- Email: [email protected]
Neuronal plasticity: adaptation and readaptation to the environment of space
Brain Research Reviews 28 Ž1998. 61–65
Short review
Neuronal plasticity: adaptation and readaptation to the environment of space Manning J. Correia
)
Departments of Otolaryngology and Physiology and Biophysics, UniÕersity of Texas Medical School at GalÕeston, GalÕeston, TX, USA
Abstract While there have been few documented permanent neurological changes resulting from space travel, there is a growing literature which suggests that neural plasticity sometimes occurs within peripheral and central vestibular pathways during and following spaceflight. This plasticity probably has adaptive value within the context of the space environment, but it can be maladaptive upon return to the terrestrial environment. Fortunately, the maladaptive responses resulting from neuronal plasticity diminish following return to earth. However, the literature suggests that the longer the space travel, the more difficult the readaptation. With the possibility of extended space voyages and extended stays on board the international space station, it seems worthwhile to review examples of plastic vestibular responses and changes in the underlying neural substrates. Studies and facilities needed for space station investigation of plastic changes in the neural substrates are suggested. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Vestibular system; Space flight; Adaptation; Sensorimotor integration
Contents .................................................
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1. Neurological changes seen during and after spaceflight 2. Vestibular sensory-motor rearrangement . 3. Changes in the neural substrate . 4. Conclusions .
5. Vestibular neuroscience studies
6. Facilities needed to conduct vestibular neuroscience studies aboard the international space station 7. Summary
Acknowledgements . References
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1. Neurological changes seen during and after spaceflight General neurological changes seen during and following spaceflight have been reviewed elsewhere w1x. These in)
Fax: q1-409-772-2694
clude space motion sickness ŽSMS. or space adaptation syndrome ŽSAS., postural illusions, visual disturbances, neuromuscular fatigue and weakness as well as postural imbalance and ataxia upon return to earth. For historical and medical reasons, much of the neuroscience research related to spaceflight in the past has focused on a sensory system, the vestibular apparatus Žthe semicircular canals
0165-0173r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 0 1 7 3 Ž 9 8 . 0 0 0 4 3 - 5
62
M.J. Correiar Brain Research ReÕiews 28 (1998) 61–65
and the otolith organs. and its related motor pathways. This is probably because Cosmonaut Titov, during the second human spaceflight in 1961, complained of disorientation, dizziness and emesis provoked by head movements Žsigns of SMS.. Furthermore, SAS has continued to afflict up to 67% of the astronauts w2x in the space shuttle era. This review will focus on neuro-vestibular research. However, in the era of the international space station, investigations in all areas of neuroscience will take place. The prospect of more experimental time to conduct protracted studies should attract payload specialists with varied interests and experience in many areas of neuroscience 2. Vestibular sensory-motor rearrangement Some of the clearest behavioral changes seen as a result of the space environment are the plastic sensory-motor rearrangements that occur during and following exposure to the space environment. For example, decreased postural stability following return to earth is observed in most astronauts immediately following spaceflight w3x. Thirteen crew members from six spaceflight missions were studied pre- and postflight using a modified commercial posturography system. Postural equilibrium control was found to be seriously disrupted immediately following spaceflight in all astronauts. However, readaptation to the terrestrial environment began immediately upon landing, proceeded rapidly for the first 10–12 h, and then continued much more slowly for the subsequent 2–4 days until preflight stability levels were achieved. Thus, it appears that the overall postflight recovery of postural stability follows a predictable time course w3x. In a number of spaceflight studies w4–7x, it has been concluded that the largest increases in postflight postural sway Žinstability. occurred during those test paradigms where both visual and proprioceptive sensory feedback information used for postural control were diminished thereby requiring reliance primarily upon vestibular function for control of upright stance. One study w8x used muscle potentials to investigate changes in the neural substrate Žotolith–spinal pathways. that might underlie postflight postural instability. Recordings were made from the soleus muscle during forced drops Žlinear translations. of astronauts in space and upon return to earth. It was found that during test periods early inflight the ‘H-reflex’ amplitudes were similar to those recorded during preflight testing but that measurements made later in the flight Žday seven. did not show a change in potentiation as a function of the different drop to shock intervals. Immediately postflight, ‘H-reflex’ responses in three of four astronauts tested showed a rebound effect. These results suggest that the otolith–spinal neural pathways might undergo a reversible change during and following short term spaceflight. Inflight and postflight responses related to the other major vestibular pathway, the vestibuloocular pathway, appear to change if the head movement stimulus does
involve or has at one time, in the earth’s gravity environment, involved stimulation of the otolith organs Žimplying a learned sensorimotor association.. When these prerequisite conditions do not exist, such as during pure horizontal head movements, changes during and following spaceflight are inconsistent. For example, the four payload crew members of the Spacelab Life Sciences 9-day spaceflight in 1991 were subjected to limited vestibular testing in flight. The eye movements and subjective responses to sudden stops following yaw angular rotation Žstimulation of the semicircular canals. and head pitching Žthat produces co-stimulation of the semicircular canals and otolith organs on earth. were measured both in space and on the ground. Although estimates of subjective duration of rotation for the tests in flight were shorter than that for the preflight tests, the postrotatory nystagmus duration, with or without head pitch, was lengthened relative to preflight w9,10x. The lengthening of the postrotatory nystagmus time constant without head pitch suggests that the environment of spaceflight can modify the horizontal vestibuloocular response initiated by the semicircular canals without costimulation of the otolith organs. But conflicting results come from studies of nine subjects during two space shuttle missions w11x. Active unpaced yaw head oscillation at 0.3 Hz was used as the stimulus to examine the gain and phase of eye movements relative to head movements with and without concomitant visual input Žto study visual suppression of the vestibuloocular response ŽVOR... No statistically significant changes were noted inflight in the gains or phase shifts of the VOR during any test condition. It was concluded that at this stimulus frequency, horizontal VOR gain was unaffected by spaceflight. Published reports of stimulation of the otolith organs following spaceflight have consistently cited VOR changes. Modulation of vergence of horizontal eye movements produced by off-axis rotation and presumably stimulation of the otolith organs was reduced 50% in two rhesus monkeys exposed to 11 days of spaceflight ŽCOSMOS 2229. w12x. Ocular counterrolling Žstimulation of the otoliths by tilt. was modified in the same two flight rhesus monkeys during testing; the counterrolling response was reduced by 70% w12x. Two responses that normally result from otolithic co-stimulation during pitch and roll head movements were also decreased during COSMOS 2229 postflight studies. The gain of torsional VOR was decreased by 15% and 50% in the two monkeys and up–down asymmetries in the vertical VOR noted preflight were decreased following exposure to microgravity w12x. By 10 days postflight, none of these responses had returned to preflight control levels. It remains to be determined whether these plastic changes are temporary or permanent. 3. Changes in the neural substrate Because of technical difficulties, direct electrophysiological studies of single or a small number of multiple
M.J. Correiar Brain Research ReÕiews 28 (1998) 61–65
neurons within the vestibuloocular and vestibulospinal pathways have been sparse. Sample numbers have been small and therefore interpretation of results have been difficult. The seminal efforts to record from otolith afferents in space were made by Bracchi et al. w13x in the early nineteen seventies. Recordings were made with metal microelectrodes chronically implanted in the otolith nerves of bullfrogs. Inflight, periodic fluctuations were observed in the responses of otolith afferents and unusual otolith afferent responses were noted during on board centrifugation. For example, two units changed their response to centrifugation from a phasic response to a tonic response and then back to a phasic response. For the past 20 years, no efforts have been made to repeat those studies even though it has been speculated for 35 years that the otolith organs are somehow involved in SMS and the unusual postural and ocular inflight and postflight responses summarized above. The international space station with an on board small animal centrifuge would provide the time and opportunity for a neurophysiologist to measure directly the adaptive responses of otolith afferents in the space environment. Single and multi-unit recordings have been made from a very small number of neurons in rhesus monkeys’ vestibular nerves and vestibular nuclei in space w14–16x. These studies were conducted on flights 1667 and 1887 of the COSMOS biosatellite series. Microelectrodes were chronically implanted in the medial vestibular nucleus, the vestibular nerve and the flocculus of the cerebellum. Neural recordings were taken while the monkeys made active horizontal head and eye movements to acquire a LED target for reward. Recordings were also made while the chair in which the monkeys sat was lifted and dropped. During the first flight ŽCOSMOS 1667. multi-unit activity in the medial vestibular nucleus increased during both the gaze and drop tests during flight days 2–5 but returned to preflight levels by flight day 6. During the second flight ŽCOSMOS 1887., increased neural activity was noted for recordings from the vestibular nerve and flocculus during flight days 1–3 when the gaze test was performed. By flight day 10, the neural responses in one case remained above and in another case declined below preflight levels. Vestibular nerve responses to the chair lift–drop test increased on the first flight day and remained elevated during the 10 day duration of the flight. Also as part of the COSMOS biosatellite program, single unit recordings were made from horizontal semicircular canal afferents in four rhesus monkeys within the first 48 h following spaceflight recovery and for 8–11 days thereafter. The alert monkeys were exposed to a series of passive yaw rotations about an earth vertical axis. Following flight 2044 Žstudies of two rhesus monkeys., it was found w17x that on postflight day 1, mean parameters characterizing the gain and degree of neural adaptation to step rotational velocities of 608rs of 9 horizontal semicircular canal afferents from two monkeys were statistically significantly higher Ž P - 0.001. than mean values from 15 control afferents. The mean gain and
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adaptation parameters remained higher than control values for postflight days 3–4 but had decreased by day 5 and by days 6–8 Žpooled data. the means had essentially returned to preflight control levels. These results were based on analysis of 107 responses from 29 afferents. Following flight 2229 two different monkeys were tested using the same rotational paradigms Žunpublished observations, Correia, Dickman, Perachio, and Kozlovskaya.. Two hundred forty six step responses were obtained from 72 horizontal semicircular canal afferents. On postflight day 1, mean gain from 12 afferents were statistically significantly lower Ž P - 0.001. than the mean Ž24 afferents. from preflight and synchronous controls. This statistically significant difference was still present on the 11th postflight day Žlast test day.. The mean parameter characterizing neural adaptation was only statistically significantly different from controls on the 11th postflight day. It is not clear why postflight recordings made from afferents following one flight ŽCOSMOS 2044. showed mean parameters indicating an increase in gain and neural adaptation while the mean postflight recordings made from a second flight ŽCOSMOS 2229. showed mean parameters indicating a decrease in gain and no change in neural adaptation. These conflicting results could be due to differences in flight conditions, individual differences in the monkeys’ strategies for dealing with the environment of space, the amount of monkey postflight testing, the postflight health of the animals or numerous other factors. But for both flights, the postflight responses of primary afferents innervating the horizontal semicircular canals were statistically significantly different from those of preflight and synchronous controls. These differences were present while concurrent tests of the horizontal VOR w12,18,19x, using the same step paradigms, revealed no differences in slow phase eye velocity between control animals and those that flew in space. These results suggest that compensation for the altered input from the vestibular sensory receptor Žthe semicircular canal. probably occurred within the central nervous system ŽCNS. vestibular pathways. This suggestion should be testable aboard the space station by making multiple single unit recordings from the vestibular nerve or the vestibular nuclei while recording eye movements. A series of neuroanatomical spaceflight studies w20,21x further suggests that plasticity occurs within the neural substrate of the vestibular pathways. Utricular maculae were harvested from ten flight and ten ground control rats beginning at ; 4.5 h. postflight. An almost equal number of maculae Žnine flight and nine control. were obtained nine days later. Flown rats showed abnormal posture and movement on the first day postflight and on the ninth postflight day flown animals’ posture had returned to that of the controls but some of them showed signs of acute stress. The total number of ribbon synapses between both type I and II hair cells and primary afferent terminals were statistically significantly higher in the flown animals. On postflight day nine, the total count of ribbon synapses were
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M.J. Correiar Brain Research ReÕiews 28 (1998) 61–65
still elevated in both types of hair cells but only for type I hair cells was the comparison with controls statistically significantly different.
4. Conclusions From the data reviewed above, it seems reasonable to conclude that as a result of spaceflight, changes occur in the peripheral vestibular system w17,20,21x Žboth semicircular canal and otolith end organs and nerves.. These changes persist for at least 9–11 days postflight. Behavioral manifestations of these changes are evident in vestibulo-spinal responses w3,5,7x and apparently most profoundly in vestibulo-ocular responses involving the otolith organs w12,18,19x. It is currently unknown whether vestibulo-ocular responses Žinvolving the otolith organs. or responses from the vestibular nerve return to preflight levels. Furthermore, it is unknown whether extended spaceflight will lengthen the duration or severity of the ill effects of terrestrial readaptation. There may be considerable variability between space travelers.
5. Vestibular neuroscience studies Following the format of this special issue, vestibular neuroscience studies that should conducted aboard the international space station and the facilities to support those studies are presented below. It is assumed that the space station environment will be one of microgravity. Ž1. It should be tested whether changes occur in the response of otolithic primary afferents in the space environment. Based on ground based studies it would be predicted that the response of otolith afferents to reduced levels of gravity should be the interpolated values between those observed for different magnitudes of positively and negatively directed polarization vectors w22,23x. However, other factors such as synaptic plasticity, ionic imbalance, release of excitatory or inhibitory second messengers or other factors could modify this expected response. Data should be taken at monthly intervals to determine the long term effects of the space environment. Correlative neuroanatomical studies of the ultrastructure of the otolith organs should be made. Data should be taken from flown animals as soon as possible following return to earth and at monthly intervals thereafter to determine the time course of readaptation. Ž2. It should be determined if the primary afferent response from the semicircular canals change in space. Ground based tests have suggested that in primates w17,24x Žbut not in all mammals w25x., the responses of the semicircular canals are not influenced by gravity. But factors other than the absence of gravity Že.g., stress, fluid shifts etc.. produced by the space environment may modulate this response which would be worth knowing to help
interpret findings that might result from inter-labyrinthine sensory conflicts in space. Correlative neuroanatomical studies should be made. Ž3. A series of electrophysiological recordings over time should be made in the vestibular nuclei to track CNS compensatory responses during adaptation to the space environment. These changes could take place in response to changes in primary afferent or other Že.g., cerebellar. inputs. Ž4. Ground based studies of the ultrastructure, neuronal response of the vestibular nerve and vestibular nuclei should be conducted postflight from animals exposed to very different periods of exposure to the space environment. For example, during ground based studies tissue and neural responses from animals exposed to the space environment for one to two years should be compared to age matched controls and animals exposed to the space environment for only several months. These studies could address the question of whether difference in exposure to the space environment augments or attenuates terrestrial readaptation and whether long space environment exposures permanently preclude terrestrial readaptation. Ž5. Studies of neuronal development and change within the vestibular pathways should be made. Since gravity is one of the factors that has persisted throughout our evolutionary history, it would be of fundamental interest to determine what role it has played in the development of neuronal structures in general and specifically in the development of one of the biological sensors of gravity, the otolith organs. Studies could be made of changes in the anatomy and physiology of neurons and nerve fibers within the vestibular pathways in general and of the otolith organs in particular during successive generations reared in microgravity.
6. Facilities needed to conduct vestibular neuroscience studies aboard the international space station The critical and indispensable piece of equipment for conducting high stringency studies of the effects of microgravity on the vestibular system aboard the space station is a small animal rotator with the capability to place the animal on the axis of rotation Žangular rotator. or off the axis of rotation Žsmall-arm centrifuge.. When used as a centrifuge, the device could provide a control for microgravity in numerous types of studies. The rotator could provide passive controlled stimulation of the otolith organs when used as a centrifuge and controlled stimulation of the semicircular canals when used as a rotator. Equally critical pieces of equipment should include the capability to make multiple extracellular recordings of action potentials from nerve fibers and cell bodies on the space station. Finally, facilities must be provided to permit fixation and manipulation of tissue aboard the space station. These facilities are critical for cellular and molecular biology studies in
M.J. Correiar Brain Research ReÕiews 28 (1998) 61–65
microgravity uncontaminated by the hyper-gravity associated with animal transport to and from the space station. 7. Summary There is provocative evidence from recent studies that the environment of space, with accompanying microgravity, produces plastic neural changes in the vestibular apparatus and its related pathways. Some of these changes underlie behavioral changes that are probably adaptive Žhave survival value. in the space environment. To date these changes, while initially maladaptive upon return to earth, significantly diminish following a readaptation period. But it is not known how difficult readaptation to the earth’s terrestrial environment will be following long and possibly a lifetime exposure to the microgravity of space. To understand the neurological and behavioral consequences of the adaptation and readaptation to different gravity environments will be the challenge of future space biology research. Acknowledgements Some of the studies cited in this mini-review were supported in part by a grant from NASA, NAG-2-446 to MJC. References w1x M.D. Fujii, B.M. Patten, Neurology of microgravity and space travel, Neurol. Clin. 10 Ž1992. 999–1013. w2x J.R. Davis, J.M. Vanderploeg, P.A. Santy, Space motion sickness during 24 flights of the space shuttle, Aviat. Space Environ. Med. 59 Ž1988. 1185–1189. w3x W.H. Paloski, M.F. Reschke, F.O. Black, D.D. Doxey, D.L. Harm, Recovery of postural equilibrium control following spaceflight, Ann. New York Acad. Sci. 656 Ž1992. 747–754. w4x D.J. Anderson, M.F. Reschke, J.E. Homick, S.A. Werness, Dynamic posture analysis of Spacelab-1 crew members, Exp. Brain Res. 64 Ž1986. 380–391. w5x F.O. Black, W.H. Paloski, D.D. Doxey-Gasway, M.F. Reschke, Vestibular plasticity following orbital spaceflight: recovery from postflight postural instability, Acta Oto-Laryngol.—Suppl. 520 ŽPt. 2. Ž1995. 450–454. w6x J.J. Collins, C.J. De Luca, A.E. Pavlik, S.H. Roy, M.S. Emley, The effects of spaceflight on open-loop and closed-loop postural control mechanisms: human neurovestibular studies on SLS-2, Exp. Brain Res. 107 Ž1995. 145–150. w7x W.H. Paloski, F.O. Black, M.F. Reschke, D.S. Calkins, C. Shupert, Vestibular ataxia following shuttle flights: effects of microgravity on otolith-mediated sensorimotor control of posture, Am. J. Otol. 14 Ž1993. 9–17.
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w8x M.F. Reschke, D.J. Anderson, J.L. Homick, Vestibulo-spinal response modification as determined with the H-reflex during Spacelab-1 flight, Exp. Brain Res. 64 Ž1986. 367–379. w9x L.R. Young, C.M. Oman, D. Merfeld, D. Watt, S. Roy, C. DeLuca, D. Balkwill, J. Christie, N. Groleau, D.K. Jackson et al., Spatial orientation and posture during and following weightlessness: human experiments on Spacelab Life Sciences 1, J. Vestib. Res. 3 Ž1993. 231–239. w10x C.M. Oman, C.F. Pouliot, A. Natapoff, Horizontal angular VOR changes in orbital and parabolic flight: human neurovestibular studies on SLS-2, J. Appl. Physiol. 81 Ž1996. 69–81. w11x W.E. Thornton, J.J. Uri, T. Moore, S. Pool, Studies of the horizontal vestibulo-ocular reflex in spaceflight, Arch. Otolaryngol.—Head Neck Surg. 115 Ž1989. 943–949. w12x M. Dai, T. Raphan, I. Kozlovskaya, B. Cohen, Modulation of vergence by off-vertical yaw axis rotation in the monkey: normal characteristics and effects of space flight, Exp. Brain Res. 111 Ž1996. 21–29. w13x F.T. Bracchi, T. Gualtierotti, A. Morabito, E. Rocca, Multiday recordings from the primary neurons of statoreceptors of the labyrinth of the bullfrog, Acta Otolaryngol., Suppl. 334 Ž1975. 5–27. w14x I.B. Kozlovskaya, B.M. Babayev, V.A. Barmin, Y.V. Kredich, M.G. Sirota, The effect of weightlessness on motor and vestibulo-motor reactions, Physiol. 27 Ž1984. S111–S114. w15x I.B. Kozlovskaya, E.A. Ilyin, M.G. Sirota, V.I. Korolkov, B.M. Babayev, I.N. Beloozerova, S.B. Yakushin, Studies of space adaptation syndrome in experiments on primates performed on board of soviet biosatellite ‘Cosmos-1887’, Physiol. 32 Ž1989. S45–S48. w16x M.G. Sirota, B.M. Babayev, I.B. Beloozerova, A.N. Nyrova, S.B. Yakushin, I.B. Kozlovskaya, Characteristics of vestibular reactions to canal and otolith stimulation at an early stage of exposure to microgravity, Physiol. 30 Ž1987. S82–S84. w17x M.J. Correia, A.A. Perachio, J.D. Dickman, I.B. Kozlovskaya, M.G. Sirota, S.B. Yakushin, I.N. Beloozerova, Changes in monkey horizontal semicircular canal afferent responses after spaceflight, J. Appl. Physiol. 73 Ž1992. 112S–120S. w18x B. Cohen, I. Kozlovskaya, T. Raphan, D. Solomon, D. Helwig, N. Cohen, M. Sirota, S. Yakushin, Vestibuloocular reflex of rhesus monkeys after spaceflight, J. Appl. Physiol. 73 Ž1992. 121S–131S. w19x M. Dai, L. McGarvie, I. Kozlovskaya, T. Raphan, B. Cohen, Effects of spaceflight on ocular counterrolling and the spatial orientation of the vestibular system, Exp. Brain Res. 102 Ž1994. 45–56. w20x M.D. Ross, Morphological changes in rat vestibular system following weightlessness, J. Vestib. Res. 3 Ž1993. 241–251. w21x M.D. Ross, A spaceflight study of synaptic plasticity in adult rat vestibular maculas, Acta Oto-Laryngol.—Suppl. 516 Ž1994. 1–14. w22x C. Fernandez, J.M. Goldberg, Physiology of peripheral neurons innervating otolith organs of the squirrel monkey: I. Response to static tilts and to long duration centrifugal force, J. Neurophysiol. 39 Ž1976. 970–984. w23x C. Fernandez, J.M. Goldberg, Physiology of peripheral neurons innervating otolith organs of the squirrel monkey: II. Directional selectivity and force response relations, J. Neurophysiol. 39 Ž1976. 985–995. w24x J.M. Goldberg, C. Fernandez, Responses of peripheral vestibular neurons to angular and linear accelerations in the squirrel monkey, Acta Oto Laryngol. 80 Ž1975. 101–110. w25x A.A. Perachio, M.J. Correia, Responses of semicircular canal and otolith afferents to small angle static head tilts in the gerbil, Brain Res. 280 Ž1983. 287–298.
Short review
Neuronal plasticity: adaptation and readaptation to the environment of space Manning J. Correia
)
Departments of Otolaryngology and Physiology and Biophysics, UniÕersity of Texas Medical School at GalÕeston, GalÕeston, TX, USA
Abstract While there have been few documented permanent neurological changes resulting from space travel, there is a growing literature which suggests that neural plasticity sometimes occurs within peripheral and central vestibular pathways during and following spaceflight. This plasticity probably has adaptive value within the context of the space environment, but it can be maladaptive upon return to the terrestrial environment. Fortunately, the maladaptive responses resulting from neuronal plasticity diminish following return to earth. However, the literature suggests that the longer the space travel, the more difficult the readaptation. With the possibility of extended space voyages and extended stays on board the international space station, it seems worthwhile to review examples of plastic vestibular responses and changes in the underlying neural substrates. Studies and facilities needed for space station investigation of plastic changes in the neural substrates are suggested. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Vestibular system; Space flight; Adaptation; Sensorimotor integration
Contents .................................................
61
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62
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62
.......................................................................
64
.............................................................
64
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64
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65
1. Neurological changes seen during and after spaceflight 2. Vestibular sensory-motor rearrangement . 3. Changes in the neural substrate . 4. Conclusions .
5. Vestibular neuroscience studies
6. Facilities needed to conduct vestibular neuroscience studies aboard the international space station 7. Summary
Acknowledgements . References
.....................................................................
65
..........................................................................
65
1. Neurological changes seen during and after spaceflight General neurological changes seen during and following spaceflight have been reviewed elsewhere w1x. These in)
Fax: q1-409-772-2694
clude space motion sickness ŽSMS. or space adaptation syndrome ŽSAS., postural illusions, visual disturbances, neuromuscular fatigue and weakness as well as postural imbalance and ataxia upon return to earth. For historical and medical reasons, much of the neuroscience research related to spaceflight in the past has focused on a sensory system, the vestibular apparatus Žthe semicircular canals
0165-0173r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 0 1 7 3 Ž 9 8 . 0 0 0 4 3 - 5
62
M.J. Correiar Brain Research ReÕiews 28 (1998) 61–65
and the otolith organs. and its related motor pathways. This is probably because Cosmonaut Titov, during the second human spaceflight in 1961, complained of disorientation, dizziness and emesis provoked by head movements Žsigns of SMS.. Furthermore, SAS has continued to afflict up to 67% of the astronauts w2x in the space shuttle era. This review will focus on neuro-vestibular research. However, in the era of the international space station, investigations in all areas of neuroscience will take place. The prospect of more experimental time to conduct protracted studies should attract payload specialists with varied interests and experience in many areas of neuroscience 2. Vestibular sensory-motor rearrangement Some of the clearest behavioral changes seen as a result of the space environment are the plastic sensory-motor rearrangements that occur during and following exposure to the space environment. For example, decreased postural stability following return to earth is observed in most astronauts immediately following spaceflight w3x. Thirteen crew members from six spaceflight missions were studied pre- and postflight using a modified commercial posturography system. Postural equilibrium control was found to be seriously disrupted immediately following spaceflight in all astronauts. However, readaptation to the terrestrial environment began immediately upon landing, proceeded rapidly for the first 10–12 h, and then continued much more slowly for the subsequent 2–4 days until preflight stability levels were achieved. Thus, it appears that the overall postflight recovery of postural stability follows a predictable time course w3x. In a number of spaceflight studies w4–7x, it has been concluded that the largest increases in postflight postural sway Žinstability. occurred during those test paradigms where both visual and proprioceptive sensory feedback information used for postural control were diminished thereby requiring reliance primarily upon vestibular function for control of upright stance. One study w8x used muscle potentials to investigate changes in the neural substrate Žotolith–spinal pathways. that might underlie postflight postural instability. Recordings were made from the soleus muscle during forced drops Žlinear translations. of astronauts in space and upon return to earth. It was found that during test periods early inflight the ‘H-reflex’ amplitudes were similar to those recorded during preflight testing but that measurements made later in the flight Žday seven. did not show a change in potentiation as a function of the different drop to shock intervals. Immediately postflight, ‘H-reflex’ responses in three of four astronauts tested showed a rebound effect. These results suggest that the otolith–spinal neural pathways might undergo a reversible change during and following short term spaceflight. Inflight and postflight responses related to the other major vestibular pathway, the vestibuloocular pathway, appear to change if the head movement stimulus does
involve or has at one time, in the earth’s gravity environment, involved stimulation of the otolith organs Žimplying a learned sensorimotor association.. When these prerequisite conditions do not exist, such as during pure horizontal head movements, changes during and following spaceflight are inconsistent. For example, the four payload crew members of the Spacelab Life Sciences 9-day spaceflight in 1991 were subjected to limited vestibular testing in flight. The eye movements and subjective responses to sudden stops following yaw angular rotation Žstimulation of the semicircular canals. and head pitching Žthat produces co-stimulation of the semicircular canals and otolith organs on earth. were measured both in space and on the ground. Although estimates of subjective duration of rotation for the tests in flight were shorter than that for the preflight tests, the postrotatory nystagmus duration, with or without head pitch, was lengthened relative to preflight w9,10x. The lengthening of the postrotatory nystagmus time constant without head pitch suggests that the environment of spaceflight can modify the horizontal vestibuloocular response initiated by the semicircular canals without costimulation of the otolith organs. But conflicting results come from studies of nine subjects during two space shuttle missions w11x. Active unpaced yaw head oscillation at 0.3 Hz was used as the stimulus to examine the gain and phase of eye movements relative to head movements with and without concomitant visual input Žto study visual suppression of the vestibuloocular response ŽVOR... No statistically significant changes were noted inflight in the gains or phase shifts of the VOR during any test condition. It was concluded that at this stimulus frequency, horizontal VOR gain was unaffected by spaceflight. Published reports of stimulation of the otolith organs following spaceflight have consistently cited VOR changes. Modulation of vergence of horizontal eye movements produced by off-axis rotation and presumably stimulation of the otolith organs was reduced 50% in two rhesus monkeys exposed to 11 days of spaceflight ŽCOSMOS 2229. w12x. Ocular counterrolling Žstimulation of the otoliths by tilt. was modified in the same two flight rhesus monkeys during testing; the counterrolling response was reduced by 70% w12x. Two responses that normally result from otolithic co-stimulation during pitch and roll head movements were also decreased during COSMOS 2229 postflight studies. The gain of torsional VOR was decreased by 15% and 50% in the two monkeys and up–down asymmetries in the vertical VOR noted preflight were decreased following exposure to microgravity w12x. By 10 days postflight, none of these responses had returned to preflight control levels. It remains to be determined whether these plastic changes are temporary or permanent. 3. Changes in the neural substrate Because of technical difficulties, direct electrophysiological studies of single or a small number of multiple
M.J. Correiar Brain Research ReÕiews 28 (1998) 61–65
neurons within the vestibuloocular and vestibulospinal pathways have been sparse. Sample numbers have been small and therefore interpretation of results have been difficult. The seminal efforts to record from otolith afferents in space were made by Bracchi et al. w13x in the early nineteen seventies. Recordings were made with metal microelectrodes chronically implanted in the otolith nerves of bullfrogs. Inflight, periodic fluctuations were observed in the responses of otolith afferents and unusual otolith afferent responses were noted during on board centrifugation. For example, two units changed their response to centrifugation from a phasic response to a tonic response and then back to a phasic response. For the past 20 years, no efforts have been made to repeat those studies even though it has been speculated for 35 years that the otolith organs are somehow involved in SMS and the unusual postural and ocular inflight and postflight responses summarized above. The international space station with an on board small animal centrifuge would provide the time and opportunity for a neurophysiologist to measure directly the adaptive responses of otolith afferents in the space environment. Single and multi-unit recordings have been made from a very small number of neurons in rhesus monkeys’ vestibular nerves and vestibular nuclei in space w14–16x. These studies were conducted on flights 1667 and 1887 of the COSMOS biosatellite series. Microelectrodes were chronically implanted in the medial vestibular nucleus, the vestibular nerve and the flocculus of the cerebellum. Neural recordings were taken while the monkeys made active horizontal head and eye movements to acquire a LED target for reward. Recordings were also made while the chair in which the monkeys sat was lifted and dropped. During the first flight ŽCOSMOS 1667. multi-unit activity in the medial vestibular nucleus increased during both the gaze and drop tests during flight days 2–5 but returned to preflight levels by flight day 6. During the second flight ŽCOSMOS 1887., increased neural activity was noted for recordings from the vestibular nerve and flocculus during flight days 1–3 when the gaze test was performed. By flight day 10, the neural responses in one case remained above and in another case declined below preflight levels. Vestibular nerve responses to the chair lift–drop test increased on the first flight day and remained elevated during the 10 day duration of the flight. Also as part of the COSMOS biosatellite program, single unit recordings were made from horizontal semicircular canal afferents in four rhesus monkeys within the first 48 h following spaceflight recovery and for 8–11 days thereafter. The alert monkeys were exposed to a series of passive yaw rotations about an earth vertical axis. Following flight 2044 Žstudies of two rhesus monkeys., it was found w17x that on postflight day 1, mean parameters characterizing the gain and degree of neural adaptation to step rotational velocities of 608rs of 9 horizontal semicircular canal afferents from two monkeys were statistically significantly higher Ž P - 0.001. than mean values from 15 control afferents. The mean gain and
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adaptation parameters remained higher than control values for postflight days 3–4 but had decreased by day 5 and by days 6–8 Žpooled data. the means had essentially returned to preflight control levels. These results were based on analysis of 107 responses from 29 afferents. Following flight 2229 two different monkeys were tested using the same rotational paradigms Žunpublished observations, Correia, Dickman, Perachio, and Kozlovskaya.. Two hundred forty six step responses were obtained from 72 horizontal semicircular canal afferents. On postflight day 1, mean gain from 12 afferents were statistically significantly lower Ž P - 0.001. than the mean Ž24 afferents. from preflight and synchronous controls. This statistically significant difference was still present on the 11th postflight day Žlast test day.. The mean parameter characterizing neural adaptation was only statistically significantly different from controls on the 11th postflight day. It is not clear why postflight recordings made from afferents following one flight ŽCOSMOS 2044. showed mean parameters indicating an increase in gain and neural adaptation while the mean postflight recordings made from a second flight ŽCOSMOS 2229. showed mean parameters indicating a decrease in gain and no change in neural adaptation. These conflicting results could be due to differences in flight conditions, individual differences in the monkeys’ strategies for dealing with the environment of space, the amount of monkey postflight testing, the postflight health of the animals or numerous other factors. But for both flights, the postflight responses of primary afferents innervating the horizontal semicircular canals were statistically significantly different from those of preflight and synchronous controls. These differences were present while concurrent tests of the horizontal VOR w12,18,19x, using the same step paradigms, revealed no differences in slow phase eye velocity between control animals and those that flew in space. These results suggest that compensation for the altered input from the vestibular sensory receptor Žthe semicircular canal. probably occurred within the central nervous system ŽCNS. vestibular pathways. This suggestion should be testable aboard the space station by making multiple single unit recordings from the vestibular nerve or the vestibular nuclei while recording eye movements. A series of neuroanatomical spaceflight studies w20,21x further suggests that plasticity occurs within the neural substrate of the vestibular pathways. Utricular maculae were harvested from ten flight and ten ground control rats beginning at ; 4.5 h. postflight. An almost equal number of maculae Žnine flight and nine control. were obtained nine days later. Flown rats showed abnormal posture and movement on the first day postflight and on the ninth postflight day flown animals’ posture had returned to that of the controls but some of them showed signs of acute stress. The total number of ribbon synapses between both type I and II hair cells and primary afferent terminals were statistically significantly higher in the flown animals. On postflight day nine, the total count of ribbon synapses were
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still elevated in both types of hair cells but only for type I hair cells was the comparison with controls statistically significantly different.
4. Conclusions From the data reviewed above, it seems reasonable to conclude that as a result of spaceflight, changes occur in the peripheral vestibular system w17,20,21x Žboth semicircular canal and otolith end organs and nerves.. These changes persist for at least 9–11 days postflight. Behavioral manifestations of these changes are evident in vestibulo-spinal responses w3,5,7x and apparently most profoundly in vestibulo-ocular responses involving the otolith organs w12,18,19x. It is currently unknown whether vestibulo-ocular responses Žinvolving the otolith organs. or responses from the vestibular nerve return to preflight levels. Furthermore, it is unknown whether extended spaceflight will lengthen the duration or severity of the ill effects of terrestrial readaptation. There may be considerable variability between space travelers.
5. Vestibular neuroscience studies Following the format of this special issue, vestibular neuroscience studies that should conducted aboard the international space station and the facilities to support those studies are presented below. It is assumed that the space station environment will be one of microgravity. Ž1. It should be tested whether changes occur in the response of otolithic primary afferents in the space environment. Based on ground based studies it would be predicted that the response of otolith afferents to reduced levels of gravity should be the interpolated values between those observed for different magnitudes of positively and negatively directed polarization vectors w22,23x. However, other factors such as synaptic plasticity, ionic imbalance, release of excitatory or inhibitory second messengers or other factors could modify this expected response. Data should be taken at monthly intervals to determine the long term effects of the space environment. Correlative neuroanatomical studies of the ultrastructure of the otolith organs should be made. Data should be taken from flown animals as soon as possible following return to earth and at monthly intervals thereafter to determine the time course of readaptation. Ž2. It should be determined if the primary afferent response from the semicircular canals change in space. Ground based tests have suggested that in primates w17,24x Žbut not in all mammals w25x., the responses of the semicircular canals are not influenced by gravity. But factors other than the absence of gravity Že.g., stress, fluid shifts etc.. produced by the space environment may modulate this response which would be worth knowing to help
interpret findings that might result from inter-labyrinthine sensory conflicts in space. Correlative neuroanatomical studies should be made. Ž3. A series of electrophysiological recordings over time should be made in the vestibular nuclei to track CNS compensatory responses during adaptation to the space environment. These changes could take place in response to changes in primary afferent or other Že.g., cerebellar. inputs. Ž4. Ground based studies of the ultrastructure, neuronal response of the vestibular nerve and vestibular nuclei should be conducted postflight from animals exposed to very different periods of exposure to the space environment. For example, during ground based studies tissue and neural responses from animals exposed to the space environment for one to two years should be compared to age matched controls and animals exposed to the space environment for only several months. These studies could address the question of whether difference in exposure to the space environment augments or attenuates terrestrial readaptation and whether long space environment exposures permanently preclude terrestrial readaptation. Ž5. Studies of neuronal development and change within the vestibular pathways should be made. Since gravity is one of the factors that has persisted throughout our evolutionary history, it would be of fundamental interest to determine what role it has played in the development of neuronal structures in general and specifically in the development of one of the biological sensors of gravity, the otolith organs. Studies could be made of changes in the anatomy and physiology of neurons and nerve fibers within the vestibular pathways in general and of the otolith organs in particular during successive generations reared in microgravity.
6. Facilities needed to conduct vestibular neuroscience studies aboard the international space station The critical and indispensable piece of equipment for conducting high stringency studies of the effects of microgravity on the vestibular system aboard the space station is a small animal rotator with the capability to place the animal on the axis of rotation Žangular rotator. or off the axis of rotation Žsmall-arm centrifuge.. When used as a centrifuge, the device could provide a control for microgravity in numerous types of studies. The rotator could provide passive controlled stimulation of the otolith organs when used as a centrifuge and controlled stimulation of the semicircular canals when used as a rotator. Equally critical pieces of equipment should include the capability to make multiple extracellular recordings of action potentials from nerve fibers and cell bodies on the space station. Finally, facilities must be provided to permit fixation and manipulation of tissue aboard the space station. These facilities are critical for cellular and molecular biology studies in
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microgravity uncontaminated by the hyper-gravity associated with animal transport to and from the space station. 7. Summary There is provocative evidence from recent studies that the environment of space, with accompanying microgravity, produces plastic neural changes in the vestibular apparatus and its related pathways. Some of these changes underlie behavioral changes that are probably adaptive Žhave survival value. in the space environment. To date these changes, while initially maladaptive upon return to earth, significantly diminish following a readaptation period. But it is not known how difficult readaptation to the earth’s terrestrial environment will be following long and possibly a lifetime exposure to the microgravity of space. To understand the neurological and behavioral consequences of the adaptation and readaptation to different gravity environments will be the challenge of future space biology research. Acknowledgements Some of the studies cited in this mini-review were supported in part by a grant from NASA, NAG-2-446 to MJC. References w1x M.D. Fujii, B.M. Patten, Neurology of microgravity and space travel, Neurol. Clin. 10 Ž1992. 999–1013. w2x J.R. Davis, J.M. Vanderploeg, P.A. Santy, Space motion sickness during 24 flights of the space shuttle, Aviat. Space Environ. Med. 59 Ž1988. 1185–1189. w3x W.H. Paloski, M.F. Reschke, F.O. Black, D.D. Doxey, D.L. Harm, Recovery of postural equilibrium control following spaceflight, Ann. New York Acad. Sci. 656 Ž1992. 747–754. w4x D.J. Anderson, M.F. Reschke, J.E. Homick, S.A. Werness, Dynamic posture analysis of Spacelab-1 crew members, Exp. Brain Res. 64 Ž1986. 380–391. w5x F.O. Black, W.H. Paloski, D.D. Doxey-Gasway, M.F. Reschke, Vestibular plasticity following orbital spaceflight: recovery from postflight postural instability, Acta Oto-Laryngol.—Suppl. 520 ŽPt. 2. Ž1995. 450–454. w6x J.J. Collins, C.J. De Luca, A.E. Pavlik, S.H. Roy, M.S. Emley, The effects of spaceflight on open-loop and closed-loop postural control mechanisms: human neurovestibular studies on SLS-2, Exp. Brain Res. 107 Ž1995. 145–150. w7x W.H. Paloski, F.O. Black, M.F. Reschke, D.S. Calkins, C. Shupert, Vestibular ataxia following shuttle flights: effects of microgravity on otolith-mediated sensorimotor control of posture, Am. J. Otol. 14 Ž1993. 9–17.
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w8x M.F. Reschke, D.J. Anderson, J.L. Homick, Vestibulo-spinal response modification as determined with the H-reflex during Spacelab-1 flight, Exp. Brain Res. 64 Ž1986. 367–379. w9x L.R. Young, C.M. Oman, D. Merfeld, D. Watt, S. Roy, C. DeLuca, D. Balkwill, J. Christie, N. Groleau, D.K. Jackson et al., Spatial orientation and posture during and following weightlessness: human experiments on Spacelab Life Sciences 1, J. Vestib. Res. 3 Ž1993. 231–239. w10x C.M. Oman, C.F. Pouliot, A. Natapoff, Horizontal angular VOR changes in orbital and parabolic flight: human neurovestibular studies on SLS-2, J. Appl. Physiol. 81 Ž1996. 69–81. w11x W.E. Thornton, J.J. Uri, T. Moore, S. Pool, Studies of the horizontal vestibulo-ocular reflex in spaceflight, Arch. Otolaryngol.—Head Neck Surg. 115 Ž1989. 943–949. w12x M. Dai, T. Raphan, I. Kozlovskaya, B. Cohen, Modulation of vergence by off-vertical yaw axis rotation in the monkey: normal characteristics and effects of space flight, Exp. Brain Res. 111 Ž1996. 21–29. w13x F.T. Bracchi, T. Gualtierotti, A. Morabito, E. Rocca, Multiday recordings from the primary neurons of statoreceptors of the labyrinth of the bullfrog, Acta Otolaryngol., Suppl. 334 Ž1975. 5–27. w14x I.B. Kozlovskaya, B.M. Babayev, V.A. Barmin, Y.V. Kredich, M.G. Sirota, The effect of weightlessness on motor and vestibulo-motor reactions, Physiol. 27 Ž1984. S111–S114. w15x I.B. Kozlovskaya, E.A. Ilyin, M.G. Sirota, V.I. Korolkov, B.M. Babayev, I.N. Beloozerova, S.B. Yakushin, Studies of space adaptation syndrome in experiments on primates performed on board of soviet biosatellite ‘Cosmos-1887’, Physiol. 32 Ž1989. S45–S48. w16x M.G. Sirota, B.M. Babayev, I.B. Beloozerova, A.N. Nyrova, S.B. Yakushin, I.B. Kozlovskaya, Characteristics of vestibular reactions to canal and otolith stimulation at an early stage of exposure to microgravity, Physiol. 30 Ž1987. S82–S84. w17x M.J. Correia, A.A. Perachio, J.D. Dickman, I.B. Kozlovskaya, M.G. Sirota, S.B. Yakushin, I.N. Beloozerova, Changes in monkey horizontal semicircular canal afferent responses after spaceflight, J. Appl. Physiol. 73 Ž1992. 112S–120S. w18x B. Cohen, I. Kozlovskaya, T. Raphan, D. Solomon, D. Helwig, N. Cohen, M. Sirota, S. Yakushin, Vestibuloocular reflex of rhesus monkeys after spaceflight, J. Appl. Physiol. 73 Ž1992. 121S–131S. w19x M. Dai, L. McGarvie, I. Kozlovskaya, T. Raphan, B. Cohen, Effects of spaceflight on ocular counterrolling and the spatial orientation of the vestibular system, Exp. Brain Res. 102 Ž1994. 45–56. w20x M.D. Ross, Morphological changes in rat vestibular system following weightlessness, J. Vestib. Res. 3 Ž1993. 241–251. w21x M.D. Ross, A spaceflight study of synaptic plasticity in adult rat vestibular maculas, Acta Oto-Laryngol.—Suppl. 516 Ž1994. 1–14. w22x C. Fernandez, J.M. Goldberg, Physiology of peripheral neurons innervating otolith organs of the squirrel monkey: I. Response to static tilts and to long duration centrifugal force, J. Neurophysiol. 39 Ž1976. 970–984. w23x C. Fernandez, J.M. Goldberg, Physiology of peripheral neurons innervating otolith organs of the squirrel monkey: II. Directional selectivity and force response relations, J. Neurophysiol. 39 Ž1976. 985–995. w24x J.M. Goldberg, C. Fernandez, Responses of peripheral vestibular neurons to angular and linear accelerations in the squirrel monkey, Acta Oto Laryngol. 80 Ž1975. 101–110. w25x A.A. Perachio, M.J. Correia, Responses of semicircular canal and otolith afferents to small angle static head tilts in the gerbil, Brain Res. 280 Ž1983. 287–298.