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Symposium on the Role of the Vestibular Organs in Space Exploration (1970)

Chapter: INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS

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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Suggested Citation:"INTERACTION BETWEEN VESTIBULAR AND NONVESTIBULAR SENSORY INPUTS." National Research Council. 1970. Symposium on the Role of the Vestibular Organs in Space Exploration. Washington, DC: The National Academies Press. doi: 10.17226/18593.
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Interaction Between Vestibular and Nonvestibular Sensory Inputs\ OTTAVIO POMPEIANO University of Pisa, Italy SUMMARY During the deep phase of sleep the activity of the second-order vestibular neurons increases phasically due to extralabyrinthine inputs to the vestibular nuclei. This activity leads to sudden con- tractions of somatic and extrinsic eye muscles (rapid eye movements, or REM sleep). Experiments have been performed to find out whether the increase in the vestibular discharge is also able to effect trans- mission of somatosensory volleys through the ascending lemniscal pathway. The orthodromic lemniscal response recorded from the contralateral medial lemniscus on single- shock stimulation of the forelimb nerves is phasically depressed during the bursts of REM. This effect rs still present after interruption of the spinocervical (Morin's) pathway, thus indicating that somatic afferent transmission through the cuneate nucleus is phasically depressed at this time. The synaptic mechanisms responsible for this effect have been investigated. In particular, the antidromic group II cutaneous and group I muscular volleys led, respectively, from the superficial and the deep radial nerves on single-shock stimulation of the cuneate nucleus are phasically enhanced during the bursts of REM. This increased excitability of the central endings of the cuneate tract fibers is taken to indicate presynaptic depolarization of the terminals of the primary afferents within the cuneate nucleus, thus leading to presynaptic inhibition of synaptic transmission through the cuneate nucleus. The excitability of the cuneate neurons has also been tested during sleep. It is shown that the direct excitability of the cuneothalamic relay neurons is depressed during REM, an effect which is attributed to postsynaptic inhibition of the cuneate neurons. This postsynaptic event, together with the presynaptic mechanism, contributes to the phasic depression of transmission of somatic afferent volleys through the cuneate nucleus at the time of the REM. Lesion experiments indicate that the increase in the vestibular activity occurring during REM is able to block the transmission of somatic afferent volleys within the dorsal-column nuclei through the roundabout way of the sensory-motor cortex. Contrary to the depressed transmission of somatic afferent volleys at dorsal-column level, the transmission of somatic volleys through the nucleus ventralis posterolateralis (V PL) is greatly facilitated during REM due to an increased postsynaptic responsiveness of the thalamic neurons. It is postulated that some part of the efferent vestibular activity giving rise to contractions of the limb musculature during REM is fed into the somatic sensory system, particularly the VPL nucleus, where it interacts with the incoming somatic information filtered at dorsal-column level. The reduced amplitude of the orthodromic volley due to active inhibitory events within the cuneate .nucleus has thus to be weighted against an increased excitability of the thalamocortical neurons. Further experi- ments are required to find out whether the vestibular control of somatic afferent transmission described during the deep phase of sleep is also operative during the motor activities produced by natural labyrin- thine stimulations in the awake animal. 1 This study was supported by PHS research grant NB 05695-03 from the National Institute of Neurological Diseases and Blindness, Public Health Service. 209

210 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION INTRODUCTION It is well known that physiological sleep of mammals consists of a synchronized phase, or light sleep, characterized by large-amplitude slow waves in the electroencephalogram (EEG), fre- quently grouped in spindles (ref. 1); a desyn- chronized phase, or deep sleep, characterized by low-voltage, fast cortical waves (refs. 2 and 3): and by complete abolition of the postural muscle activity (refs. 4 and 5). One of the typical fea- tures of this desynchronized phase of sleep is the sudden appearance from time to time of bursts of rapid eye movements, REM (refs. 2 to 7), often associated with a typical motor pattern, charac- terized by the occurrence of quick muscular contractions (ref. 8). This phase of sleep is present in man also, where a striking relation has been found between eye movements and dream activity (refs. 3, 6, 7, 9, and 10). In the attempt to investigate the central mech- anisms responsible for the hypnic discharges of the oculomotor and spinal motoneurons, the ob- servation was made that during this phase of sleep, the vestibular activity increases phasically (refs. 11 to 14). While during wakefulness the activity of the second-order vestibular neurons largely depends upon the discharge of different types of labyrinthine receptors, during desyn- chronized sleep the increase in the activity of the vestibular neurons, particularly those localized in the medial and descending vestibular nuclei, depends upon internal extralabyrinthine volleys. There is evidence that pontine structures, which are rhythmically active during desynchronized sleep (refs. 4 and 5), are at the origin of the out- bursts of vestibular discharge (ref. 15). While most of the electrophysiological investigations so far performed on the vestibular system utilized anesthetized or decerebrate preparations, we have given thought to the possibility of using the REM periods of desynchronized sleep as a tool to study central vestibular mechanisms in un- restrained, unanesthetized animals with the whole brain intact. It will be shown here that the vestibular dis- charge typical of the desynchronized phase of sleep is able to excite not only the oculomotor but also the spinal motoneurons (refs. 16 to 19). Muscle contractions which affect the somatic musculature during the bursts of REM are actu- ally associated with pyramidal discharges (refs. 20 to 22) which are triggered by ascending ves- tibular volleys (refs. 23 and 24). After the demonstration that the motor pat- tern typical of the REM phase of sleep depends upon the activity of the vestibular nuclei, we decided also to study how sensory communica- tion to the brain is processed during motor activities induced under strictly physiological conditions by vestibular volleys. The main result of these investigations is that during the REM phase of sleep, the centrally induced vestibular discharge is able to effect the trans- mission of sensory volleys at different relay stations of several sensory pathways (refs. 16 to 19). Paradigmatic in this connection is the series of events which affects the ascending transmis- sion of somatic sensory volleys through the dor- sal-column medial lemniscal pathway. The result is that just at the time of the REM bursts, i.e., when the vestibular activity increases thus leading to motoneuronal excitation, the ortho- dromic transmission of somatosensory volleys along the lemniscal pathway is partially blocked by active inhibitory processes which operate at the level of the dorsal-column nuclei through both mechanisms of presynaptic and postsynaptic inhibition (refs. 25 to 32). On the contrary, a facilitation of the sensory-evoked responses occurs at the level of the specific thalamic nuclei (ref. 33). RESULTS Vestibular Influences on the Oculomotor Nuclei Miii-in?; REM Experiments were performed in order to local- ize the structures responsible for REM. We have concentrated our attention on the vestib- ular complex, because the second-order vestib- ular neurons project directly or indirectly to the oculomotor nuclei, thus controlling their activity (ref. 34). It was then assumed that the vestib- ular nuclei which control eye movements were involved during the outbursts of REM of desyn- chronized sleep. A microelectrode analysis of the spontaneous activity of the vestibular nuclei

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 211 performed in the unrestrained, unanesthetized cat during natural sleep and wakefulness has shown that most of the neurons localized in the medial and descending vestibular nuclei, but not in the superior and lateral vestibular nuclei, increase their activity during desynchronized sleep (refs. 11 to 13). In particular, the pat- tern of discharge consists of bursts of rapid firing (80 to 160 spikes per second) which are invariably associated with the ocular movements typical of this phase of sleep. The increased activity of the units localized in the medial and descending vestibular nuclei indicates that these structures are in some way related to REM occurring during desynchronized sleep. The crucial proof was provided by the lesion of vestibular nuclei (refs. 35 to 37). The most impressive finding of these experiments is the demonstration that after well-defined vestibular lesions, the episodes of desynchro- nized sleep are still characterized by typical low-voltage, fast activity in the EEG and by complete electrical silence of the cervical antigravity muscles. However, the bursts of REM are completely abolished (fig. 1). The abolition of the typical bursts of REM lasted throughout the survival of the animal; i.e., up to 36 days after the lesion. Histologic control indicated that a complete and persistent abolition of REM occurs only when the lesion affects completely the medial and descending vestibular nuclei on both sides in their entire rostrocaudal extent. Bilateral and symmetrical lesions of either the superior or the lateral ves- tibular (Deiters') nucleus do not prevent the appearance of the bursts of REM. The abolition of REM is due neither to inter- ruption of primary vestibular fibers nor to lesion of cerebellofugal fibers which cross the area of the vestibular regions before reaching the brain- stem (refs. 38 and 39). A regular occurrence of REM could still be observed after bilateral chronic A EEG EOG B EEG EOG PT FIGURE I. —Integrated pyramidal discharge during desynchronized sleep in the normal preparation or after bilateral destruction of the vestibular nuclei. A: Experiment made 4 days after the operation. Note the large phasic enhancements in the pyramidal activity during the REM periods of desynchronized sleep. B: Experiment made 2 days after chronic implantation of the electrodes and complete bilateral destruction of the medial and descending vestibular nuclei. Note the absence of the large bursts of REM and related phasic enhancements of pyramidal discharge. Desynchronized phases of sleep recorded from unrestrained, unanesthetized cats. Bipolar records. EEG: Electroencephalogram. EOG: Electro-oculogram. PT: In- tegrated activity of the pyramidal tract. Voltage calibrations: 0.2 mK (EEG) and 0.5 mK (EOG). Time calibration: 5 sec. (From ref. 24.)

212 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION section of the vestibular nerves or complete cerebellectomy (refs. 35 to 37). The conclusion is drawn that the medial and descending vestibu- lar nuclei represent a necessary link in the causal chain of events leading to the activation of the oculomotor nuclei which is responsible for the REM outbursts. Vestibular Influences on Spinal Motoneurons During REM A typical phenomenon that occurs during desynchronized sleep is represented by the rapid muscle contractions which appear at the time of REM (ref. 8). The pattern and the organization of these muscular contractions have been studied in unrestrained cats by recording simultaneously the activity from flexor and extensor muscles of proximal and distal parts of both hindlimbs and from the posterior neck muscles (ref. 8). Muscu- lar contractions have been found in all hindlimb muscles tested. They are generally more prominent in flexor than extensor muscles, and are more frequent in distal muscles than in proxi- mal ones. The fact that section of the dorsal roots does not influence the frequency nor the pattern of the muscular contractions indicates that these are basically due to phasic excitatory influences acting directly upon the a-motoneu- rons. We are not going to describe here in detail the pathways responsible for the muscular twitches. Suffice it to say that the vestibular volleys may reach the spinal motoneurons, not only through pathways coursing along the ventral funiculus, where the descending efferent projec- tions from the vestibular nuclei are located, but also particularly through pathways coursing along the dorsolateral funiculus. One of the main descending tracts located in this region is the corticospinal tract. Evarts (refs. 40 to 42) was the first to record the discharge of single pyramidal-tract neurons in precentral gyruses of unanesthetized monkeys during natural sleep and wakefulness. A simi- larity was found between wakefulness and desyn- chronized sleep with respect to the average unit activity in pyramidal-tract neurons. Striking differences, however, were found in the temporal patterns of discharge during the two experimental conditions. While relaxed wakefulness was associated with a regular discharge, bursts of activity alternating with periods of silence ap- peared during synchronized sleep (ref. 43), which became much more intense and were separated by long intervals of complete inactivity during the desynchronized phase. The same result was also obtained by recording the pyram- idal discharge from single fibers originating from the postcentral gyrus (refs. 44 and 45). Further experiments devoted to an analysis of the integrated activity of the pyramidal dis- charge during desynchronized sleep have shown that the striking increase in the activity of the pyramidal tract originating from the precentral motor cortex is related in time to the outbursts of REM (refs. 20 to 22, 44, and 45). The muscular contractions, therefore, appear to be associated not only with the REM, as stated above, but also with outbursts of pyramidal discharges. After the demonstration that the medial and descending vestibular nuclei are responsible for the oculomotor activity during the REM bursts, an attempt was made to find out (1) whether the increase in the pyramidal discharge related in time with the REM depends upon the integrity of the vestibular nuclei, and (2) whether the destruction of these nuclei also prevents the appearance of the muscular twitches (refs. 23 and 24). The bilateral destruction of the vestibular nuclei did not abolish the modulation of the inte- grated pyramidal discharge during synchronized sleep. Only the phasic increase of the integrated pyramidal activity related in time with the large bursts of REM depends upon ascending vestibu- lar volleys, since they disappeared following a bilateral destruction of the vestibular nuclei (fig. 1). It is of interest that even the large muscular contractions which occurred syn- chronously with the REM were abolished by the vestibular lesions (refs. 23 and 24). Summing up, a complete, bilateral lesion of the medial and descending vestibular nuclei abolishes the typical bursts of REM. In this experimental condition the episodes of desyn- chronized sleep are simply characterized by the typical low-voltage, fast activity in the EEG and by complete abolition of the neck muscular activity. The integrity of the medial and de- scending vestibular nuclei is necessary not only

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 213 for the occurrence of the bursts of REM during desynchronized sleep, but also for the appear- ance of the phasic increases in the pyramidal discharge and the related muscular contractions. Transmission of Sensory Volleys Through the Cuneate Nucleus During REM A preliminary study was concerned with the modulation during sleep of synaptic trans- mission at the level of the dorsal column nuclei in the lemniscal system (refs. 25 and 30). Pre- vious experiments had shown that the ortho- dromic lemniscal response elicited by cutaneous afferent volleys is not affected by sleep (refs. 46 and 47). In particular, neither the amplitude (refs. 46 and 47) nor the latency of this response (refs. 48 and 49) appeared to be modified during desynchronized sleep as compared with the synchronized phase. However, the electro- oculogram was not recorded in these experi- ments; the phasic effects that could be related in time with the REM were possibly missed. Our experiments were performed in un- restrained, unanesthetized cats (refs. 25 and 30). The electroencephalogram (EEG), the electro- myogram (EMG) of the posterior cervical muscles, and the electro-oculogram (EOG) were recorded through chronically implanted electrodes as described in a previous paper (ref. 50). To stimulate the left superficial or deep radial nerve, a bipolar collar-type electrode was applied to the nerve at the level of the elbow, while the lem- niscal response was recorded from the contra- lateral side through a pair of stainless-steel electrodes (100 microns) completely insulated except at the tip (interelectrodic distance less than 0.5 mm). All the electrode leads were then soldered on tube sockets held tightly on the skull by dental cement. The experiments started 36 to 48 hours after the end of the operation, when the effects of the anesthesia had worn off. Depression of Orthodromio Lemniscal Response Single-shock stimulation of the superficial radial nerve with rectangular pulses 0.05 msec in duration produces a large action potential in this preparation, which can be recorded from the contralateral medial lemniscus. It appears at a latency of about 3.7 msec (range 3.5 to 4.0 msec) and increases with increasing stimulus strengths until it reaches a maximum amplitude for stimu- lus intensities corresponding to about 2.2 to 2.5 times the threshold (T) for the response. Ob- servations in which the orthodromic lemniscal response was recorded simultaneously with the antidromic volley led from a branch of the super- ficial radial nerve, distally to the stimulating electrode, clearly showed that the threshold for the orthodromic lemniscal response corresponded to about 1.05 times the threshold for the anti- dromic group II volley (ref. 51). Since, with our recording technique, there was no further growth in both amplitude and duration of the lemniscal potential for intensities above 2.2 to 2.5 r, it is apparent that the orthodromic lem- niscal response was exclusively a result of stimulation of group II cutaneous afferents. Excitation of group III cutaneous afferents gen- erally occurs at stimulus strengths above 3.5 to 4.0 T times the threshold for group II cutaneous afferents. At the beginning of the experiment the animal soon became accustomed to the volleys elicited by single-shock stimulation of group II afferent fibers of the superficial radial nerve. No EEG arousal was observed when the stimulation was carried out at the repetition rate of one every 1.6 to 2.0 seconds on a background of cortical synchronization. This can be easily understood since no collaterals are given off by the axons of the cuneothalamic relay neurons to the reticular formation (refs. 52 to 58). During transition from quiet-waking to synchronized sleep, there was no significant change in the amplitude of either the early or the late component of the orthodromic lemniscal response. Nor was any significant difference found in the amplitude of the evoked potentials by comparing the spindle periods with the interspindle lulls (fig. 2A). A distinction has been made previously be- tween tonic manifestations, which occur through- out the desynchronized phase of sleep, and phasic phenomena, such as the rapid eye movements (REM) and the muscular twitches (ref. 8). No tonic changes of the lemniscal response can be detected during transition from synchronized to desynchronized sleep, nor at the end of the episode, when the EMG activity reappears in

214 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION 3O 20 - I0 - ../ ••'• v •••".• •" ' • •••.. • ."• •• • •• • c ."' mVl -05 mV I 30 -\ 20 - 10 • a.. b. c IOms« FIGURE 2.—Modulation of the orthodromic lemniscal response during a typical episode of desynchronized sleep. A: Synchronized sleep. B and C: Desynchronized sleep with large bursts ofREM. There is a great stability of the lemniscal response durinf synchronized sleep and no tonic change in amplitude of the response appears during the desynchronized episode. A phasic depression of the evoked potential occurs only during the large bursts of REM, as indicated by the arrows. Note, however, the stability of the responses during isolated ocular jerks or during the small train of low frequency ocular movements in C. See figure 3 for explanation of dashed horizontal lines a through c. Unrestrained, unanesthetized cat. Experiment per- formed 2 days after chronic implantation of the electrodes. 1: Signals of the electrical shocks applied to the left superficial radial nerve (rectangular pulses: 1 every 1.9 seconds, 0.05-msec pulse duration, 3 times the threshold (T) for the lemniscal response). 2: Electro-oculogram (EOG); 3: Left parieto-occipital (EEG). 4: Right parieto-occipital (EEG). 5: Electromyo- gram (EMG) from posterior cervical muscles. The amplitude of the orthodromic response of the right medial lemniscus is represented by the dots. (From ref. 30.)

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 215 C 10msec FIGURE 3.— Phasic depression of the orthodromic lemniscal response during a REM period of desynchronized sleep. Same animal and experiment as in figure 2. The records indicate the orthodromic lemniscal responses recorded from the right medial lemniscus following stimulation of the left superficial radial nerve before (a), during (b), and after (c) a burst of REM, as illustrated in figure 2 where the amplitudes of the responses are plotted diagrammatically. Note the large phasic depres- sion of the lemniscal response which appears during a large burst of REM, particularly when the ocular movements reach a very high repetition rate (compare b in figs. 2 and 3). (From ref. 30.) the cervical muscles. The orthodromic lemnis- cal responses, however, are phasically de- pressed during the bursts of REM. Figure 26 and C shows that the phasic depressions (arrows) are related in time with the large bursts of REM. The records a, b, and c, of figure 3 were taken at the moments labeled as a, b, and c in figure 2C. The third record from the left, in figure 36, shows a striking reduction in amplitude. It is clearly related in time with a strong outburst of REM (see fig. 2C). The average depression of the lemniscal re- sponse during the REM corresponds to about 15 to 20 percent of the average amplitude recorded during the intervals between the REM. It should be noted, moreover, that not every burst of REM was associated with a depression of the orthodromic lemniscal response. Only when the REM bursts were strong and pro- longed was the depression observed; it generally did not outlast the end of the outburst. A clear-cut relationship between intensity of the lemniscal depression and repetition rate of ocular movements within a burst of REM is shown by figure 4. This fact would suggest that mechanisms of temporal summation are involved both in the production of the large bursts of REM and in the depression of the lemniscal responses. The phasic depression of the lemniscal re- sponse is not due to interaction between the electrically induced volley and the propriocep- tive afferent volleys related with the short- lasting contractions of the limb musculature, since it is observed also in the absence of these muscle contractions. The hypothesis of a phasic inhibition of synaptic transmission at the level of the dorsal-column nuclei is supported by experiments to be reported in the next section. One might simply ask now which pathway contributing to the orthodromic lemniscal re- sponse is influenced during sleep. The classi- cal scheme postulates that proprioceptive and exteroceptive volleys ascending along the dorsal column are relayed by the gracile and cuneate nuclei and project, through the medial lemniscus, onto the ventrobasal thalamic nuclei of the oppo- site side. There are, however, two subsidiary pathways to the sensory cortex; their primary relays are localized in the spinal cord, not far above the segmental level of the dorsal roots of entry. One pathway, discovered by Morin (ref. 59), ascends along the dorsolateral funiculus

216 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION - 5 -10 -15 -20 -25 -30 1234567 REM(c/s) FIGURE 4. —Relation between repetition rate of ocular move- ments during the bursts of REM and the amplitude of the orthodromic lemniscal responses. Same animal as in figures 2 and 3; same experiment. The abscissa gives the repetition rate of the ocular movements (c/s) within each burst of REM. The ordinate gives the amplitude of the response of the right medial lemniscia to single-shock stimu- lation of the left superficial radial nerve during the trains of REM. The amplitude is calculated as percentage of the mean control value X obtained during the intervals between the REM. Each point represents the average value of meas- urements taken during 3 bursts of REM. The greater the depressions of the orthodromic lemniscal responses, the higher the repetition rate of the ocular movements. (From ref. 30.) of the same side to the lateral cervical nucleus, to relay thence to the thalamus and hence to the cortex. The other is the spinothalamic tract ascending contralaterally to the nuclei of the thalamus and hence to the cortex. It is generally stated, however, that there are few if any spino- thalamic fibers in the cat. It has recently been shown, moreover, that the dorsal-column tracts contain not only primary afferents but also axons of spinal units synaptically driven by afferent fibers. These secondary fibers are located in the deep part of the dorsal funiculi and are in- fluenced by cutaneous fibers and by high- threshold muscular afferents (refs. 60 and 61). Our experiments clearly show that the lemniscal responses recorded from the right medial lemnis- cus on single-shock stimulation of the left superficial radial nerve and their sleep modu- lation were apparently unmodified after sec- tion of the dorsolateral funiculus, leading to interruption of the spinocervical pathway (ref. 62) as well as after interruption of the deep part of the dorsal funiculi. The dorsal-column tracts (gracile and cuneate). which were spared by the lesion, were therefore responsible for the transmission of the cutaneous afferent volleys to the contralateral medial lemniscus. The results show that after that lesion, a phasic depression of the orthodromiC lemniscal response occurred during the REM. On the other hand, after the section limited to the dorsal funiculi, thus sparing the spinocervical tract, the sleep changes of the lemniscal responses were no longer statistically significant. Summing up, in the free-moving, unanesthe- tized cat, the orthodromic lemniscal response elicited by single-shock stimulation of the super- ficial radial nerve was not modified during relaxed wakefulness and synchronized sleep. Striking changes, however, were observed during the phase of desynchronized sleep. Although the orthodromic lemniscal responses were not altered tonically during the desynchronized phase of sleep, a phasic depression occurred synchronous with the large bursts of REM. Moreover, a depression of the orthodromic lemniscal response during the REM bursts was still present after interruption of the ipsilateral spinocervical path- way. It can be concluded that somatic afferent transmission through the dorsal-column system is greatly depressed during the REM periods of desynchronized sleep. Presynaptic and Postsynaptic Inhibition of Transmis- sion of Somatic Afferent Volleys Through the Cuneate Nucleus During REM The experiments reported in the previous section have led to the conclusion that the sleep modulation of the orthodromic lemniscal response was mainly caused by reduced transmission of somatic afferent volleys through the dorsal- column pathway. It has been shown in acute experiments that a depression of synaptic trans- mission through the dorsal-column nuclei may be produced under several experimental condi-

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 217 lions through both mechanisms of presynaptic and postsynaptic inhibition (refs. 63 to 66). A presynaptic mechanism is indicated by the occur- rence of depolarization of the terminals of primary afferent fibers within the cuneate nucleus (refs. 64 and 65), an effect exactly comparable to the depolarization of the intraspinal endings of pri- mary afferent fibers (ref. 67).2 The hypothesis of presynaptic inhibition is also supported by the fact that, in the cuneate nucleus, there are inter- neurons with properties similar to those inter- neurons in the spinal cord which are postulated to be interpolated as the presynaptic inhibitory pathway (ref. 66). Electron-microscopic obser- vations have recently shown the existence of axo-axonic contacts in the cuneate nucleus (refs. 68 to 70). A postsynaptic inhibitory mecha- nism can be documented (1) by the appearance of inhibitory postsynaptic potentials (IPSP's) recorded intracellularly from the cuneothalamic relay cells, and (2) by a decrease in the excita- bility of cuneate cells to direct electrical stimula- tion. Experiments were then performed in order to analyze whether these mechanisms of presynap- tic and postsynaptic inhibition were involved in the modulation of synaptic transmission occur- ring at the level of the dorsal-column nuclei dur- ing physiological sleep (refs. 26 to 28 and 31). Since these experiments had to be performed in unrestrained, unanesthetized animals, no intra- cellular recording could be made. Indirect evi- dence to be presented in this paper leads to the conclusion that both mechanisms of presynaptic and postsynaptic inhibition are responsible for the phasic depression of the orthodromic lemnis- cal response occurring during the periods of REM. The presynaptic hypothesis was tested by studying sleep changes in the excitability of the cutaneous and muscular primary afferents to the cuneate nucleus close to their synaptic terminals. Antidromic volleys were elicited in the superficial and deep radial nerves by single- 2 It is assumed that prrsynaptic depolarization leads to a reduction in the si/.e of the orthodromic spikes at the pre- synaptic terminals and. hence, to a reduction in their effective- ness in exciting the postsynaptic membrane. At the same time presynaptic depolarization implies an increase in the antidromic response to direct stimulation of the terminals. shock stimulation of the cuneate nucleus, follow- ing Wall's method (ref. 71). The postsynaptic hypothesis was tested by studying the excita- bility changes of the cuneate cells, by recording the lemniscal responses to direct electrical stimulation of the cuneate nucleus. For this purpose, a stimulating electrode was implanted chronically within the cuneate nucleus. This electrode was made from a steel wire, 100 microns in diameter, sharpened electrolytically until the tip reached a diameter of less than 5 microns. It was then completely insulated except at the tip and the resistance was usually of the order of 500 kilohms. The cuneate nucleus was stimulated monopolarly with single rectangular pulses, negative in polarity, 0.02 to 0.05 msec in duration. The intensity of the stimulus was expressed in multiples of the threshold (T) for the antidromic or the direct lemniscal response. It was then possible to study in the unrestrained, unanesthetized animal either the modulation during sleep of the anti- dromic responses, recorded monopolarly from the superficial or the deep radial nerve, or the modu- lation of the orthodromic lemniscal responses to direct stimulation of the cuneate nucleus. In some experiments both types of responses could be recorded simultaneously or separately during successive episodes of sleep. Excitability Changes of Presynaptic Fibers in the Cuneate Nucleus Figure 5 gives the anatomical localization of the tip of the stimulating microelectrode in the cuneate nucleus in one of our experiments. After unipolar stimulation of the cuneate nucleus, antidromically conducted impulses were recorded in the superficial or deep radial nerves. Figure 5 shows the antidromic responses led from the superficial (a) and the deep radial nerve (6) on single-shock stimulation of the ipsilateral cuneate nucleus in unanesthetized, free-moving animals. In figure 5a the antidromic volley recorded from the superficial radial nerve started with a latency of about 1.92 msec and had a total duration of about 1.70 msec. Since the conduc- tion distance was 160 mm. the conclusion can be drawn that in this experiment, the conduc- tion velocity of the fastest antidromically invaded fibers corresponded to 83 m/sec. The conduc-

218 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION I I I FIGURE 5.— Antidromic and orthodromic responses elicited by single-shock stimulation of the cuneate nucleus in unrestrained, unanesthetized cat. In the upper part of the figure a transverse section of the medulla, stained with Nissl's method, shows the localization of the tip of the stimulating electrode in the cuneate nucleus, a: Anti- dromic responses of the superficial radial nerve to single- shock stimulation of the ipsilateral cuneate nucleus with an electrical pulse of 0.02 msec, 2.0 times the threshold for the antidromic response (T). Time scale in msec. Voltage calibration: 10 p.V. b: Antidromic responses of the deep radial nerve to single-shock stimulation (0.03 msec, 2.5 T) of the ipsilateral cuneate nucleus. Time scale in msec. Voltage calibration: 20 fJiV. c and d: Responses of the medial lemniscus to single-shock stimulation of the contralateral cuneate nucleus. Single electrical pulses (0.02 msec) at increasing stimulus strengths (from c to d) have been used. Time scales in msec. Voltage calibration: 100 p.V. Note the higher sweep speed in d. In c and d the latency of the initial a-spike is 0.77 msec while the secondary, or fi-spike, has a latency of 1.43 msec, i.e., 0.66 msec longer than the a-spike. Note the double configuration in c of the fi-spike due to a second com- ponent beginning about 1.2 msec after the first and the presence on the decaying phase of this second fi-spike of a third wavelet. (From ref. 31.) tion velocities of the fastest group II cutaneous fibers in the dorsal columns and peripheral nerves are of the same order (ref. 51). When recording was made from the deep radial nerve (fig. 56), an antidromic volley started with a latency of about 1.85 msec and had a total duration of about 0.65 msec. Since in this experiment the conduction distance was 185 mm, the conduction velocity of the fastest antidromically invaded afferent fibers corre- sponded to 100 msec. This high conduction velocity indicates that group I afferent muscle fibers are involved in the antidromic response from the deep radial nerve. The excitability changes of the intracuneate endings of group II (cutaneous) and group I (muscular) afferents were then studied during the different episodes of sleep and wakefulness. The size of the antidromic potential was taken as an approximate measure of the number of primary afferent fibers to the cuneate nucleus excited by the stimulus. Continuous recording started 10 to 20 minutes after the beginning of low-rate repetitive stimulation of the cuneate nucleus (1/1.5 to 2.0 seconds, 1.3 to 1.8 T). Movements were not elicited by the cuneate stimulation, nor was any EEG arousal produced when the stimulation was carried out on a back- ground of behavioral drowsiness and cortical synchronization. The antidromic potentials led from group II cutaneous fibers were rather constant during quiet wakefulness. Fluctuations in amplitude were of course detected, as shown by the fact that the standard deviation corresponded on the average to 10 percent of the mean amnlitude. During the transition from quiet waking to synchronized sleep, no significant changes in either mean amplitude or standard deviation of group II antidromic volleys were recorded from the superficial radial nerve, nor was there any clear-cut difference found between the periods characterized by trains of synchronous waves and the interspindle lulls. The main changes in amplitude of the antidromic volley occurred during desynchronized sleep. In this stage of sleep there was a slight increase in the mean amplitude of the antidromic group II volley, which never exceeded the value of 5 to 8 percent with respect to that obtained during the synchronized phase. A detailed analysis of the relation between

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 219 excitability changes of the intracuneate terminals of primary somatosensory fibers and phasic events occurring during desynchronized sleep indicates that the average size of the antidromic responses recorded during the REM corre- sponded to 125 percent of the mean value found during synchronized sleep. During these out- bursts the standard deviation increased to reach 20 to 25 percent of the mean amplitude. On the contrary, the mean amplitude and the standard deviation of the responses recorded during the same episodes of desynchronized sleep in the absence of REM closely corre- sponded to the values obtained during syn- chronized sleep. A correlation between in- crease in the antidromic group II cutaneous volley and ocular movements turned out to be particularly evident when the bursts of REM were composed of high-rate, large-amplitude move- ments (fig. 6). The phasic enhancement of the a b d sec 500 >jV 50 50 - 5 . II-I5 •* lv*» I6-20 I0 juV 5 msec FIGURE 6. — Phasic increase in amplitude of the antidromic group II cutaneous volley during a REM period of desynchronized sleep. Unrestrained, unanesthetized cat. Experiment made 2 days after implantation of the electrodes, a: Signals of the electrical stimuli (0.02 msec, 2 T, I every 1.6 seconds) applied to the left cuneate nucleus, b: Electro-oculogram (EOG). c: Left parieto-occipital {EEG), d: Posterior cervical muscles (EMC). The cathode-ray oscilloscope records show 20 anti- dromic responses of group II cutaneous fibers of the left superficial radial nerve following single-shock stimulation of the cuneate nucleus before (1-6), during (7-13), and after (14-20) a burst of REM, as illustrated above. Note the enhancement of the antidromic response (7-13) that occurs during the REM burst. (From ref. 31.)

220 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION antidromic volley in most cases lasted through- out the duration of the outburst. Although the correlation between bursts of REM and enhancement of the antidromic potentials is clear, we noted that not every ocular burst was associated with an enhance- ment of the antidromic potential. To explain this finding, a correlation was made between excitability changes of intracuneate endings of group II cutaneous fibers and repetition rate of the ocular movements within the REM. In particular, the average amplitudes of the anti- dromic responses recorded during bursts of REM in which the ocular movements occurred at the same repetition rate were compared with the average value obtained from the responses that occurred during the same episode of de- synchronized sleep but in the absence of REM. Figure 7 shows that the higher the repetition rate of the ocular movements within the REM burst, the greater was the increase of the antidromic response. It had been previously shown that not only cutaneous but also group I muscle afferents from forelimb nerves project to the dorsal-column-medial-lemniscal system (refs. 72 to 80). It is of interest that the anti- dromic group I volley recorded from the deep radial nerve on single-shock stimulation of the ipsilateral cuneate nucleus also showed modu- lation during wakefulness and sleep similar in kind to that which affected the antidromic group II volley recorded from the superficial radial nerve. Figure 8 shows the phasic enhancement of the antidromic group I volley during desynchro- nized sleep occurring at the time of a large burst of REM. The degree of enhancement was of the same order as that described for the group II cutaneous volley in the same experi- mental condition. These results indicate that depolarization of presynaptic intracuneate endings of both cu- taneous and muscular afferent fibers occurs dur- ing REM. It is well established that presynap- tic inhibition acts by decreasing the amplitude of the presynaptic impulses, thus reducing their excitatory influence on the postsynaptic mem- brane (ref. 67). These observations fit the hypothesis that, synchronously with the REM 10 I 2 3 4 5 6 7 REM (c/sI FIGURE 7. —Relationship between rate of ocular movements within bursts of REM and the enhancement of the ami- dromic group Il cutaneous volley. Same animal and ex- periment as in figure 6. The dots represent the amplitudes of the antidromic group 11 cutaneous volley recorded from the left superficial radial nerve on single-shock stimulation of the ipsilateral cuneate nucleus during the REM periods of desynchronized sleep. The abscissa indicates the repeti- tion rate (c/s) of ocular movements within the bursts of REM; the ordinate indicates the amplitude of the anti- dromic response during the trains of REM calculated as percentage of the mean control value X obtained during the intervals between the REM. Each point represents the average value of measurements taken during .3 bursts of REM. The enhancement of the antidromic response ii clearly related with the repetition rate of the ocular move- ments within the bursts of REM. (From ref. 31.) outbursts, the synaptic transmission at the level of the relay neurons of the dorsal column nuclei is inhibited by a presynaptic mechanism. In fact, a phasic depression of the orthodromic medial lemniscal response to single-shock stim- ulation of the radial nerves always occurred during the REM phase of desynchronized sleep (refs. 25 and 30). This phasic depression of the lemniscal response, however, is not simply the consequence of a presynaptic inhibitory action. It will be shown in the next section that post- synaptic inhibition is likely to contribute to the

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 221 a 1 1 1 1 1 1 1 I i 1 1 1 1 1 1 500>jV c 50 sec 50 juV 6 -i0 -15 I msec FIGURE 8. — Phasic increase in amplitude of the antidromic group I muscular volley during a period of REM of desynchronized sleep. Experimental arrangment same as in figure 6 (electrical pulses: 0.03 msec, 1.54 T). The records show 15 anti- dromic responses of group 1 muscular fibers led from the left deep radial nerve following single-shock stimulation of the cuneate nucleus before (1-5), during (6, 7), and after (8-15) a burst of REM. A clear-cut enhancement of the antidromic response (6, 7) occurs during the REM burst. (From ref. 31.) phasic depression of the orthodromic responses during REM. Excitability Changes of the Cuneothalamic Relay Neurons It has been shown by previous authors (ref. 63) that when a brief current pulse is applied through a microelectrode to the cuneate nucleus of the anesthetized cat, an initial brief positive spike (a-spike), followed by a much more pro- longed and complex positive potential (j8-spike), can be recorded from the lemniscal axons in the contralateral ventrobasal complex of the thala- mus. Similar potentials could be easily identi- fied also in our experiments, where single- shock stimulation of the cuneate nucleus was made in the unanesthetized cat through an im- planted microelectrode, while the evoked poten- tial was recorded from the contralateral medial lemniscus with a narrow bipolar electrode (refs. 26 to 28 and 31). Figure 5c and d shows the kind of evoked potentials recorded in our experimental conditions at various sweep speeds. In agreement with the finding of previous authors, we observed that the latency of the initial spike (a-spike) is so short (0.7 to 0.8 msec)

222 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION that it must be due to impulses generated by direct stimulation of cuneothalamic relay neurons or their axons. The secondary, or /3-spike, had a latency of 0.7 to 0.8 msec longer than the a-spike, a time just adequate for monosynaptic transmis- sion; it was attributed, therefore, to direct excitation of presynaptic fibers and consequent synaptic excitation of cuneate neurons (ref. 63). The /3-spike may have a simple configuration, characterized by a rising phase, followed by a slow decay. It may have, however, a double configuration, the second wave beginning about 1.0 to 1.2 msec after the first (ref. 63). This observation has been attributed to the fact that transsynaptic excitation evokes a double discharge from most of the cuneate neurons (ref. 66). In figure 5c, the decaying phase of the /3-spike complex indicates that some cuneate neurons discharged three or even more impulses. During relaxed wakefulness, both the a- and the /3-spikes were produced by each stimulus. These responses were regular in amplitude and only slight fluctuations occurred. The standard deviation with respect to the mean amplitude was slightly higher for the a- than for the/3-spike, and corresponded to 15 and 10 percent of the mean amplitude, respectively. During the transition from quiet wakefulness to synchronized sleep, there were no significant changes in both mean amplitude and standard deviation of the a- and /3-spikes, nor was there any clear-cut difference found between the periods characterized by trains of synchronous waves and interspindle lulls. The main changes in cuneate cell excitability occurred during desynchronized sleep. In this phase of sleep there was a slight depression of both the a- and /J-spikes; the mean amplitudes corresponded to 96 and 94 percent, respectively, of the value obtained during synchronized sleep. The decrease in the mean amplitude of the re- sponses was accompanied only by slight changes in the standard deviation. A detailed analysis of the relation between cuneate neuron excita- bility and the events occurring during desyn- chronized sleep indicated that the depression of both the a- and /3-spike was not a tonic phe- nomenon, since it did not occur during the inter- vals between the large bursts of REM; it did not occur, moreover, when the ocular movements appeared to be isolated or grouped in small bursts. A depression of the lemniscal responses actually occurred only when large bursts of REM appeared in the electro-oculogram. At this time both a- and /8-spikes were generally depressed. Figure 9 shows the changes in amplitude of both the lemniscal responses elicited by direct stimulation of the cuneate nucleus during desynchronized sleep and their depression at the time of the large bursts of REM, while figure 10 illustrates those responses plotted in figure 9 which occur at the time of two large bursts of REM. To obtain a statistical evaluation of the rela- tive depression affecting a- and /3-spikes during REM, the mean amplitude of both the responses occurring during phasic bursts of ocular move- ments was compared with the mean amplitude of the responses that occurred during the same episodes of desynchronized sleep, but in the absence of REM. The a-depression was gen- erally smaller than the /3-depression. This finding is particularly evident in figure 11, where a correlation has been made between the fre- quency of the ocular movements within the bursts of REM and the depression of the responses. This analysis was performed since it had been found that not every ocular outburst was asso- ciated with a depression of the lemniscal re- sponses. Figure 11 shows that the more frequent the ocular movements within the REM burst, the greater was the a- and ^-depressions. However, the degree of depression was greater for the /3-spike than for the a-spike. When this occurred, the /3-depression was generally longer lasting than the a-depression. This different time course of the depression of a- and /3-excita- bility during the REM episodes is particularly evident in figures 96 and 106, where a-depression is limited to the larger amplitude, higher fre- quency ocular movements, associated and fol- lowed by a larger and more prolonged /3-depres- sion. Whenever a depression of the lemniscal re- sponses elicited by direct stimulation of the cuneate nucleus occurred at the time of the REM, there was also a phasic depression of the ortho-

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 223 A1 /~\ r 1 05 mVl FIGURE 9. — Modulation of the lemniscal responses to direct stimulation of the cuneate nucleus during the large bursts of REM. Unrestrained, unanesthetized cat. Experi- ment made 5 days after implantation of the electrodes. Bipolar records. 1: Signals of the electrical shocks applied to the left cuneate nucleus {rectangular pulses: I every 2 sec, 0.05 msec, 2.15 times the threshold (T)/or the direct lemniscal response); 2: Elec- tro-oculogram (EOK); 3: Left pnrieto-occipital (EEG); 4: Posterior cervical muscles (EMG). The amplitudes of both the a-spike (empty circles) and the ft-spike \filledcircles) recorded from the right lemniscus on single-shock stimulation of the left cuneate nucleus have been plotted below. A. B. C: Episode of desynchronized sleep, during which time there are phasic depressions of the lemniscal responses. They are observed only synchronausly with the largest bursts of REM. The early potentials (empty circles) are less depressed than the late potentials (filled circles). See figure 10 for explanation ofdasheii lines a thrnugh f. (From ref. 31.)

224 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION I °A A A b A A A -A A A A A ,' »\ ,< -A A FlGURE 10. — Phasic depressions of the lemniscal responses to direct stimulation of the cuneate nucleus during REM periods of desynchronized sleep. Same animal and ex- periment as in figure 9. The records indicate the responses recorded before (a, d), during (b, e) and after (c, f) the bursts of REM, as illustrated in figure 9. In this same figure the amplitude of the cathode-ray oscilloscope re- sponses has been plotted diagrammatically. Note the large phasic depression of the lemniscal responses that appears during two bursts of REM characterized by high repetition rate of ocular movements. Note also in b the quick recovery in the amplitude of the a-spike, as compared to some persistent depression of the ft-spike, following the underlined response. (From ref. 31.) dromic lemniscal response recorded from the medial lemniscus on single-shock stimulation of the superficial radial nerve. Also, this depres- sion occurred during the REM periods. In figure 12 the mean amplitude and the standard deviations of such orthodromic and direct lem- niscal responses recorded in the same experi- ment during different EEG backgrounds can be compared with the mean amplitude and the standard deviation of the antidromic group II cutaneous volley recorded in another experiment from the superficial radial nerve on single- shock stimulation of the cuneate nucleus during corresponding EEC backgrounds. It is clear from this figure that the depression of the a- and /3-excitability during REM parallels that of the orthodromic lemniscal response, while the enhancement of presynaptic excitability is vir- tually a mirror image of that depression. The conclusion of our experiments is that excitability changes of the cuneothalamic relay neurons as tested by direct stimulation of the cuneate nucleus actually occur during a certain phase of sleep. In agreement with previous findings (refs. 25 and 30) that the orthodromic lemniscal response + 5 X - 5 - 10 - 15 -20 -25 -30 -35 -40 - I 23456 REM (c/s) FIGURE 11. — Relationships between repetition rate of ocular movements within bursts of REM and the amplitude of the orthodromic lemniscal responses elicited by direct stimulation of the cuneate nucleus. Same animal as in figures 9 and 10; same experiment. The symbols represent the amplitudes of both the early potential (empty circles! and the late potential (filled circles) recorded from the right lemniscus on single-shock stimulation of the left cuneate nucleus, during bursts of REM. The abscissa indicates the repetition rates of the eye movements (c/s) within the REM; the ordinate indicates the amplitude of the fu» components of the lemniscal responses during the same trains of REM calculated as percentage of the mean control values X obtained during desynchronized sleep, in the in- tervals between the REM. Each point represents the average value of measurements taken during 3 bursts of REM. Greater depression of the lemniscal responses occur with higher frequencies of ocular movements within the bursts of REM. Furthermore, for the same bursts of REM. depression is greater for the late potential than for the early potential. (From ref.31.)

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 225 + 60 - «CR . . U 1 On * NI + 50 o o CUN— > ML at &- —•* CUN — > ML <* + 40 A- -—A CUN^ SR + 30 - > k + 20 — X ' tl 1 I X X + 10 I-••-1] ^-JJ If X X X X~ • ' D " " t f 1 'i 1 ^ ' - 10 T " c'v^< I - 20 '* 1 "» , -30 - -40 - - 50 - -60 _ I I J QW - SS DS DS without REM DS with REM FIGURE 12. — Effects of sleep on the orthodromic lemniscal response and on the excitability both of cuneate neurons and of the presynaptic terminals in the cuneate nucleus. Filled circles: Orthodromic responses recorded from the right medial lemniscus (ML) on single-shock stimulation of the left superficial radial nerve (SR). Open circles and open triangles: Responses recorded from the right ML on single-shock stimulation of the left cuneate nucleus (CUN). The initial a-spike and the later fi-spike due to direct and synaptic excitation of the cuneate neurons have been plotted with different symbols. Filled triangles: Antidromic responses recorded from the left SR on single-shock stimulation of the CUN. The average values of measurements during desynchronized sleep (DS) are calculated as percentage of the mean control values (X) during quiet wakefulness-synchronized sleep (QW-SS). The vertical segments represent the standard deviations. The responses during DS have been further divided into two groups: (1) the responses recorded during the intervals between the REM (DS without REM) and (2) the responses recorded during the large bursts of REM (DS with REM). About 2000 responses for each experimental situation were statistically evaluated. (From ref. 31.) elicited by peripheral nerve stimulation is un- modified during synchronized sleep, as compared with relaxed wakefulness, the present observa- tions show that both a- and /3-excitability of the cuneate nucleus are also unmodified in the same experimental conditions. A marked decrease of a- and /3-excitability occurs only during desyn- chronized sleep, at the time of the REM (refs. 26 to 28 and 31). It has been clearly shown that the test for a-spike depression provides a direct assessment of postsynaptic inhibition of cuneothalamic relay

226 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION neurons (ref. 63). Therefore, the depression of the a-excitability during the desynchronized phase of sleep indicates that postsynaptic in- hibition has an important depressant influence on many cuneothalamic relay neurons during REM. The depression of the /3-spike during the REM is more difficult to interpret. We have shown that the presynaptic depolarization of the primary afFerents to the cuneate nucleus pro- duced by REM results in a large increase in the number of presynaptic fibers being excited by the cuneate stimulus. This would tend to increase the size of the /3-spike. This increase, however, has to be weighed against (1) the de- pression of synaptic excitation that results from the presynaptic depolarization, i.e., presynaptic inhibition, and (2) the depression that results from the postsynaptic hyperpolarization, i.e., postsynaptic inhibition. Of course the effectiveness of the presynaptic inhibitory action during REM is indicated by the depression of synaptic transmission in cases in which /3-depression is coupled with very little or no a-depression of cuneate neurons. However, as pointed out by previous authors (ref. 63), the /3-depression of cuneate neurons does not give a simple index of synaptic excita- tion and its depression by presynaptic inhibition, since the /3-depression is minimized by the large increase in presynaptic excitability. Summing up, the structures which are respon- sible for the phasic depression of the orthodromic lemniscal response during desynchronized sleep must operate through both mechanisms of pre- synaptic and postsynaptic inhibition. Transmission of Sensory Volleys Through the Nucleus Ventralis Posterolateralis During REM Accumulated evidence indicates that during desynchronized sleep the transmission of somatic centripetal impulses elicited either by peripheral stimulation (refs. 47 and 81 to 84) or by central, lemniscal (refs. 47, 81, and 85 to 87), or thalamic (refs. 47, 81, 85, 86, 88, and 89), stimulation is constantly facilitated. This effect occurs at the level of the nucleus ventralis posterolateralis (VPL) and lasts throughout the episode of desyn- chronized sleep. There is also a constant parallelism between the facilitation of the thalamic responses and those recorded from the cortex (ref. 90). Moreover, a further increase in the lemniscocortical (refs. 86, 87, and 91) and thalamocortical responses (ref. 86) has been found to occur synchronously with the REM. We are not going to discuss here the tonic changes in somatic afferent transmission through the VPL nucleus, since they last throughout the desynchronized phase of sleep, and therefore are not vestibular in origin. We are inter- ested mainly in the observation that during the desynchronized phase of sleep, the thalamic output resulting from stimulation of second- order somatosensory neurons shows sudden brief increases (ref. 92). These happen at the same time as REM's and deep-sleep waves (refs. 86 and 93). Suppression of proprioceptive oculomotor and/or retinal inputs does not pre- vent the occurrence of such phasic changes in thalamic transmission (refs. 87 and 94). Experi- ments were recently made (ref. 33) in order to investigate the synaptic changes occurring in the nucleus ventralis posterolateralis during desynchronized sleep, particularly at the time of the REM. Similar to the approach used in our previous experiments on the dorsal column nuclei (refs. 26 to 28 and 31), both presynaptic and postsynaptic events have been investigated at thalamic level (ref. 33). In particular, the responsiveness of the presynaptic and post- synaptic components of thalamic synapses was studied by implanting chronically bipolar electrodes in the medial lemniscus (ML), the nucleus ventralis posterolateralis (VPL), and the somesthetic radiations (SR). Each electrode could then be used either for stimulation or for recording. Facilitation of the Orthodromic Thalamic Response The orthodromic response evoked in the VPL nucleus by stimulation of the medial lemniscus consisted of a short-latency—positive-negative deflection followed by a slower positive wave. The first component of the response can be attributed to the action potential of the presynap- tic terminals, while the second may be ascribed to the postsynaptic activity of thalamic neurons. It was found in particular that while the pre- synaptic component of the VPL response did not significantly change in amplitude during the

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 227 desynchronized phase of sleep, the mean ampli- tude of the postsynaptic component was signifi- cantly higher during REM than during non-REM periods (fig. 13, upper records). Only in some instances a slight decrease of the presynaptic component in the VPL occurred during the bursts of REM. EEG EOG VPL ML J EEG EOG VPL ML EEG EOG SR VPL FIGURE 13. — Presynaptic and postsynaptic changes in the nucleus ventralis posterolateralis (VPL) during the REM periods of desynchronized sleep. Unrestrained, muni esthetized cats. Upper records: Changes in orthodromi- cally evoked responses recorded from the VPL to medial lemniscus (ML) stimulation during a REM burst of de- synchronized sleep. Middle records: Changes in anti- dromic responses recorded from ML to intrathalamic (VPL) stimulation during a REM burst of desynchronized sleep. Lower records: Changes in the excitability of thalamic neurons recorded from the somesthetic radiation (SR) by stimulating the VPL nucleus. EEG: Electro- encephalogram; EOG: Electro-ocu/ogrum. Cathode-ray oscilloscope calibration for the evoked responses: I msec and 50 iiV. (From ref. 33.) Excitability Changes of Presynaptic Fibers in the VPL Nucleus Experiments were performed to test the excitability of presynaptic terminals of second- order sensory neurons by antidromic stimulation (ref. 71) of the VPL nucleus. The antidromic responses recorded from the medial lemniscus consisted of two positive components, probably due to excitation of two groups of nerve fibers with different conduction velocity. These anti- dromic responses did not show significant changes in amplitude during the REM periods (fig. 13, middle records). On some occasions, however, a slight increase of the antidromic response in the medial lemniscus was observed. This finding together with the observation that, during the same phase of sleep, the presynaptic component of the thalamic response evoked by stimulation of the medial lemniscus is sometimes slightly reduced in amplitude suggests that depolarization of the presynaptic terminals within the thalamus may occur at the time of the REM. Excitability Changes of the VPL Neurons The increase in amplitude of the postsynaptic component of the discharge evoked in the VPL nucleus by stimulation of the medial lemniscus during REM's suggests that the thalamic cells have become more responsive to incoming affer- ent impulses. Direct stimulation of the VPL nucleus evokes in the corresponding thalamo- cortical radiation a response consisting of an initial brief positive deflection (a-spike) followed by a second positive component of longer dura- tion (/3-spike). While the a-spike is due to direct excitation of thalamic relay cells, the /3-spike, occurring one synaptic delay later, is produced by direct excitation of presynaptic fibers in the thalamic nucleus, with consequent synaptic activation of thalamic neurons (ref. 95). The a-spike is thus a suitable index for evaluating changes in excitability of thalamic neurons. The /3-spike cannot be used for this purpose, however, because its amplitude is affected as well by changes in presynaptic terminals. The amplitude of the a-spike always increased during REM in the somesthetic radiation when VPL was stimu- lated (fig. 13, lower records). It is of interest that even the antidromic response recorded in

228 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION the VPL nucleus by stimulating the somesthetic thalamocortical radiations increased during the REM periods. The invariable increase in size of the postsynaptic component of the thalamic responses evoked by stimulation of the medial lemniscus as well as the increased discharge of the thalamic neurons produced by direct stimula- tion of the VPL nucleus or antidromic stimulation of the somesthetic radiations supports the con- clusion that REM's are associated with a phasic enhancement of the responsiveness of thalamic cells in the VPL. In summary, postsynaptic facilitation occurs in the VPL nucleus during REM. Only on some occasions this phenomenon is associated with depolarization of the presynaptic terminals within the thalamus. Reduced transmission of orthodromic volleys at the level of the pre- synaptic endings within the thalamus is appar- ently overwhelmed by increased postsynaptic responsiveness of thalamic cells. Vestibular Control of Somatic Afferent Transmission in the Cuneate Nucleus and the VPL Nucleus It has been shown that, during the REM, there is a phasic depression of the orthodromic lemniscal response (refs. 25 and 30) which is due to both mechanisms of presynaptic and post- synaptic inhibition (refs. 26 to 28 and 31). Ex- periments were performed to localize the structures which are responsible for the inhibitory control of synaptic transmission in the cuneate nucleus during desynchronized sleep (refs. 29 and 32). Attention was devoted to the vestibular nuclei which we have proved to be responsible not only for the REM (refs. 35 to 37) but also for the phasic enhancement of the pyramidal dis- charge, related in time with the REM (refs. 23 and 24). Since stimulation of the sensory-motor cortex, performed in acute experiments, is able to inhibit the transmission of cutaneous afferent volleys through the cuneate nucleus by both mechanisms of presynaptic and postsynaptic inhibition (ref. 63), the possibility exists that excitation of the pyramidal neurons elicited by the ascending vestibular volleys during the REM periods of desynchronized sleep is respon- sible for the inhibition of synaptic transmission in the cuneate nucleus which occurs at the time of the REM. We have shown that bilateral destruction of the medial and descending vestibular nuclei abolishes not only the REM but also the related phasic depression of the orthodromic lemniscal response evoked by single-shock stimulation of the superficial radial nerve (fig. 14). The absence of any modulation, during sleep, of the lemniscal response following vestibular lesions is also duplicated by experiments of bilateral ablation of the sensory-motor cortex, which, on the other hand, does not prevent the appearance of the typical bursts of ocular movements. Summing up, the depression of the orthodromic lemniscal response elicited by single-shock stimulation of the superficial radial nerve during the bursts of REM is abolished by a bilateral lesion of the vestibular nuclei, or by complete ablation of the sensory-motor cortex. It appears, therefore, that during REM, the vestibular nuclei depress the synaptic transmission at the level of the dorsal column nuclei through the roundabout way of the sensory-motor cortex and the py- ramidal tract (fig. 15). Further experiments are required to find the pathways and structures which are responsible for the facilitation of sensory transmission through the VPL nucleus during the REM periods of desynchronized sleep. It may well be postulated, however, that the efferent discharge originating from the second- order vestibular neurons at the time of the REM represents the common triggering mechanism which is responsible not only for the depression in the orthodromic transmission of somatic afferent volleys through the dorsal-column nuclei (refs. 29 and 30) but also for the increased responsiveness of thalamic cells within the VPL nucleus during the REM bursts (refs. 33. 87, and 96). CONCLUSION An analysis of the central mechanisms re- sponsible for the motor events occurring during desynchronized sleep, made by microelectrode recording of single vestibular neurons in un- restrained unanesthetized animals (refs. 11 to 13), as well as by lesion experiments, clearly indicates that the medial and descending vestibular nuclei

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 229 are responsible not only for REM (refs. 35 to 37), but also for the phasic excitation of spinal 10 • I X 1 . - - £ - — ~" 10 - 1 20 • 30 . 20 10 - 10 -20 QW SS DS DS-tPwrfREM DS-.i«. REM T I 1 1 I - - I—-.>—i— -i--—= - I 1 I I I QW SS DS DS without Smati bursts ot REM ocuiar movements FIGURE 14. — Effects of different backgrounds of sleep on the orthodromic lemniscal responses recorded in the intact animal or after vestibular lesion. Unrestrained, un- anesthetized cats. Upper diagram: Intact preparation. Lower diagram: Animal submitted to bilateral electrolytic lesion of the vestibular nuclei, sparing only the ventral part of the medial and descending vestibular nuclei of both sides. In both instances the responses were recorded from the right medial lemniscus on single-shock stimulation of the left superficial radial nerve. The results obtained during several episodes of desynchronized sleep have been statistically evaluated. The average values of measure- ments during quiet wakefulness (QW) and desynchronized sleep (DS) are calculated as percentage of the mean control values (X) during synchronized sleep (SS). The vertical segments represent the standard deviations. The re- sponses during DS have been further divided in two groups: (1) the responses recorded during absence of ocular move- ments (DS without REM). and (2) the responses recorded during the large bursts of rapid eye movements (DS with REM). In the lower diagram this group contains only the responses recorded during the residual ocular movements which remained after the vestibulnr lesion (small bursts of ocular movements). Note the depression of the ortho- dromic lemniscal responses during the large bursts of REM (DS with REM) in the intact preparation and the absence of any significant change in the amplitude of the responses during the residual ocular movements after vestibular lesion. (From refs. 30 and 32.) motoneurons (refs. 23 and 24). It is of interest that (1) during desynchronized sleep the py- ramidal discharge increases during the bursts of REM, and (2) the abolition of the hypnic con- tractions following lesion of the vestibular nuclei is always associated with the abolition of the pyramidal discharges that occur synchronously with the periods of REM (refs. 23 and 24). CORTEX THALAMUS VENTRO-BASAL NUCLEUS FIGURE 15. — Anatomical schema of the neutral mechanisms involved in the sleep modulation of somatic afferent trans- mission through the cuneate nucleus. Synaptic trans- mission of cutaneous impulses (superficial radial nerve) to cuneothalamic relay neurons (white) is blocked by inhibitory cuneate interneurons (black) through presynaptic and postsynaptic mechanisms. The hypothesis is made that the inhibitory interneurons are driven by collaterals of the pyramidal tract, the corticospinal neurons being in turn excited by ascending vestibular volleys through unknown polysynaptic pathways (dotted line). D: De- scending vestibular nucleus; L: Lateral vestibular nucleus (of Deiters); M: Medial vestibular nucleus; S: Superior vestibular nucleus. (From ref. 32.)

230 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION The demonstration that, during sleep, vestib- ular afferent volleys impinge upon the sensory- motor cortex is supported by the observation that in acute experiments, labyrinthine volleys are able to alter the pattern of discharge of some neurons localized in this cortical area (refs. 97 to 99). Moreover, a discharge of impulses can also be recorded from the bulbar pyramid on single-shock stimulation of the vestibular nerves performed under chloralose anesthesia (ref. 100). In summary, a motor pattern is formed during desynchronized sleep due to increased activity of the vestibular neurons. It consists not only of REM, due to direct excitation of the oculomotor neurons, but also of muscular con- tractions related in time with REM. These phasic events are associated with reflex excita- tion of corticospinal neurons due to ascending vestibular volleys impinging upon the motor cortex. Other structures, however, also trig- gered by the ascending vestibular system, are likely to contribute to the phenomenon. For sake of simplicity they have not been considered in the present report. Parallel to the phasic excitation of the ex- trinsic ocular and spinal motoneurons occurring during desynchronized sleep, phasic events influence the transmission of sensory inputs along the dorsal-column—medial-lemniscal sys- tem. In particular, the experimental evidence clearly indicates that the orthodromic lemniscal response is phasically depressed during REM due to mechanisms of presynaptic and postsynaptic inhibition occurring within the cuneate nucleus (refs. 25 to 28, 30, and 31). An analysis of the central structures responsible for the phasic depression of these lemniscal responses during REM shows that this effect is abolished after bilateral lesions localized to the medial and descending vestibular nuclei (refs. 29 and 32). Bilateral destruction of the sensory-motor cortex also duplicates the effects of the vestibular lesions, although the appearance of the bursts of REM is not prevented by the cortical ablation. Both these lesions in fact abolish the phasic depression of somatic afferent transmission through the dorsal column nuclei during the REM. These observations suggest that volleys ascending from the vestibular nuclei are able to excite neurons of the somatosensory cortex, whose efferent discharge is finally responsible for the depressed transmission at dorsal column level. It has been pointed out above that the phasic depression of transmission of somatic afferent volleys through the cuneate nucleus during the bursts of REM is due to both mecha- nisms of presynaptic and postsynaptic inhibition (refs. 26 to 28 and 31). It is of interest that the same mechanisms occurring during physiolog- ical sleep in unrestrained animals can also be elicited in acute experiments on repetitive stim- ulation of the sensory-motor cortex (refs. 63 to 66). We may conclude that the vestibular activity occurring during the REM periods of desynchronized sleep is able to block the trans- mission of somatic afferent volleys within the dorsal column nuclei through the roundabout way of the sensory-motor cortex (fig. 15). It is quite surprising that, contrary to the de- pressed transmission of somatic afferent vol- leys at dorsal column level, the transmission of somatic volleys through the VPL nucleus is greatly facilitated during REM (refs. 33, 86, 87. and 91). Therefore, within the VPL nucleus the reduced amplitude of the orthodromic volleys has to be weighted against an increased excita- bility of the thalamocortical neurons. It has been assumed by several authors that the sensory feedback dependent upon active movement plays an important role in motor coordination (refs. 101 to 103). It is of interest that, while during the movements associated with REM, the somatic sensory volleys are partially inhibited at medullary level, a postsynaptic facili- tation occurs simultaneously within the spe- cific thalamic nuclei. We can postulate, there- fore, that some part of the efferent vestibular activity giving rise to contraction of the limb mus- culature is fed into the somatic sensory system, particularly the nucleus ventralis postero- lateralis, where it interacts with the incoming somatic information filtered at dorsal-column level. The result is that external stimulation due to sensory feedback is partially substi- tuted by internal stimulation which is incorpo- rated at thalamic level and elaborated by the somatosensory cortex. It has been assumed for years that the ves-

VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 231 tibular nuclei represent a premotor center which controls the oculomotor and spinal motoneurons. The present experiments clearly indicate that the efferent discharge originating from the ves- tibular nuclei affects the transmission of somatic sensory volleys at the different relay stations of the medial lemniscal pathway simultaneously with the efferent discharges which give rise to the hypnic contractions of the limb musculature. The existence of such "corollary" central discharges, i.e., discharges from motor to sensory structures, has been postulated in order to ac- count for the perceptual constancy of the environment during movements (ref. 104). Further experiments are required to find out whether the vestibular mechanisms described during the deepest phase of sleep are also opera- tive during the motor activities produced by natural labyrinthine stimulations. One may propose that also during the natural labyrinthine stimulations in the awake animal, the somato- sensory volleys originated at the time of the muscle contractions are not simply transmitted without alteration through the ascending lemnis- cal pathways. Similar to what has been de- scribed in the sleeping preparation, vestibular volleys may well interact with exteroceptive and proprioceptive afferent impulses at different relay stations of the somatosensory pathway, thus leading to proper perception during body movements. Appropriate experiments, however, are required to test this hypothesis. REFERENCES 1. MoRUZZl, G.: Active Processes in the Brain Stem During Sleep. Harvey Lectures, vol. 58, 1963, pp. 233-297. 2. DEMENT, W.: The Occurrence of Low Voltage, Fast Electroencephalogram Patterns During Behavioral Sleep in the Cat. EEG Clin. Neurophysiol., vol. 10, 1958, pp. 291-296. 3. DEMENT, W. C.: Eye Movements During Sleep. The Oculomotor System, M. B. Bender, ed., Hoeber Med- ical Division, Harper & Row, New York, 1964. pp. 366-416. 4. JOUVET, M.: Recherches sur les Structures Nerveuses et les Mecanismes Responsables des Differentes Phases du Sommeil Physiologique. Arch. Ital. Biol., vol. 100, 1962, pp. 125-206. 5. JOUVET, M.: Neurophysiology of the States of Sleep. Physiol. Rev., vol. 47, 1967, pp. 117-177. 6. ASERINSKY, E.: AND KLEITMAN, N.: Regularly Oc- curring Periods of Eye Motility and Concomitant Phenomena, During Sleep. Science, vol. 118, 1953, pp. 273-274. 7. ASERINSKY, E.; AND KLEITMAN, N.: Two Types of Ocular Motility Occurring in Sleep. J. Appl. Physiol., vol. 8. 1955, pp. 1-10. 8. GASSEL, M. M.: MARCHIAFAVA, P. L.: AND POMPEIANO, O.: Phasic Changes in Muscular Activity During Desynchronized Sleep in Unrestrained Cats. An Analysis of the Pattern and Organization of Myo- clonic Twitches. Arch. Ital. Biol.. vol. 102. 1964. pp. 449-470. 9. DEMENT. W. C.; AND KLEITMAN, N.: The Relation of Eye Movements During Sleep to Dream Activity: An Objective Method for the Study of Dreaming. J. Exptl. Psychol., vol. 53.1957. pp. 339-346. 10. DEMENT. W. C.; AND KLEITMAN. N.: Cyclic Variations in EEG During Sleep and Their Relation to Eye Movements, Body Motility and Dreaming. EEG Clin. Neurophysiol.. vol. 9, 1957, pp. 673-690. 11. Bizzi, E.; POMPEIANO, O.; AND SOMOGYI, L: Attivita Spontanea di Singole Unita Registrate dai Nuclei Vestibolari Nei Gatti Integri non Anestetizzati nel Corso del Sonno e della Veglia. Boll. Soc. Ital. Biol. sper., vol. 40. 1964, pp. 138-141. 12. BIZZI, E.; POMPEIANO, O.: AND SOMOGYI, I.: Vestibular Nuclei: Activity of Single Neurons During Natural Sleep and Wakefulness. Science, vol. 145, 1964, pp. 414-415. 13. BIZZI, E.; POMPEIANO, O.: AND SOMOGYI, L: Spontane- ous Activity of Single Vestibular Neurons of Unre- strained Cats During Sleep and Wakefulness. Arch. Ital. Biol., vol. 102, 1964, pp. 308-330. 14. POMPEIANO, O.: Ascending and Descending Influences of Somatic Afferent Volleys in Unrestrained Cats: Supraspinal Inhibitory Control of Spinal Reflexes During Natural and Reflexiy Induced Sleep. Aspects Anatomo-fonctionnels de la Physiologie du Sommeil, Editions du Centre National de la Recherche Scien- tifique, Paris, 1965, pp. 309-395. 15. MORRISON. A. R.; AND POMPEIANO, O.: Vestibular Influences During Sleep. IV. Functional Relations Between Vestibular Nuclei and Lateral Geniculate Nucleus During Desynchronized Sleep. Arch. Ital. Biol.. vol. 104, 1966, pp. 425-458. 16. POMPEIANO, O.: Muscular Afferents and Motor Control During Sleep. Nobel Symposium I. Muscular Affer- ents and Motor Control, R. Granit, ed., Almqvist & Wiksell, Stockholm, 1966, pp. 415-436. 17. POMPEIANO, O.: The Neurophysiological Mechanisms of the Postural and Motor Events During Desynchro- nized Sleep. Sleep and Altered States of Conscious- ness, S. S. Kety. E. V. Evarts, and H. L. Williams, eds.,

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VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 233 45. MORRISON, A. R.; AND POMPEIANO. O.: Pyramidal Discharge From Somatosensory Cortex and Cortical Control of Primary Afferents During Sleep. Arch. Ital. Biol.. vol. 103.1965, pp. 538-568. 46. FAVALE, E.; LOEB, C.; AND MANFREDI, M.: Contributo alia Conoscenza dei Meccanismi della Facilitazione delle Risposte Corticali Evocate da Stimoli Somatici Periferici e Centrali Durante il Sonno Profondo. Boll. Soc. Ital. Biol. sper., vol. 38,1962, pp. 1151-1153. 47. FAVALE, E.; LOEB, C.; MANFREDI, M.: AND SACCO, G.: Somatic Afferent Transmission and Cortical Respon- siveness During Natural Sleep and Arousal in the Cat. EEG Clin. Neurophysiol., vol. 18. 1965, pp. 354-368. 48. DAGNINO, N.: FAVALE, E.; LOEB, C.; MANFREDI. M.; AND SEITUN. A.: Tempo di Trasmissione degli Impulsi Afferenti Attraverso i Nuclei di Goll e di Burdach e il Nucleo Ventro-Postero-Laterale del Talamo Durante il Sonno Spontaneo. Boll. Soc. Ital. 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234 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION 75. OSCARSSON, O.: AND ROSEN, I.: Short-Latency Pro- jections to the Cat's Cerebral Cortex From Skin and Muscle Afferents in the Contralateral Forelimb. J. Physiol.,vol. 182,1966, pp. 164-184. 76. OSCARSSON, O.; ROSEN, I.; AND SULG, I.: Organization of Neurones in the Cat Cerebral Cortex That Are Influenced From Group I Muscle Afferents. J. Physiol., vol. 183,1966, pp. 189-210. 77. ANDERSSON. S. A.; LANDGREN, S.: AND WOLSK, D.: The Thalamic Relay and Cortical Projection of Group I Muscle Afferents From the Forelimb of the Cat. J. Physiol., vol. 183, 1966, pp. 576-591. 78. LANDGREN, S.; SILFVENIUS. H.: AND WOLSK. D.: Somato-Sensory Paths to the Second Cortical Pro- jection Area of the Group 1 Muscle Afferents. J. Physiol.. vol. 191,1967. pp. 543-559. 79. ROSEN, I.: Functional Organization of Groupl Activated Neurones in the Cuneate Nucleus of the Cat. Brain Res., vol. 6,1967, pp. 770-772. 80. SWETT, J. E.; AND BOURASSA, C. M.: Short Latency Activation of Pyramidal Tract Cells by Group i Afferent Volleys in the Cat. J. Physiol., vol. 189, 1967, pp. 101-117. 81. FAVALE, E.; LOEB, C.; AND MANFREDI. M.: Somatic Evoked Responses in Cats During Natural Sleep. Experientia, vol. 19,1963, pp. 189-192. 82. ALBE-FESSARD, D.; MASSION, J.; HALL, R.: AND ROSEN- BLITH. W.: Modifications au Cours de la Veille et du Sommeil des Valeurs Moyennes de Reponses Nerveuses Centrales Induites par des Stimulations Somatique chez le Chat Libre. C. R. Acad. Sci., vol. 258, 1964, pp. 353-356. 83. Gt'ILBAND, G.; AND YAMAGUCHI, Y.: Evolution au Cours des Diverses Phases du Sommeil des Activites Evoquees des Differentes Regions du Cortex Somato- moteur du Chat. J. Physiologie, vol. 56, 1964, pp. 370-371. 84. GUILBAND, G.; AND KUMMER, J. I .: Comparison de I'Evolution au Cours du Sommeil, des Activites Evoquees par Stimulation Somatique dans les Noyaux Ventral Posterieur et Ventral Lateral du Thalamus et au Niveau du Cortex Moteur Chez le Chat. J. Physiologie, vol. 57. 1965. pp. 617-618. 85. FAVALE. E.; LOEB, C.; AND MANFREDI, M.: Somatic Responses Evoked by Central Stimulation During Natural Sleep and During Arousal. Arch. Int. Physiol., vol. 71. 1963, pp. 229-235. 86. ALLISON, T.: Cortical and Subcortical Evoked Responses to Central Stimuli During Wakefulness and Sleep. EEG Clin. Neurophysiol., vol. 18, 1965, pp. 131-139. 87. DAGNINO, N.; FAVALE, E.: LOEB, C.: MANFREDI, M.: AND SEITUN, A.: Nervous Mechanisms Underlying Phasic Changes in Thalamic Transmission During Deep Sleep. EEG Clin. Neurophysiol., suppl. 26, 1967. pp. 156-163. 88. PISANO. M.; ROSADINI, G.; AND Rossi, G. F.: Risposte Corticali Evocate da Stimoli Dromici e Antidromici Durante il Sonno e la Veplia. Riv. Neurobiol., vol. 8. 1962, pp. 414-426. 89. Rossi. G. F.; PALESTINI. M.: PISANO, M.: AND ROSADIM. G.: An Experimental Study of the Cortical Reactivity During Sleep and Wakefulness. Aspects Anatomo- fonctionnels de la Physiologie du Sommeil, Editions du Centre National de la Recherche Scientifique. Paris, 1965. pp. 509-532. 90. FAVALE, E.; LOEB, C.; AND MANFREDI. M.: Le Risposte Corticali Somatiche Durante il Sonno Profondo: Particolare Comportamento delle Risposte Radiato- Corticali. Boll. Soc. Ital. Biol. sper., vol. 39.1963, pp. 430-432. 91. DAGNINO, N.: FAVALE, E.; LOEB. C.; AND MANFREDI. M.: Trasmissione Talamica e Movimenti Oculari Durante il Sonno Profondo. Boll. Soc. Ital. Biol. sper., vol. 41.1965. pp. 1269-1271. 92. FAVALE, E.; LOEB, C.; AND MANFREDI. M.: Modificazioni delle Risposte Corticali Evocate da Stimole Centrali nelle Diverse Fasi del Sonno e al Risveglio. Boll. Soc. Ital. Biol. sper.. vol. 38. 1962, pp. 1146-1148. 93. DAGNINO. N.; FAVALE, E.: LOEB, C.: AND MANFREDI. M.: Thalamic Transmission Changes During the Rapid Eye Movements of Deep Sleep. Arch. Int. Physiol.. vol. 73. 1965, pp. 858-861. 94. DAGNINO, N.; FAVALE, E.; LOEB. C.; MANFREDI, M.: MASSAZZA. G.; AND SElTUN. A.: Afferenze Oculari (Retiniche e Propriocettive) e V ariazioni Fasiche di'll.! Trasmissione Talamica Durante il Sonno Pru- fondo. Boll. Soc. Ital. Biol. sper.. vol. 42. 1966. pp. 1775-1777. 95. ANDERSEN, P.; BROOKS. C. McC.: ECCLES. J. C.; AND SEARS, T. A.: The Ventro-Basal Nucleus of the Thal- amus: Potential Fields, Synaptic Transmission and Post-Synaptic Components. J. Physiol., vol. 174, 1964, pp. 348-369. 96. DAGNINO. N.; FAVALE, E.: LOEB, C.; MANFREDI, M.: AND SEITUN, A.: Pontine Triggering of Phasic Changes in Sensory Transmission During Deep Sleep. Arch. Int. Physiol., vol. 74. 1966, pp. 889-894. 97. JUNG. R.; KORNHUBER, H. H.; AND DA FONSECA. J. S.: Multisensory Convergence on Cortical Neurons. 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VESTIBULAR AND NONVESTIBULAR SENSORY-INPUT INTERACTION 235 101. HELD. R.: Plasticity in Sensory-Motor Systems. Sci. Amer., vol. 213,1965, pp. 84-94. 102. HELD, R.; AND KREEDMAN, S. J.: Plasticity in Human Sensorimotor Control. Science, vol. 142, 1963, pp. 455-462. 103. KOEZE, T. H.; PHILLIPS, C. {.',.-. AND SHERIDAN, J. L>.: Thresholds of Cortical Activation of Muscle Spindles DISCUSSION Tang: Do I understand correctly that, during rapid eye movements, there is a spinal block of the somatic afferent which provides for protection or for better sleeping? The somatic aflerents would be blocked at the spinal level in order that the animal not be awakened by its own muscle contractions. On the other hand, the ventral posterior lateral nucleus increases the excitability. Would that not be a built-in protection? In other words, if the external stimuli could get through the spinal nuclei, this would auto- matically awaken the animal very rapidly because the sen- sitivity of the higher level is increased. Would that be a correct interpretation? Pompeiano: It is true that just at the time of the motor contractions synchronous with the REM bursts, there is a depression of somatic afferent transmission not only to the spinal motoneurons but also to the dorsal-column nuclei. On the other hand, this effect is associated with a facilita- tion of the orthodromic response through the nucleus ven- tralis posterolateralis (VPL). The interpretation of our re- sults that you gave may well be correct. I think, however, that the significance of our findings is more far reaching. It was found in our experiments that all the effects described depend upon vestibular discharges which are responsible not only for the rapid eye movements but also for the appear- ance of the related contractions of the limb musculature. One may propose that even during the motor contractions elicited by natural labyrinthine stimulation in the awake animal, vestibular volleys interact with proprioceptive afferent impulses at different relay stations of the somatosensory pathway. It has been postulated by several authors that the sensory feedback dependent upon active movements plays an im- portant role in motor coordination (R. Held: Plasticity in Sensory-Motor Systems. Sci. Amer., vol. 213, 1965, pp. 84-94). Our experiments indicate that the integration of the somatosensory volleys during the muscular contractions related in time with the bursts of REM involves inhibitory events at the level of the dorsal-column nuclei as well as facilitatory events at the level of the specific thalamic nuclei. The result is that external stimulation due to somatic afferent volleys is partially substituted by internal stimulation due to vestibular afferent volleys which are incorporated at thalamic level and elaborated by the somatosensory cortex. It appears, therefore, as if a central discharge originating from the oculo- motor centers in the brainstem reaches the VPL neurons simul- taneously with the efferent discharge which gives rise to the limb and eye movements. The existence of such "corol- and a-Motoneurones of the Baboon's Hand. J. Physiol., vol. 195, 1968, pp. 419-449. 104. TEUBER, H. L.: The Riddle of Frontal Lobe Function in Man. The Frontal Granular Cortex and Behavior. J. M. Warren and K. Akert, eds., McGraw-Hill Book Co., Inc., 1964, pp. 410-444. lary" central discharges, i.e., discharges from motor to sen- sory structures, has been postulated in order to account for the perceptual constancy of the environment during body movements (H. L. Teuber: In: The Frontal Granular Cortex and Behavior, J. M. Warren and K. Akert, eds., McGraw-Hill. 1964. pp. 410-444). Snider: Professor Pompeiano, that is a very fine presenta- tion. No doubt we could spend the rest of the afternoon on some of the implications of this. It seems to me that one point I missed was which comes first, the eye movements or the vestibular discharges. As I see it, you have not elimi- nated the so-called trigger zones in the pontine region. What happens in these animals if the extraocular muscles are ablated acutely (i.e., the extraocular muscles are removed), thus removing the feedback into the pontine system or even into the cerebellum? What, for example, does the vestibule have to do with this? Your thesis, as I see it, is proposing spontaneous activity in the vestibular nuclei. Perhaps I am reading ahead of the data here. In our subsequent paper on the cerebellum (Ray S. Snider and Karl Lowy, "Evoked Potential and Microelectrical Analy- sis of Sensory Activity Within the Cerebellum"), we believe the cerebellum is tied up with relating eye movements to some of these discharges. I would also like to know how you were relating the vestibular nuclei to the VPL. That is not a monosynaptic pathway. It must have been acting through the reticular formation. Do you not feel that the spontaneous activity, at least the trigger zones, is still in the reticular for- mation and the vestibular system is carrying out the dictates of it? Pompeiano: Our experiments indicate that the bursts of REM as well as all the related events depend upon the activity of the medial and descending vestibular nuclei. This activity still occurs after cerebellectomy or bilateral section of the VIII nerves. The persistence of a rhythmic pontine activity in spite of the destruction of the vestibular nuclei suggests that the increase in the vestibular discharge during desynchronized sleep is triggered by central volleys origi- nating from a pontine center. There is also evidence indi- cating that the phasic changes in sensory transmission dur- ing the bursts of REM do not depend upon retinofugal dis- charges nor can they be attributed to afferent discharge from eye muscle proprioceptors because the same effects were obtained also following enucleation of eyes or extraocular muscles. So far, we have studied only the pathways responsible for the depression of the orthodromic lemniscal responses elicited

236 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION by single-shock stimulation of forelimb nerves during the bursts of REM. It appears that during these rapid eye move- ments, the vestibular nuclei depress the synaptic transmission at the level of the dorsal-column nuclei through the round- about way of the sensory-motor cortex and the pyramidal tract. The pathway responsible for the vestibular influences on the VPL has not been investigated yet. Graybiel: Have you watched for REM sleep in persons who had lost all four limbs? Pompeiano: Nobody has so far watched for REM sleep in subjects who had lost all four extremities. Our observa- tion that the REM bursts depend upon the activity of the vestibular nuclei has been recently confirmed in man (O. Ap- penzeller and A. P. Fischer, Jr.: Disturbances of Rapid Eye Movements During Sleep in Patients With Lesions of the Nervous System. EEG Clin. Neurophysiol., vol. 25, 1968, pp. 29-35). These authors found that REM's were absent in patients with severe Wernicke-Korsakoff s disease, in whom the vestibular nuclei are known to be often affected. One of the fields in which the investigations should be directed in the future is that concerned with the relationship existing between REM sleep and vestibular function. It is well known that artificial interruption of REM sleep in humans is followed by a striking compensatory increase in amount and percentage of the REM time if the subjects are allowed unin- terrupted sleep. It has been proposed that the REM mecha- nism is triggered by a neurochemical substance which ac- cumulates to a critical threshold level within a pontine center and is then released. One may postulate that the sensi- tivity of the subjects to natural labyrinthine stimulation is inversely related to the amount of time previously spent in REM sleep and that the intensity of the labyrinthine responses increases during REM deprivation. In view of the possible relationship between REM sleep, REM deprivation, and intensity of labyrinthine reflexes, one may eventually begin to sort out ways in which drugs may alter the sensitivity to labyrinthine reaction via the mechanism of permanently altering the nature of REM sleep. Obviously all these hypotheses should be tested experimentally.

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