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Neurological Effects of Space Radiation
1. Gravitational and Space Biology 22(2) September 2009 33
NEUROLOGICAL EFFECTS OF SPACE RADIATION
Gregory A. Nelson, Ph.D.
Loma Linda University, Loma Linda, CA
ABSTRACT
In this brief review, several aspects of radiation effects on the
central nervous system are considered. Low to moderate levels
(~ 1 to 2 Gy) of charged particle radiation exposure will
characterize the environment experienced by astronauts on long-
term space missions. These doses are well below those
associated with gross pathological changes and tissue
breakdown; however, they may cause persistent functional
changes. The intrinsic membrane properties of mature neurons
appear be stable to space-like radiation exposures but their
connectivity and information processing properties are
persistently altered. These alterations result in altered
excitability with reductions in synaptic remodeling for many
months post irradiation. Changes in information processing due
to synaptic changes as well as depletion of neural precursor cells
may in turn lead to reduced cognitive abilities. Supporting this
idea, behavioral studies on irradiated rodents and human
children have shown that performance decrements do occur in
the space operations dose range. An analysis of charged particle
track interactions with neuron structure suggests that nearly
every nerve cell’s dendritic or axonal arborizations will be
traversed by multiple cosmic rays during a long duration space
mission. The functional changes observed experimentally are
associated with the complex arborizations of nerve cells and
their structural specializations. Although the data for charged
particle radiation exposures are sparse, the available
observations from all exposure regimens point to a credible risk
of cognitive or performance decrements during long term space
missions.
KEYWORDS
Central nervous system, hippocampus, neurogenesis,
space radiation, synapse.
INTRODUCTION
The effects of radiation on the central nervous system
(CNS) have been investigated for many years, but
primarily in the context of radiotherapy. In this context,
survival of cells is the key indicator as the emphasis is on
tumor control, while minimizing side effects to normal
tissue. Most of these studies have employed gamma rays
or X-rays and typically, high doses (> 20 Gy) are applied
to local areas. This results in steep dose response curves
for white matter degeneration in either cortex
(leukencephalopathy) or the spinal cord (myelopathy)
which appears after a substantial time lag of many months
(Debus et al., 2003). This may be accompanied by
edema, breakdown of the blood-brain barrier, swelling of
vessels (telangiaectasia), inflammatory reactions and
sometimes necrosis. In this literature, there has been an
active debate about whether vascular endothelial cells or
parenchymal cells (especially oligodendrocytes) are the
dose limiting cells of the tissue which is characterized
overall by low rates of cell division and replacement.
Three excellent reviews of this literature are: Wong and
Van der Kogel, 2004; Tofilon and Fike, 2000; Schultheiss
et al.,1995. Many of the mainstream opinions about CNS
radiation responses are derived from results that result
from high dose exposures. These may not extrapolate
well to effects of the space environment in which the
relevant exposures are in the dose range of < 2 Gy
delivered slowly to the whole body by mixed fields of
charged particles. In this exposure regime there is much
less known, and NASA’s interest is in establishing
whether: 1) there are acute risks that could lead to mission
compromising performance impairments, and 2) whether
the severity and onset of neurodegenerative conditions
later in life may be enhanced or accelerated. The
following presentation will consider some selected studies
that address this lower dose regime, with emphasis on
charged particle effects if known.
Charged Particle Radiation
The unique properties of charged particles are associated
with their track structure. Unlike X-rays and gamma rays
which are absorbed in an exponential fashion with depth
in tissue, charged particles have a defined range and
deposit their energy at an increasing rate until they reach
the end of their range. This rate of energy loss is termed
the linear energy transfer or LET and is commonly used
as a measure of the quality of the radiation or its
ionization density. Charged particle interactions with
electrons in the target material are primarily electrostatic
rather than through processes such as Compton scattering.
Because the particles have significant mass, they travel in
relatively straight lines and about half of the energy they
deposit is confined to a narrow cylinder (track core) about
20 nm in diameter along the track. The other half of their
energy is deposited through radially scattered electrons
around the track core. These properties tend to
concentrate damage along the track rather than in the
more diffuse damage patterns produced by X-ray and
gamma ray exposures. Unique DNA damage,
genotoxicity and tissue responses have been described for
such densely ionizing radiation and many of these
properties have been reviewed in volume 16 of this
Bulletin (Nelson, 2003).
Cellular Level Responses
The first level of biological organization to explore is the
neuron with its excitable membrane that is the basic
____________________
* Correspondence to: Gregory A. Nelson
Radiobiology Program
Loma Linda University
Loma Linda, CA 92354
Email: gnelson@dominion.llumc.edu
Phone: 909-558-8364; Fax: 909-558-0825
2. G.A. Nelson — Neurological Effects of Space Radiation
34 Gravitational and Space Biology 22(2) September 2009
functional unit of the nervous system. It might be
expected that radiation-induced lipid peroxidation
reactions would compromise neuronal electrochemical
gradients, membrane receptors and ion channels
Extensive studies of membrane fluidity, cell leakage and
activities of Na+
/K+
ATPases and acetylcholinsterases
show that only doses in excess of 100 Gy are significantly
deleterious, although lipid chain shortening is observed at
lower dose (Benderitter et al., 2003; Krokosz and
Szweda-Lewandowska,2005). However, isolated rat
synaptosomes show decreased 22
Na+
uptake after 1 Gy of
gamma rays (Mullin et al., 1986) and some tissue culture
cells exhibit alterations in Ca2+
transport after 1-4 Gy of
electrons (Todd and Mikkelsen, 1994) suggesting
sensitivity of ion channels. Direct measurements of
charged particle-induced lipid peroxidation of liposomes
shows that they are much less effective than X-rays
(Ziegler & Wessels, 1998).
In early studies, the conduction velocities of compound
action potentials along isolated frog and rabbit sciatic
nerves was found to be very resistant to radiation,
requiring in excess of 500 Gy to show conduction block
(Gerstner et al., 1955). Recent studies using patch clamp
recordings from mouse hippocampal slices indicate that
intrinsic membrane properties of pyramidal neurons are
resistant to change after 1-4 Gy of iron ions or 1-8 Gy of
protons (NSCOR, unpublished). Together these results
emphasize the stability of nerve functional properties to
radiation exposure. By contrast, the survival of cultured
NT2 human neural precursor cells is quite sensitive to
charged particles and shows significant LET-dependent
apoptosis and necrotic death at doses < 0.5 Gy (Guida et
al. 2005). Growth of new processes (neuritogenesis)
from neurons in chick retinal explants is also sensitive to
iron ions at doses below 0.5 Gy (Vazquez et al., 1994).
So, survival, growth and different-tiation properties of
neurons are radio-sensitive in the space radiation dose
range while the functional integrity of fully differentiated
neurons appears to be relatively stable.
Electrical Output of Nerve Ensembles
The primary function of systems of nerves is to generate
output signals in response to input from other neurons and
environmental cues. Early experiments using implanted
microelectrodes in rabbits measured spontaneous
electrical activity from a number of brain locations
including hippocampus, thalamus and cortex. Significant
decreases in the frequency and amplitude of spikes were
observed in most brain regions after 4 – 5 Gy at times up
to 6 hr, but the hippocampus exhibited hyperexcitability
along with changes in spike train organization that may be
associated with inhibitory neuron malfunction (Monnier
and Krupp, 1962). At higher doses (9 Gy) all activity was
suppressed. Visually-evoked potentials in mice irradiated
with 20 MeV deuterons exhibited spike amplitude and
firing pattern modifications after 5 Gy (Ordy et al., 1968)
and the pedal-pleural ganglion of the sea slug Aplysia
exhibited increased excitability after 10 Gy of 137
Cs
gamma rays (Clatworthy et al., 1999). Pellmar and
collaborators performed recordings on Guinea Pig
hippocampal slices during or shortly after irradiation and
demonstrated increases in synaptic efficacy (dendritic
response) while population spikes (somatic response)
were inhibited at gamma ray doses above 30 Gy (Pellmar
et al., 1990; 1993). All of the above observations
demonstrate that changes in output may occur within
hours after > 4 Gy of low LET radiation but do not
address late changes or responses to high LET radiation.
Recent field recording experiments conducted by
Vlkolinsky et al. (2007) under NASA funding (NSCOR,
unpublished) examined mouse hippocampal slices
isolated from 1 to 18 months following 0 to 4 Gy of
accelerated iron ions or protons. These demonstrated that
synaptic efficacy was increased long after irradiation and
led to hyperexcitability. However, in the simple long
term potentiation (LTP) model of memory, synaptic
remodeling between pyramidal neurons was inhibited
months after 1-2 Gy of iron ions. LTP is correlated with
hippocampus functions in spatial memory and learning
using behavioral measures. These electrophysiological
paradigms report alterations in the number and strength of
synapses as well as glutamate receptor function and are
mostly post-synaptic in their anatomical distribution.
Observations on the important neural adhesion molecule
NCAM, which regulates synaptic plasticity, show that it is
down-regulated after doses of 2.5 Gy of 1 GeV/n iron
ions in rats (Casadesus et al., 2005) and > 0.5 Gy of iron
ions in mice (NSCOR, unpublished). These observations
suggest that the output of systems of neurons (and their
associated glia) is altered after irradiation at the level of
connectivity between cells in the networks. Further, these
systems are vulnerable to charged particle doses of the
same order as predicted for long term space missions and
exhibit defects in information processing that underlies all
CNS functions. The observed hyperexcitability may also
indicate an enhanced susceptibility to seizures.
Neural Precursor Cells
The most radiosensitive cells of the CNS are neural
precursor cells (NPC). These astrocyte-like stem cells
located in the linings of the ventricles and in the
subgranular layer of the hippocampus continue to divide
throughout life in mammals. They differentiate into
astrocytes, oligodendrocytes and neurons which become
incorporated into neuronal circuits and contribute to
learning and memory. J.R. Fike and others have
demonstrated that X-ray doses of 2-5 Gy cause substantial
apoptosis of NPCs and continued reduction in the
production of immature neurons (Mizamatsu et al., 2003;
Rola et al., 2004). Lower doses of ~1 Gy iron ions result
in similar elimination of NPCs (NSCOR, unpublished).
Further, irradiation causes remodeling of the CNS
microenvironment resulting in a state that inhibits
differentiation of resident NPC descendents (or grafted
unirradiated NPCs) and the continued elevated production
of reactive oxygen species (Monje et al., 2002; Limoli et
al., 2007) and chronic activation of microglia (Rola et al.,
2004). Iron ions are much more effective than 250 MeV
3. G.A. Nelson — Neurological Effects of Space Radiation
Gravitational and Space Biology 22(2) September 2009 35
protons or X-rays (NSCOR, unpublished). The loss of
NPC regenerative capacity may lead to accelerated
learning and memory decline with age.
Behavioral and Cognitive Effects
Electrophysiological and neurogenesis experiments are
consistent with behavioral observations on rats and mice
irradiated with charged particles. Morris water maze and
Barnes maze experiments indicate that spatial memory
and learning are inhibited by doses as low as 0.1 Gy of
iron ions (Shukitt-Hale et al., 2000; Raber et al., 2004).
These behaviors are believed to be largely associated with
the hippocampus. Conditioned taste aversion to
amphetamine (but not lithium) in rats is inhibited at doses
of >0.1 – 0.8 Gy iron ions in rats implicating dopamine
pathways. Ascending scale operant conditioning studies
(food reward after lever pressing) also indicate that, in
rodents, cognitive abilities may be susceptible to low
doses of charged particles (2 Gy iron ions) (Rabin et al.,
2004).
But are humans susceptible to radiation in the low dose
regime? Adult radiotherapy patients treated for head,
neck and brain tumors have commonly reported
depression, confusion and lethargy; but these are
individuals receiving high localized doses and who have
underlying medical conditions. There are, however,
observations on human children that have shown
sensitivity of still-developing nervous systems to low
LET radiation. In Israel, a large cohort of children
(~20,000 of average age 7 years) were treated with a
mean dose of 1.3 Gy X-rays to cause depilation of the
scalp in order to facilitate treatment of tinea capitis fungal
infections. These children later showed poorer outcomes
in high school aptitude and IQ performance and more
frequent psychiatric disturbances in later life. (Ron et al.,
1982). A group of 6-18 month-old Swedish children
treated for cutaneous hemangioma (strawberry
birthmarks) on the head were followed-up at the time of
comprehensive testing prior to military enlistment (age 18
– 19 years). They showed cognitive impairments at doses
above 0.1 Gy and up to 32% decreases in high school
attendance (corrected for social influences) after frontal
lobe X-ray doses > 0.25 Gy (Hall et al., 2004). So,
human CNS tissue that is still undergoing growth and
differentiation is susceptible to space-like doses of low
LET radiation. Together with animal behavioral studies
this suggests that low doses of charged particles may be
of concern in adults, especially with respect to brain
regions or processes dependent on continued
neurogenesis.
Fluence-Based Assessment of the Cellular Target
In estimating risks from fields of charged particles,
especially at low doses, it has been useful to consider the
fluence of particles rather than the dose The planar
fluence is the number of particles that traverse a unit area
and dose is proportional to fluence and LET. In this way
the contributions from different particles expressed as the
probability of exhibiting an endpoint (such as mutation or
cell death) per particle type can be summed to estimate
the total probability. Using this strategy, Curtis et al.
have estimated the number of traversals of cell nuclei or
soma in different CNS structures for a reference 3-year
Mars mission (Curtis et al., 1998). They showed that
approximately 46% of cell somas (areas from 180 – 486
µm2
) and 7.6% of cell nuclei (areas 40 – 100 µm2
) in
human hippocampal cells would be traversed by at least
one particle of atomic number Z ≥ 15. By extension,
16,000 cells in the retinal macula, 2x107
cells of the
hippocampus, and 850,000 cells of the thalamus would be
“hit” by such heavy ions. These calculations were
motivated by cell survival as the significant endpoint but
experiments suggest that fully differentiated cells are
radioresistant for survival. Extensive modeling of
network failure modes in the hippocampus have shown
that a very high proportion of cells in the hilar region
must be lost before there are significant changes in
connectivity (Dyhrfjeld-Johnsen et al., 2007). This
suggests that minor cell loss would not lead to major
functional changes. The situation may be different for
radiosensitive NPCs, however. If they are preferentially
incorporated into new memories, then lower fractions of
cell loss may be significant.
From the discussion above on functional output, it can be
argued that dendritic and axonal arborizations may be the
more relevant cellular targets, so a re-examination of the
impact of fluence is in order. Neuroanatomical studies
have characterized the number and topology of neuronal
processes; from these studies, the properties of
hippocampal CA1 (subfield cornu ammonis 1) pyramidal
neurons are summarized below for the rat (Pyapali et al.,
1998; The Hippocampus Book, 2007):
• Cell soma diameter: 15 µm with cross sectional
area = 193 µm2
• Total dendritic length per cell: 1.2 – 1.3 cm at
1.0 to 2.5 µm diameter.
• Total axon length per cell: ~ 0.2 cm and diameter
< 1 µm.
• Total dendritic spines per cell: ~30,000.
• Total spine synapses per cell: 10,000 – 30,000
(of which only 16-26 need to fire
synchronously to generate action potentials).
From these dimensions and three dimensional
reconstructions of cells it was possible to calculate the
cross sectional area of a typical pyramidal cell at 11,800
+/- 3,200 µm2
(N=11) and the number density of
synapses at between 1 and 2 per µm3
. Using these areas
and the estimated Mars mission fluences from Curtis et al.
(1998), Poisson distribution calculations yield the
following. At solar minimum, with a fluence for Z ≥ 15
ions of 107,000/cm2
, each cell body would be traversed,
on average, by 0.21 particles (1 out of 5 cells) whereas
each arbor area would be traversed by 12.8 particles (a
128-fold greater value). At solar maximum, with a Z ≥ 15
fluence of 59,300/cm2
, the values are 0.14 hits per soma
and 7.1 hits per arbor (a 71-fold greater value). Thus,
essentially every cell will be traversed multiple times and
4. G.A. Nelson — Neurological Effects of Space Radiation
36 Gravitational and Space Biology 22(2) September 2009
the high interconnectivity of neurons is likely to spread
the influence of each traversal to many cells.
Another estimate can be made from the track structure of
the particles. Chatterjee and collaborators (Chatterjee and
Schaefer, 1976) employed a model for particle tracks that
describes the local dose as a function of radial distance
from the track axis. Applying their model to 600 MeV/n
iron ions or 250 MeV/n protons (which are relevant
energies for accelerator experiments, cosmic rays and
solar particle events) one may estimate that cylindrical
regions within 4.5 µm of an iron ion track axis will
receive ≥ 1 cGy dose and regions within 2 µm will receive
at least 5 cGy. For protons the corresponding radial
distances are 0.32 and 0.05 µm. At 2 synapses per µm3
this means that for iron ions, 25,132 synapses per
millimeter track length receive ≥ 5 cGy dose and
127,235/mm receive ≥ 1 cGy. For protons the values are
16/mm and 643/mm, respectively. If only 16-26 synapses
must be activated to initiate an action potential (The
Hippocampus Book, 2007), and if 5 cGy has a 10%
chance of activating a synapse, then for each millimeter of
iron track length, approximately 2500 synapses could be
activated and could, in turn, result in 100 action potentials
in interconnected neurons participating in the same
pathway or local circuit. Sufficient activation might
mimic the effects of high frequency (tetanic) stimulation
to neuron ensembles leading to persistent changes in their
synaptic strengths and efficacies. Perhaps the light
flashes perceived by astronauts during to the passage of
charged particles through their retinas reflect such
activation processes.
SUMMARY
In this brief review, several aspects of radiation effects on
the central nervous system were considered. It was
shown that although major necrotic and demyelinating
changes are not expected from exposures to space
radiation, there may still be enduring functional
consequences. While the excitability properties of mature
neurons are expected to be stable, their connectivity and
information processing properties may be persistently
altered. These alterations result in hyperexcitability,
perhaps with attendant seizure risks. Changes in
information processing due to synaptic changes and/or
depletion of newly-born neurons may also lead to reduced
cognitive abilities. Radiation-induced alterations in the
CNS microenvironment could stabilize an unfavorable
milieu for cell function and replacement possibly through
oxidative stress and inflammatory mechanisms.
Behavioral studies on young adult rodents exposed to
charged particles and observations of human children
exposed to photons have shown that performance
decrements can occur in the dose range associated with
space operations. Finally, a reconsideration of how
charged particle tracks interact with neuron structure
suggests that nearly every nerve cell’s dendritic or axonal
arborizations will be traversed by multiple cosmic rays
during a long duration space mission. Thus, earlier
estimates focusing on cell survival alone may
underestimate the potential for deleterious functional
changes.
ACKNOWLEDGEMENTS
The author wishes to thank the many co-investigators on
the NSCOR program project investigating the effects of
charged particles on the mouse hippocampus for
providing focus and perspective on the properties of the
central nervous system. Funding for this effort was
provided by NASA grant NNJ04HC90G.
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