Astronauts Study the Brain in Space

After I flew on the 1998 Neurolab Space Shuttle mission, people often asked me, “Why would you want to study the brain in space?” and “What did you learn?”

To answer those questions, we must go back to 1993, when NASA began preparing for Neurolab by sending out a request for research proposals to scientists around the world. From the proposals, 26 studies were chosen. During the 16-day mission, launched in April 1998 aboard the Space Shuttle Columbia, our seven-member crew not only conducted the experiments but often served as the subjects for them. Most of this work was performed in the Spacelab module, a bus-sized structure that fits in the payload bay of the space shuttle orbiter. Five areas of research—balance, sensory integration, sleep, blood pressure control, and nervous system development—were the focus of the Neurolab mission. The following cases illustrate why these areas are important.

Case #1: A 38-year-old man complains of unsteadiness while walking. Walking heel to toe is particularly difficult. He has no dizziness, but he did have an episode when he felt as though the room were moving when he turned his head from side to side. He has no weakness or numbness. Interestingly, he completed a 14-day trip on the Space Shuttle Columbia just two hours previously.

Could the trip in space have anything to do with his symptoms? The answer, of course, is yes. Exposure to weightlessness is the key factor. The balance system, composed of the gravity sensors in the inner ear and the connections they make within the brain to the eyes, cerebellum, and postural muscles, works against gravity every day on Earth. In weightlessness, when the usual clear gravitational sense of up and down disappears, the balance system must adapt and establish a new way to interpret the changed environment. The result of this adaptation is apparent after the flight when astronauts often have difficulty with balance. They have returned to Earth with a balance system that has adjusted to space.

The brain’s adaptations in space could take many forms. Perhaps the gravity sensors, noting that the inputs they usually receive have dropped dramatically, try to increase their sensitivity. Perhaps the neurons processing the balance information start to make new connections or use the existing connections in novel ways. Perhaps the information from the balance organs is interpreted differently, leading to unusual sensations for the astronauts. All of these possibilities were explored on the Neurolab mission.

Case #2: On Earth, an astronaut sticks out his hand to catch a ball dropped from the ceiling. The ball accelerates continuously, traveling faster as it falls, and the astronaut’s nervous system anticipates the movement and tightens his arm muscles before the ball hits his hand. In space, however, the ball would have to be pushed toward his hand and would not accelerate but, instead, move at a constant speed. When the astronaut tries to catch the ball in space, his arm muscles tighten sooner than they need to, before the ball hits.

This experiment suggests that the brain has an “internal model” of how gravity works, which would make it easier for the brain to anticipate where a ball (or another thrown object) is going to be. It also suggests something more profound: Gravity may not be just a pervasive force around us; a sense of gravity may actually be within us. Elements of the environment on Earth (the force of gravity, for example, or the fact that light comes from above) may be planted firmly within our nervous system. Studies in weightlessness could reveal how ideas about gravity or lighting are incorporated into the nervous system. Neurolab carried out studies to test these possibilities.

Several other questions could be asked about the integration of the senses and how this might change in space. Vision, balance, and position sense work together to provide the information needed for equilibrium, movement, and navigation. The brain can change the importance given to each of these senses. Also, the brain can use shortcuts to help solve movement and navigation problems more quickly, shortcuts that may include a built-in notion of how gravity works. Because in weightlessness the balance organs in the inner ear may not provide the usual inputs to the brain, perhaps the brain would start to depend on other senses, such as vision. Or the brain might interpret differently the information it receives from the balance organs.

Case #3: A 49-year-old shuttle commander goes to his physician for help with insomnia. He has no problems sleeping on Earth, but in flight he frequently uses medication to fall asleep. He shows the physician the package insert for the sleeping pill temazepam, which says: “Use extreme care while doing anything that requires complete alertness, such as driving a car, operating machinery, or piloting an aircraft.” Although flying a shuttle is not specifically mentioned, the physician is concerned. The physician notes that weightlessness does affect circadian rhythms in animals. Maybe spaceflight is affecting the commander’s circadian rhythms, making him feel jet-lagged. Should the physician suggest melatonin?

In space, sleep is often poor, particularly on short missions, and sleeping medications are among the most common drugs taken in flight. One possible reason for poor sleep is that the astronauts’ internal clocks get out of synchrony with their daily activities. Sleepiness, heart rate, hormone concentrations, and other physiological values rise and fall on a roughly 24-hour schedule. People who try to sleep when their internal clock says they should be awake, and those who try to function when their clock says they should be sleeping, may be fighting a losing battle against their own physiology.

One hormone that rises and falls on a 24-hour schedule is melatonin. Because the spike in its concentration closely matches the propensity for people to fall asleep, melatonin might offer a remedy for people who are jet-lagged or are trying to fall asleep when their biological clock says they should be wide awake. Melatonin might be a way to correct changes in astronauts’ circadian rhythms and improve their sleep. This question and others were an important part of the Neurolab sleep experiments.

Case #4: A 41-year-old woman complains of lightheadedness and feels faint when standing. She has never had symptoms like these before. She has no palpitations, diarrhea, or vomiting and takes no medications. She completed a space shuttle flight just hours ago.

Again, the exposure to weightlessness is critical to the diagnosis here. The head is above the heart when humans stand upright, so the cardiovascular system must work against gravity to keep blood flowing to the brain. Usually this happens easily and quickly, but this astronaut is having trouble maintaining brain blood flow when standing. How did her cardiovascular system change in space so that lightheadedness while standing became an issue after the flight?

Every time a person stands up, some blood leaves the chest and moves into the legs and abdomen. This means that the pressure at the input to the heart drops, which, in turn, reduces the amount of blood the heart pumps. If the cardiovascular system did not respond to this change, the pressure at the output of the heart (blood pressure) would fall markedly also, and the person would faint. But the cardiovascular system has sensors in the heart and main arteries that detect when blood pressure drops and signal the brain that action is needed. These pressure sensors, the baroreceptors, send information to the brain, and the brain in turn signals the heart and blood vessels to keep blood pressure stable.

Several possibilities may explain why astronauts have difficulty with blood pressure control after a flight. Perhaps the drop in pressure at the input to the heart when standing up is greater after spaceflight, or the pressure sensors are not responding as quickly or efficiently. The brain’s interpretation of the information from the pressure receptors may change, leading to an inadequate response. Or the blood pressure control system may be functioning normally, but the response of the heart and blood vessels to the signals from the brain may be inadequate. An examination of these different possibilities was part of the Neurolab mission.

Case #5: A female astronaut is considering a long space voyage with much time to be spent in weightlessness. She wonders what would happen if she were pregnant when she left and delivered her baby during the voyage. Would her child develop normally, or is gravity essential for normal development?

Balancing Acts—On Earth and Off

As shuttle crew members, we not only studied the brain and body changes that took place, but also, in many instances, directly experienced them. Effects on our balance system, for example, were noticeable right after landing. After Columbia touched down, back in the Earth’s gravity after 16 days, my crewmate Jim Pawelczyk, Ph.D., said, “Hey, lean your head forward.” I did and immediately felt as if I were tumbling forward. Small changes in head position produced exaggerated sensations of motion. Also, my gait was unsteady, and, when I climbed stairs, it felt as if the stairwell were moving up and down as I took each step. I could get around, but I was moving much more slowly and carefully than I had before I left.

The increased sensations we felt after the flight might have occurred because the saccule or utricle was more sensitive. Because the basic balance function of the inner ear is quite similar in fish and humans, studies of fish can be useful for understanding what happens in people. Using a novel electrode technology, a team of Neurolab researchers led by Stephen Highstein, M.D., Ph.D., examined the vestibular nerves supplying the utricle of four oyster toadfish, recording directly from these nerves during and after the flight. Using an apparatus that could move the fish in various rotations at various speeds, the researchers found that, on the first day after returning to Earth, the response from the utricle after a side-toside movement was three times greater in the rotated fish than with similar fish that had remained on Earth. Apparently the lack of gravity in flight had ramped up the sensitivity of the fish’s gravity sensors. But by 30 hours after returning, their responses were the same as those of the control fish that had stayed on Earth. Interestingly, 30 hours after returning to Earth, most of the obvious changes in my balance were gone, too.

Another team of Neurolab investigators, led by Muriel Ross, Ph.D., examined inner-ear hair cells. Previous spaceflight experiments showed a dramatic increase in the synapses between hair cells. Synapses are the points of contact at which nerve cells communicate, either by sending and receiving chemical messengers or through electrical impulses. This team wanted to confirm the increase in synapses and to determine how early this change takes place and how long it lasts. Tissue samples taken from the balance organs of rats on board showed that in the utricle the number of synapses increased dramatically as early as day 2 of the flight. Although the number declined by day 14, Neurolab rats still had more synapses overall than control rats on the ground.

One hypothesis is that the additional synapses gave the rats more information they could use in adjusting to their new environment. Indeed, an increase in synapses is a routine way in which the brain adapts to its environment. Learning new physical skills, for example, produces new synapses in the part of the brain devoted to the task. Another study, led by Gay Holstein, Ph.D., showed that weightlessness produced integral changes in the brain itself. The cerebellum, which is involved in movement coordination and motor learning, receives input from the gravity-sensing saccule and utricle. After 24 hours of spaceflight, key neurons in the cerebellum called Purkinje cells had reorganized some of their component parts into stacks, and the centers of enzyme activity within these neurons— the mitochondria—had become gigantic. On the basis of previous research, we know  that both phenomena can result from excitotoxicity (a type of cell damage resulting from excessive amounts of the chemical messenger glutamate), but also from the Purkinje cells’ adaptation to gravity.

Taken together, these discoveries demonstrated the ways in which weightlessness could have altered the astronauts’ nervous systems, but they also confirmed how adaptable the brain is, because it can adjust to weightlessness and then change itself back after a space mission. The Neurolab studies also showed that on a spacecraft situations may exist where sensory information from the balance system is unreliable. During landing, when gravity has been reintroduced, a sudden gust of wind or unexpected roll of the spacecraft might lead the pilot to overcompensate drastically if he relies solely on the information about tilt or roll he perceives with a space-adapted balance system. The space craft’s instruments will tell the truth, but the balance organs probably will not.

Information about balance gained through the Neurolab studies may also help researchers understand what happens to people with disorders that affect balance, such as vertigo or damage to the gravitational information pathways, which can occur with strokes and trauma.

Sensory Integration

In a remarkable book called Pride and a Daily Marathon, author and neurologist Jonathan Cole, M.D., tells the story of 19-year-old Ian Waterman, who woke up one morning unable to move. He had not been paralyzed—his muscles were fully functional—but Waterman had lost what is called position sense. The nerves carrying information about the location of his arms and legs from the sensors in muscles, tendons, and joints (information critical to control body movements) had been irreparably damaged by a rare neurodegenerative disease. Waterman was advised to get used to life in a wheelchair. But Waterman was a proud man, and, by the force of will, he trained himself gradually to navigate through the world by using his other senses. Eventually, against all expectations, he returned to work. The daily marathon in the book’s title refers to the enormous effort he invested in simple tasks such as standing and walking. Neurologically, the story reveals how a deficiency in one sense can sometimes be compensated by another. Because Waterman did not have position sense, he depended on vision and balance sense. Astronauts need to make a similar, although less dramatic, change. In space, they lose much of the information that the inner ear provided on Earth about movement. This may be compensated by a greater dependence on vision.

One of the experiments on Neurolab, led by Charles Oman, Ph.D., explored this change. If you have ever sat on a stationary train when the train on the next track started moving, you might have felt a strong, but erroneous, sense that you were moving. What happens in that situation is that the visual information about motion briefly overrides data from your balance system and position sense. This misleading feeling that one is moving can be produced by using a virtual reality headset. The wearer views a scene that appears to be a long hallway with walls moving past the viewer on either side, sometimes producing the sense that the viewer is moving down the hallway, instead of the hallway moving past the viewer. On Neurolab, we had a virtual reality system that produced a scene like this. In tests before flight, the sensation of motion produced by the hallway scene was weak, if it occurred at all. Toward the end of the Neurolab mission, I put on the headset and started the hallway scene while I was floating in front of one of the equipment racks. As soon as the scene began, the visual sense of motion was so strong that I instinctively put my hand out in front of me because I felt as though I was going to slam right into the rack. This reaction suggested that my brain had adapted in space and now was ranking visual information much more highly than on Earth.

Another experiment on Neurolab, designed by Alain Berthoz, Ph.D., and his team, looked at whether the brain has incorporated a model of how gravity works and uses this understanding in planning and integrating movements. The ball-catching experiment, described in Case #2, showed that the brain acted as though it assumed that the laws of gravity were still in operation and expected the ball to accelerate as it fell; therefore, arm muscles tightened before needed. This internal model, however, did adapt over time in weightlessness and became less pronounced.

Gravity and a Sense of Place

Mental maps that help us know where we are and how to get where we want to go are another kind of internal model. We know we have these maps, because we can navigate around familiar places, such as our homes, in the dark. The maps are contained in the hippocampus, a part of our brain that gives us our sense of space, place, and visual recognition. This structure is one of the most vulnerable to Alzheimer’s disease, and we know that people with Alzheimer’s can wander in neighborhoods they have lived in for years, unable to find their way home. They have lost the maps that once guided them.

The hippocampal neurons that encode our mental maps are remarkably specific. In a study published in 2003 in Nature, a team of researchers traced navigation and image recognition to individual neurons. From animal studies, we know that such neurons develop their codes (the link between a particular neuron and a particular place in the environment) by using information from balance organs, position sense, and vision, as well as from external landmarks. Understanding how this system works presents a significant challenge to neuroscientists because on Earth it is difficult to separate the possible roles of vision and balance in linking a particular neuron with a particular place.

Sleep and Circadian Rhythms

On Earth, the bright light of day keeps the body’s internal clock synchronized with the cycle of day and night. But when lighting cues become weak, the internal clock can get out of synch with the environment. On Neurolab, we did not have a consistent 12 hours each of light and darkness; the sun rose or set every 45 minutes, and the light levels inside the shuttle were dim and often erratic. This made it difficult to keep the body’s circadian rhythms linked to the activity schedule on board the shuttle. In addition, we were following a hectic schedule and wanted to make sure we completed all the experiments successfully. If this meant missing part of our scheduled sleep time, we did.

Sleeping was different in space. With nothing to settle into, my first attempt to sleep on the mission was disconcerting. Instead of sinking into a firm mattress and soft pillow, I floated above the surface of my sleep station (a kind of long cabinet that provided darkness and privacy). If I let my arms free, they floated in front of my face. Of course, some astronauts like to sleep floating, but I started putting things such as sweaters and running shoes underneath my sleeping bag to have the sense that something was supporting my back.

The Neurolab studies included a comprehensive look at sleep, circadian rhythms, and performance on the space shuttle, including a complete double-blind trial of the hormone melatonin for use in space. As the subjects of this study, on certain nights we wore suits with an array of sensors that measured our brain waves, respiration, and other biological activities. Our sleep-monitoring system provided the same data that a fully equipped sleep lab at a large research center could offer. Continuous recordings from an activity meter worn on the nondominant wrist kept track of when we were active or resting. Measurements of body temperature (from a pill we swallowed that measured temperature) gave an indication of our circadian rhythms.

Blood Pressure

Previous Spacelab studies showed that before flight all crew members could easily stand upright for 10 minutes. But given the same test shortly after landing, more than half of the crew members had to sit down before the time was up. Some investigators had suspected that this was because their autonomic nervous systems had become less active or less sensitive in space. The brain uses the autonomic system to regulate blood flow by slowing down or speeding up the heart or by constricting or dilating the arteries. These responses seem straightforward enough, but the body’s system for monitoring blood pressure is highly complex, using receptors located throughout the cardiovascular system to send information to the brain’s cardiovascular center, which makes the necessary adjustments. Surprisingly, Neurolab evidence failed to support the hypothesis that in space, without the stress of gravity, this system had become less sensitive.

In one experiment, Neurolab astronauts spent time in a clear plastic chamber that used suction on their legs to pull blood from the chest into the lower body, just as gravity does on Earth. During this stress, a type of ultrasound scan that can penetrate the skull measured blood flow in the brain. In addition, the nerve signals going to the blood vessels to make them constrict were measured with a fine electrode placed in a nerve near the subject’s knee—a technique called microneurography. By “stressing” the autonomic nervous system—decreasing air pressure inside the chamber, asking the subject to squeeze a handgrip or inserting the subject’s hand in a cold gel glove—a detailed picture emerged of blood pressure regulation in weightlessness.

Development in Space

Neuroscientists have discovered that to develop normally the brain must be exposed to normal stimuli from the environment at specific periods. In a Nobel prize-winning experiment, David Hubel, M.D., and Thorsten Wiesel, M.D., showed that when one eye of a young kitten was temporarily sealed, the animal would not see normally as an adult. Even though the formerly sealed eye was not injured, the brain regions serving the eye needed visual input at critical times for the brain to develop normally. (Sealing the eye at a late stage of development had no effect.) If this is true for vision, is there also a critical period when gravity must be present for the brain to develop normally?

A cluster of Neurolab experiments looked at the effect of weightlessness on the development of gravity sensors and balance systems. One study by Michael Wiederhold, Ph.D., and his team showed that snails reared in weightlessness developed more and 50 percent larger gravity-sensing crystals (similar to the otoliths in mammals) than their Earth-based counterparts. Eberhard Horn, Ph.D., showed that crickets brought on board as eggs and at several larval stages produced normal balance organs in space, but the connections these balance organs made further up in the nervous system were different. A study in rats by Jacqueline Raymond, Ph.D., showed similar results. Again, the gravity sensors themselves developed normally, but the connections they made in the brain, specifically within the vestibular nuclei and cerebellum, were different. Does proper wiring up of the balance system in the brain depend upon the effects of gravity?

Perhaps the most striking results were observed in the studies on the development of complex movements, such as walking. Earth dwellers seem to enter life ready to walk. Many prey animals, such as deer and horses, try to stand almost immediately after birth. In humans, within a few hours of birth, if you stretch a newborn’s arms over its head, it will make stepping movements. About a year later, the child’s first real steps are an important milestone, brought about by many months of practice. Infant rats also show a reflex related to gravity, known as the righting reflex. If you hold an infant rat on its back and then let it go, it will turn over, or right itself, in whatever way it can. As it matures, it will learn to right itself in an efficient and smooth way: first the head, then the forelimbs, then the rest of the body in one fluid motion.

A group of young rats on the Neurolab mission were in space during the time when they would ordinarily have been learning to walk and right themselves. When these rats were released from being held on their backs, they floated up without ever righting themselves. They felt no need to do so, because no input from the gravity sensors told them they were upside down. After returning to Earth, the rats could right themselves, but they never acquired the classic, smooth adult pattern. Fewer dendrites (protrusions that receive incoming signals) in their motor neurons were involved in postural control and righting. These rats may have needed gravity to develop a normal righting reflex.

Researchers also learned that, in the rats that had been on the flight, synapses were more numerous in the parts of the brain related to hind limb movement. The researchers, Kerry Walton, Ph.D., and her colleagues, surmise that rats reared in weightlessness have three dimensions to move in and six cage surfaces to “walk” on, as opposed to the usual two dimensions and one surface. This provides more stimulation to the relevant areas of the brain, which could increase the number of synapses. The data from Neurolab suggest an intriguing possibility that the flight rats, although deficient in their righting reflex, may be enriched in other areas as a result of the three-dimensional environment in which they grew up.

Weight-bearing muscles show profound changes when they have no weight to bear. On Neurolab, an antigravity muscle called the soleus grew poorly in rats 8 days old at launch. Their muscle fibers were smaller that those of the ground animals. Another study found that antigravity muscles were more impaired than muscles used for other tasks. In fact, not only was muscle growth poorer, but also the gene that produced proteins, called slow-type myosin heavy chains (MHCs), found in antigravity muscles was repressed in flight animals. This suggests that weight-bearing activity is essential for muscle development; without it, production of key proteins is slowed. What would this imply for the human fetus developing under conditions of weightlessness, since in humans some 60 percent of muscles are weight-bearing or antigravity?

In all, the development studies conducted on Neurolab suggest that crucial periods may exist in development when gravity must be present. This brings up an interesting question. Although we evolved on Earth, could we as easily live anywhere else? Most of the Neurolab work illustrates the brain has astonishing adaptability, but the adaptability does not last forever. The developing nervous system adapts to the influences it receives at particular times in development. After a critical period, however, the opportunity for wide-ranging adaptation fades; changes made during the adaptive period appear to be permanent. The Neurolab results, although not conclusive, suggest that only adults should venture into space right now. Long-term colonization of space stations or other planets may have to wait for artificial gravity.

The Neurolab Legacy

Throughout the 1990s, neuroscientists uncovered one fundamental truth after another about the nervous system. Researchers showed that neurogenesis (the birth of new neurons) continued throughout life and was integral to the brain’s wellbeing. Neurons in the damaged spinal cord proved able to regenerate, given the right conditions. New understandings took scientists beyond a strictly biochemical view. We know now that individual neurons fire in concert with each other in a highly synchronized way and that disruption of this synchronicity may lead to brain disorders. The body’s internal clock was identified in the brain, along with genes throughout the body that operate in accordance with a 24-hour day. The Decade of the Brain closed with a flourish. Research conclusively proved that both embryonic and adult brains contain stem cells—universal, protean precursors that can be manipulated to become many types of tissue—suggesting that some brain damage may be repaired.

Neurolab was NASA’s contribution to the Decade of the Brain, taking neuroscience into a novel environment: weightlessness. Gravity is such a pervasive force on Earth, it is difficult to understand its fundamental effects. Research in orbit allows questions to be asked that could not be addressed on Earth, such as whether gravity is essential for normal development, or whether the brain, when it plans movements, has some built-in notion about how gravity works. Knowledge about how the brain adapts to an environment such as weightlessness is important as space exploration moves forward. Also, many of the disturbances that astronauts experience, both in space and upon re-entry, have parallels in common brain disorders.

Often, the basic question about the value of research in Neurolab, and about research in space in general, comes down to whether it was worth the cost. It is easy, of course, to find other projects or social programs that might have been advanced using the money spent on Neurolab. But thinking this way ignores a larger issue. In the long run, the economic benefits gained from our investment both in the space program and in basic scientific research have been enormous.

Those of us using satellite services for entertainment, communications, navigation, or business probably do not give credit to the investment of government dollars in the basic technologies of rocket engines, radiation-resistant electronics, and solar cells. Similarly, when we use our computers, we may not think of the debt the microelectronics industry owes to the Apollo space program for building the first solid-state computer. Many of the biotechnology industries of today were made possible by government-funded research of previous years, much of it basic research.

When I am asked whether the research done on Neurolab will transform medicine or radically change neuroscience, I have to say that I don’t know. We made some fascinating discoveries, but, as with all basic research, only time will reveal their long-term effect. What I do know is that we must move forward with missions like Neurolab, or we may find that our greatest days of exploration and discovery are behind us.