long-term (>2 weeks) indirect deficits in open-field activity appeared as a result of impaired experiential encoding immediately following exposure. A 2-week recovery prior to testing decreased most of the direct effects of exposure, with only rotorod performance at 26 rpm being impaired. These results suggest that the performance deficits may have been mediated by radiation damage to hippocampal, cerebellar, and possibly, forebrain dopaminergic function.