Squirrel Monkeys and Space Motion Sickness

Japanese Journal of Physiology, 52, 1–20, 2002 REVIEW

Kenichi MATSUNAMI

Science and Technology Promotion Center, Kakamigahara, 509–0108 Japan

Abstract: Studies of the vestibular system in system is crucially important in the genesis of squirrel monkeys in consideration of space mo- SMS (SAS). In this connection, the ablation stud- tion sickness (SMS) or space adaptation syn- ies of labyrinth, semicircular canals, and other drome (SAS) were reviewed. First, the phyloge- SAS-related areas were referred to, and consid- netic position of the squirrel monkey was consideration was made for experiments about caloric ered. Then the anatomico-physiological studies irrigation of the ear. A hypothetic model was then of both the peripheral and the central vestibular proposed for the genesis of SAS. [Japanese systems were described, because the vestibular Journal of Physiology, 52, 1Ð20, 2002]

Key words: squirrel monkey, vestibular system, cerebral cortex, space motion sickness (SMS), space adaptation syndromes (SAS).

The construction of the new space station will be contamination of fatal B virus for human subjects; (4) completed soon, and many experiments will be under- They are relatively free from dysentery or tuberculo- taken. Many Japanese scientists will join in these new sis; (5) They are less dangerous because of their small experiments. Animal experiments are expected to size. On the other hand, (1) They are small and weak, solve problems in space physiology. Several kinds of thus vulnerable to bleeding during surgery; (2) The nonhuman primates such as the chimpanzee (Pan bone of the skull is thin, and it is difﬁcult to perma- troglodytes), common squirrel monkey (Saimiri sci- nently anchor a cylinder to the skull for a continuous urea), rhesus monkey (Macaca mulatta), and stump- recording of neuronal activity; (3) They are expensive, tailed monkey (Macaca speciosa) have already been particularly in Japan, because of their high mortality used. The rhesus monkey is the commonest and best- rate during importation from South America. known nonhuman primate used in the research of Several reviews and monographs relating to the space physiology as well as in medicine. squirrel monkey and space medicine follow. Although In this article, however, we will report on experi- it is old, “The Squirrel Monkey” [1] is a book worth ments conducted with squirrel monkeys in relation to consulting before undertaking experiments with this space motion sickness (SMS) (or space adaptation monkey. The 12th chapter of the monograph is de- syndrome (SAS)—hereafter, SAS will be used in the voted to space medicine. As for other species of mon- same sense), since they are among the most appropri- keys, refer to the work of Simonds and Bourne [2]. ate animals for experiments on earth and in the space Several works are also related to space medicine station for the following reasons: (1) They are com- [3–11]. monly used in the research of SAS; (2) They serve as appropriate experimental animals because of their Evolution and Phylogeny small size and light weight; (3) They are safe from the The squirrel monkey belongs to the New World mon-

Received on September 25, 2001; accepted on December 21, 2001 Correspondence should be addressed to: Kenichi Matsunami, Science and Technology Promotion Center, Kakamigahara, 509–0108 Japan. Tel: ϩ81–583–79–2221, Fax: ϩ81–583–79–2258, E-mail: [email protected] Abbreviations: aVOR, angular vestibulo-ocular reflex; ChAT, choline-acetyl transferase; CV, covariance; FPN, floccular projection neurons; FTN, floccular target neurons; Ig, granular insular cortex; IVN, inferior vestibular nucleus; LVN, lateral vestibular nucleus; MLF, medial longitudinal fascicules; MVN, medial vestibular nucleus; OKAN, optokinetic after nystagmus; OKN, optokinetic nystagmus; PIVC, parieto-insular vestibular cortex; PPH, nucleus prepositus hypoglossi; Ri, retroinsular cortex; SAS, space adaptation syndromes; SI, SII, somatosensory area I and II; SMS, space motion sickness; SVN, superior vestibular nucleus; VCR, vestibulo-collic reflex; VOC, vestibulo-oculo-collic; VOR, vestibulo-ocular reflex; WBR, whole body rotation; YPN, y-group projection neurons; 2V, vestibular area of area 2; 3aV, vestibular area of area 3a.

Japanese Journal of Physiology Vol. 52, No. 1, 2002 1 K. MATSUNAMI keys (the Platyrrhini), more specifically to Cebidae/ cord and cerebellum, the indices are capuchin monkey Cebidae/Cebina/Saimiri (cf. Napier and Napier [12]). (347), squirrel monkey (545), rhesus monkey (321), The common squirrel monkey (Saimiri sciureus) is chimpanzee (135), gorilla (150), and man (210). It can the one we usually see in zoos and remember as the be seen that the squirrel monkey has the largest pro- first monkey to travel into space in an American satel- gression index, except for the superior vestibular nu- lite (1958). The genus of Saimiri comprises three cleus. It must be also pointed out that the talapoin of species: S. sciureus, S. boliviensis, and S. oerstedi. In the Cercopithecus family (Cercopithecus talapoin), its customary classification, it is also known as Boli- also an arboreal habitant, is the only monkey that vian, Peruvian, or Colombian, depending on its native shows a progression index superior to the squirrel habitat. The Bolivian is considered the most sensitive monkey. to motion sickness. Here we briefly discuss the growth of the squirrel When considered from an evolutionary viewpoint, monkey, since we have no other appropriate place for the squirrel monkey shows some unique features, for it in this article. The squirrel monkey becomes adult example, the evolution of the primate brain according at 3 years old (body weights are 0.6–1.1 kg [male] and to Stephan [13]. The ratios of brain weight to body 0.4–0.8 kg [female]), and the average life span is 15 weight (brain [g]/body [g] are: howler monkey years for the Bolivian squirrel monkey [15]. It was fed (Alouatta, 51/6,400ϭ0.0080), capuchin monkey (Cebus, by standard commercial food pellets in a warm room 80/3,000ϭ0.0226), squirrel monkey (Saimiri, 22/680ϭ (recommended room temperature 26°C). In addition, 0.0324), rhesus monkey (M. mulatta, 93/6,000ϭ mill worms were supplied for enough protein (1 mill 0.0155), chimpanzee (P. troglodytes, 420/46,000ϭ worm/d). 0.0091), gorilla (Gorilla gorilla, 465/124,000ϭ0.0037), and man (Homo sapiens, 1,330/65,000ϭ0.0205). It is Anatomy of Vestibular System curious that the squirrel monkey is superior even to Two main hypotheses have been proposed for the eti- human beings in its brain weight in relation to body ology of space adaptation syndromes (SAS); i.e., the weight. However, it is only true for the progression sensory conflict theory and the fluid shift theory. Fur- index proposed by Stephan, which defines it as the thermore, the asymmetry of the left and the right ratio of the volume (which is almost equal to the otolith and the production of chemical substances in weight) of the part of the brain of the respective pri- the central spinal fluid have also been proposed. Nev- mate species to the volume of that of the most primi- ertheless, the vestibular system plays a pivotal role in tive and “imaginary” insectivora. Therefore a more the genesis of SAS; thus the anatomy of the vestibular appropriate index must be developed to distinguish system has been widely reported [16–21]. Further, an the memory and learning capability among primates. atlas of the brain of the squirrel monkey is indispens- Since the focus of the present article is on space able to research of the central nervous system [22]. physiology, especially SAS, we will consider the pro- Measurements of the vestibular organ have been gression index of the vestibular nuclear complex. The obtained in the cat, squirrel monkey, and man. The di- progression index of some representative primates ameter of the monkey’s ampulla is 1.28 mm. The [14] is capuchin monkey (Cebus albifrons; 361), squir- height of the crista is 0.23 mm, and the thickness is rel monkey (419), rhesus monkey (329), chimpanzee 0.23 mm. Other figures were obtained [23–25]. The (205), gorilla (154), and man (262). It is clear from size of the human maculae was twofold to fourfold these indices that arboreal primates have a higher pro- greater [26]. The surface area of the sacculus is gression index. Concerning the superior vestibular nu- 0.73 mm2. These values are 60–70% of those of man cleus, which mainly projects to the oculomotor nuclei and are relatively larger when the size of the skull is and is important to the vestibulo-ocular reflex, the compared to that of man [23, 26]. The plane of the progression index is capuchin monkey (542), squirrel horizontal semicircular canal tilts upward by monkey (531), rhesus monkey (471), chimpanzee 18–22 deg from the stereotaxic horizontal plane for (292), gorilla (152), and man (247), reflecting the vi- both the squirrel and rhesus monkeys. Taking these sual and vestibular dominance of the arboreal pri- values into account, a nose-down tilt of 15 deg is rec- mates. Concerning the medial vestibular nucleus, ommended for the most effective horizontal canal which is important to the vestibulo-collic reflex, the stimulation [27]. Morphological measurements of progression indices are capuchin monkey (348), squir- each angle were similarly made among the anterior, rel monkey (369), rhesus monkey (262), chimpanzee posterior, and horizontal semicircular canals. Two (224), gorilla (152), and man (247). Concerning the types of sensory hair cells exist in the sacculus and lateral vestibular nucleus, which projects to the spinal the utriculus. Type I hair cells are covered by the calyx

2 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology and situated more in the central part of the crista. Type Ultracytochemically ouabain-sensitive, Kϩ-depen- II hair cells lack the calyx. Afferent fibers connecting dent p-nitrophenylphosphatase (Kϩ-NPPase) activity to hair cells fall into three types: C (calyx) type, D (di- of the Naϩ,Kϩ-ATPase was found in the squirrel mon- morphism) type, and B (bottom) type. The C-type af- key inner ear. The reaction products for Kϩ-NPPase ferents connect only to type I hair cells with thick activity were confined to the cytoplasmic side of the fibers (diameter Ͼ1.5 ␮m) and have faster conduction plasmalemmal folding of the marginal cells in the velocity. The B-type afferents connect only to type II stria vascularis. The intensity of Kϩ-NPPase activity hair cells with thin fibers (and thus a slower conduc- was the strongest in the marginal cells, followed by tion velocity). The D-type afferents have characteris- the dark cells of the ampulla and the utricle, indicat- tics shared by the C and B fibers and connect to the ing that the dark cells in the vestibular labyrinth were type I and type II hair cells. All three afferents pene- involved in endolymph homeostasis [37]. trate perpendicularly from the lateral part of the Concerning the vestibular ganglion, the cross-sec- otolith organs toward the crista [28]. Moreover, thick tional area of pericarya was 200–650 ␮m2, and that of fibers align in two parallel rows along the long axis; in nerve fibers was 3–11 ␮m2. A more detailed morpho- the periphery of the cristae, thin fibers predominate. logical observation was also described in relation to Thick fibers and thin fibers were segregated in the su- fiber diameter in regard to the thickness of the myelin perior nerve. The thick fibers of the anterior and hori- sheath and the length of the intranodal Ranvier node zontal canals and utricle were situated in the anterior [31, 38]. superior area, and the thin fibers in the posterior part. It is well known that efferent fibers exist in vestibu- A similar segregation occurred with fibers of the pos- lar and cochlear systems. An HRP injection in the am- terior ampullary nerve and the sacculae within the in- pulla of the lateral semicircular canal retrogradedly la- ferior vestibular nerve [29]. beled vestibular efferent neurons bilaterally, lateral to Immunohistochemical studies demonstrated that all the rostral part of the abducens nucleus, forming a vestibular ganglion neurons were strongly glutamate compact cell group. All neurons were ChAT im- immunoreactive. Most cells also showed a graded munoreactive [39, 40]. ChAT and Gly immunoreactivity in a highly overlap- The projection pattern of fibers of the individual ping neuronal population. In the end organs, ChAT vestibular end organs in the brain stem was studied and Gly were colocalized; therefore it can be con- with HRP labeling [41]. Fibers from the horizontal cluded that ACh worked as a neuronal modulator or and superior semicircular canal were situated rostrally, cotransmitter in the vestibular ganglion and end or- and those from the posterior semicircular canal and gans [30]. GABA-like immunoreactivity was also sacculus were found caudally; the utricular fibers were found in squirrel monkey vestibular nerve fibers and situated intermediate between them. The secondary bouton-efferent components [31]. fibers in the vestibular tract occupied their locations in The calcium-binding protein, calbindin-D28K (CB- an end-organ specific manner; the utricular fibers were D28K), was immunohistochemically found in the hair situated dorsal to the superior and horizontal semicir- cells in the organ of Corti, vestibular hair cells, and cular canal fibers, the posterior semicircular canal spiral and vestibular ganglion cells [32]. Thus CB- fibers were situated most medially, and the saccular D28K may regulate the Ca2ϩ level for optimal trans- fibers occupied the lateral-most area. Labeled boutons mission in the vestibular and auditory afferent sys- from the all receptors were found in the rostral central tems. In the maculae, many CB-D28K immunoreac- area of the SVN, and mainly in the rostral two-thirds tive particles were found in the otoconial membrane, of the MVN. In the LVN, boutons from all the recep- indicating that CB-D28K participates in the formation tors were found in the rostro-ventral part, mostly orig- of otoconia [32]. A similar immunohistochemical inating from the utriculus and sacculus. study was conducted in the hypothalamus [33]. A The efferent and afferent connections of the comparative study with 25 different monoclonal anti- vestibular nuclei were important and were therefore bodies for cytoskelton revealed a high degree of simi- intensively studied in rat [42], squirrel monkey [43, larity in labyrinths in man and squirrel monkey [34]. 44], cat, and monkey [45, 46]. Spinocerebellar affer- Only 1 of 25 monoclonal antibodies (for S-100 pro- ents were studied in the rat, cat, and squirrel monkey tein) was found to stain differently between the two [47], as well as the otolith pathways [48]. Coerulo- species for type I vestibular hair cells in the striola of vestibular pathways were also studied in rats, rabbits, the two maculae. The expressions of substance P, and monkeys [49]. Figure 1 demonstrates the essence CGRP, and GABA were also studied with special ref- of the innervation focused on the vestibular nuclei erence to species differences [35, 36]. [42].

Japanese Journal of Physiology Vol. 52, No. 1, 2002 3 K. MATSUNAMI

Fig. 1. Projection of the vestibular nuclear neurons via the thalamus to the cerebral cortex, limbic system, and basal ganglion (in the rat). CL, cen- trolateral thalamic nucleus; FEF, frontal eye ﬁeld; LD, lateral dorsal nucleus; MGM, magnocellu- lar nucleus of the medial geniculate body; MGV, ventral nucleus of the medial geniculate body; MVN, medial vestibular nucleus; PF, parafascicular thalamic nucleus; SG, suprageniculate thalamic nucleus; SuVN, superior vestibular nucleus, SpVN, spinal vestibular nucleus; VB complex, ventrobasal complex; Vim, nucleus ventralis intermedius; VL, ventrolateral thalamic nucleus; VPL, ventral posterolateral thalamic nucleus [42].

An injection of 3H-labeled amino acid (proline or rons of the medial and inferior nuclei. Substance P leucine) into the ampulla labeled almost all the positive grains were observed around the larger neu- vestibular ganglion and nuclear cells and part of the rons of the lateral nucleus, possibly originating from cerebellum [46]. Cells in the following contralateral the vestibular ganglion cells and the reticular nuclear structures were also labeled through the commissural cells. fibers; the contralateral MVN, part of the SVN, group The origin of afferents to the oculomotor nuclei was y, the vestibulo-spinal tract, bilateral MLF with con- histochemically investigated. Cholinergic afferents tralateral dominance, the abducens, and the trochlear arose bilaterally from the medial nucleus as described neurons. Many afferents terminated in the oculomotor and from the dorsal part of the paragigant cellular complex, with intensive labeling of the nucleus of the reticular nucleus. In the latter nucleus, inhibitory burst medial rectus muscles, and the most intensive labeling neurons with fibers projecting to the contralateral ab- of the nucleus of the contralateral superior rectus ducens nucleus were observed to exist. The abducens muscle. nuclear neurons were ChAT positive. Cells of the PPH The so-called vestibular nucleus is a complex of the were ChAT negative. The ChAT positive cells in the superior, lateral (Deiter’s), medial, inferior (descend- rostral part of this nucleus did not project to the ocu- ing), f, x, y, and z nuclei. The nucleus hypoglossi lomotor nuclei. Other afferents to the oculomotor nu- (PPH) could also be included. ChAT positive neurons clei originated from the ipsilateral rostral MLF, con- were observed in the medial, superior, and inferior nu- tralateral olive nucleus, interstitial nucleus of Cajal clei. Almost all x, y, and z nuclear neurons are ChAT and inferior vestibular nucleus, and from bilateral su- positive [50] and are considered to project to the perior vestibular nuclei. All these neurons were ChAT spinal cord, cerebellum, and contralateral vestibular negative [51, 52]. nuclei through commissural fibers. A unique study reported the incorporation of 2-DG The vestibular nuclei and the vestibular ganglion (2-deoxy-D-glucose; 114C; 20 ␮Ci/100 g bw) into nuclei cells were also rich in glutamate positive neurons. in the brain stem of squirrel monkeys (nϭ5; /, GABA positive neurons were observed in the rostral 582–800 g bw [53, 54]). By the use of a special appa- part of the medial nucleus and the y nucleus, and ratus, each monkey was gently restrained to a board in GABA positive grains were observed around larger a conscious state. Forty-five minutes after the injec- cells in the dorsal part of the lateral nucleus. The tion of 2-DG into the vein, the monkey was killed and GABA positive neurons were considered to project to the brain removed to make an autoradiograph. The in- the contralateral side through the commissural fibers, tensity of 2-DG uptake was strong in the auditory sys- and GABA-positive grains were attributed to termi- tem (superior olive nucleus, inferior colliculus, lateral nals of the commissural and cerebellar afferents. Sub- lemniscus), the vestibular nuclei (medial, lateral, infe- stance P positive cells were observed in smaller neu- rior, and superior), the oculomotor system (prepositus

4 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology hypoglossi, oculomotor, and trochlear nuclei), and the areas 2 and 7ant received inputs from both 3aV and lateral cuneate nucleus, in that order. The 2-DG up- PIVC. This region probably corresponded to area 2v take into the vomit-related structure (solitary nucleus, of M. mulatta [62]. All these cortical areas received area postrema, and dorsal motor nucleus of the vagal afferents from the bilateral vestibular nuclei, with con- nerve) was small, but it is possible to incorporate tralateral dominance, probably through the thalamus more 2-DG if the monkey experiences motion sick- [63–67]. Among the seven vestibular cortices, PIVC, ness. area 3aV, and area 2v form an “inner cortical vestibu- The PPH is an important relay nucleus of the visual lar circuit,” which organizes information of the head signal in relation to VOR. In this connection, the af- and the vestibular system after receiving separate so- ferent projections from the brain stem and the cerebel- matosensory, proprioceptive (SI), and optokinetic sig- lum to the PPH were studied in detail with the WGA- nals [59]. HRP method [55]. The vestibular nuclei, the con- The direct projection from these cortices to the tralateral PPH, and the medullary and pontine reticu- vestibular nucleus acts to suppress subcortical reflexes lar formation intensively projected fibers to the PPH. such as the vestibuloocular, vestibulospinal, and opto- Substantial projections were observed from the nu- kinetic reflexes during ongoing voluntary or goal-ori- cleus raphe dorsalis and the central mesencephatic ented movements. Similar neuronal connections were reticular formation. Efferents from the PPH projected also revealed in M. mulatta [68]. These vestibular cor- fibers to the vestibular and perihypoglossal nuclei, the tices received thalamic afferents, the rostrodorsal part inferior olive, the medullary reticular formation, and of VPL projected afferents to areas 3a and 3aV, which the extraocular motor nuclei. The PPH also projected were possibly related to the vestibular and propriocep- to the restricted regions of crus I and II, the caudal tive sense. The posterior part of the dorsal VPL also vermis, and the vestibular cerebellum. In considera- projected to the posterior Ri. The medial, lateral, and tion of the parallel innervation of afferents and effer- inferior pulvinar nuclei projected to T3 [66]. Striated ents of the PPH and the abducens nucleus, it is pro- units were modulated by the vestibular nuclear stimu- posed that the PPH distribute an efferent copy of lation [69]. motor activity [55]. Quite recently, an important contribution was made The existence of seven vestibular areas in the cere- by Fukushima and his colleagues in the frontal eye bral cortex was elucidated for squirrel and rhesus field of the Japanese monkey. Existed neurons there monkeys [56–58]. Three kinds of tracers were injected related not only to smooth pursuit eye movements, but into the vestibular nuclei, and retrograde labeling into also to VOR or passive whole body rotation [70–72]. the cortex was studied after an appropriate interval (48 h for WGA-HRP and 14 d for Fast blue and Rho- Physiological Experiments damine). The seven vestibular cortices are (1) pari- Should the reader find it helpful, several reviews of eto-insular vestibular cortex (PIVC), including Ri vestibular physiology are available [16–21]. (retroinsular cortex) and Ig (granular insular cortex); The description starts with the physiology of first- (2) area 3aV; (3) parieto-temporal association cortex order vestibular nerve activity. As described, three (anterior part of area 7 (7 ant), probably correspond- types of vestibular afferent activity exist: C, D, and B. ing to area 2v of the M. mulatta at the lateral end of Spontaneous discharges of the C-type afferents were the intraparietal sulcus; (4) temporal cortex adjacent both irregular (CVϭ0.425Ϯ0.078) and low (65Ϯ43 to Ri (temporal lobe; T3); (5) area 6a; and (6) area 23 spikes/s) with the middle size of gain and the largest [59, 60]. This observation established a direct projec- phase lead of the three. Those of the B type were tion from the cortex to the vestibular nuclei. 74Ϯ34 spikes/s (CVϭ0.051Ϯ0.029), with a gain of Visuokinetic-vestibular neurons existed in layer V 0.35Ϯ0.32 and a phase lead of 10Ϯ9 deg. The sponta- of the PIVC. Cortical neurons in 3aV representing neous discharge of the D-type afferents were 79Ϯ41 neck and trunk responded to the stimulation of semi- spike/s (CVϭ0.147Ϯ0.128) with the largest gain of circular canals. On the other hand, neurons in T3 with 0.90Ϯ0.066 and the phase lead of 22Ϯ14 deg [73]. a large visual receptive field responded to optokinetic It is essential to know the characteristics of the pri- stimulation, but not to vestibular stimulation. Otolith mary vestibular afferents if the etiology of SAS is to stimulation activated neither of the cortical neurons be understood. Thus detailed experiments were con- mentioned above [58, 61]. ducted with afferents from semicircular canals and PIVC received afferent input from 8a, 6, 3a, 3aV, 2, otolith organs. and 7 ant. The 3aV received afferents from areas 24, A description starts with the experiments conducted 4, 6, 7 ant, SI, SII, Ri, and Ig. The border region of on the activity of semicircular canal afferents [74–80].

Japanese Journal of Physiology Vol. 52, No. 1, 2002 5 K. MATSUNAMI Spontaneous discharge rates were distributed over a 0.250 Hz. A more detailed description reveals that the wide range from several to 200 spikes/s (sps), with vestibular afferent response was linear when tϽϽ␶1 mean values of 91.1Ϯ2.6 sps (horizontal canal), and responded more to angular velocity v(t) than to 95.1Ϯ2.7 sps (superior canal), and 85.5Ϯ4.1 sps (infe- linear velocity: ␰1(t)ϭ(␪/␲)v(t). In this instance, er- rior canal). The spontaneous discharge rate was higher rors were less than 10% when tϽ0.2␶1, indicating that for regular (tonic) than irregular (phasic) units, and the semicircular canal organs are precise velocity de- the former was considered to be more appropriate and tectors, with the gain of ␶2ϭ␪/␲. Moreover, they de- more involved in the control of the vestibulo-ocular tected angular acceleration for a longer time, that is, reflex [81]. Semicircular canal afferents showed a di- ␰1(t)Ӏ(␪/␲)␣. rectional preference in the application of angular ac- One more important characteristic of the afferent celeration, e.g., excitation in one direction and inhibi- response to sinusoidal stimulation was revealed. The tion in the other. Adaptation was observed to develop semicircular canal detects angular acceleration in the when acceleration was applied for a longer period. An lower frequency range (Ͻ0.03 Hz), with a phase lead adaptation index was then established to classify and gain of G␣ϭ␶1␶2. In the higher frequency range semicircular canal afferents, a third of which showing (Ͼ5.0 Hz, which has no physiological significance), no adaptation. This characteristic is important because the semicircular canal detects a change of angle with a it fits the torsion-pendulum model. Another third phase lead. Between the two ranges, the frequency showed adaptation with a greater sensitivity range of component corresponds to that of head movements 0.5–4.0 sps/deg/s2 (mean valueϭ2 sps/deg/s2) and a (physiological range), and the semicircular canal de- dynamics range of 0–300 sps. tects these head movements. Thus the canal system The hair cells of the cupula of the semicircular works as a velocity detector, with the gain G␯ϭ␶2 and canal organ were bent to detect changes in position in- no phase shift. duced by angular acceleration. The activity of semi- A similar analysis was conducted on otolith affer- circular canal afferents reflected the nature of the hair ents [82–85]. cells. To quantitatively describe this nature, a pendu- dϭsFϩd (3) lum model was proposed that fits the following sec- 0 ond-order differential equation: d, discharge rate; s, sensitivity (when 1 g was applied), d , discharge rate at rest. d2␰()t d␰ ()t 0 ␪ ϩϩϭ␲ ⌬␰␪␣()tt () (1) For roll (R) and pitch (P), the following equations dt 2 dt are proposed:

The system described by this equation has two time d(0,R)ϭX sin RϪZ cos Rϩd0 (4) ␶ ϭ␲ ␦ ␶ ϭ␪ ␲ constants, 1 / (long) and 2 / (short). One can (discharge rate for roll) draw a Bode diagram for a sine wave input to its out- ϭϪ Ϫ ϩ put with respect to gain and phase versus frequency. d(P,0) Y sin P Z cos P d0 (5) The transfer function was also obtained as follows: (discharge rate for pitch)

␶␶ALSS()1ϩ The static characteristics of inferior nerve activity HS()ϭ (2) ()()()111ϩϩϩ␶␶␶SSS (the saccular nerve) reached the minimum discharge A 12 rate (60 sps) at a tilt angle of 0 deg for both roll and with the function of HTPϭ1/(1ϩ␶1S)(1ϩ␶2S), ␶1ϭ pitch, also ﬁtting Eqs. 4 and 5. The response of otolith ␲/␦ϭ5.7 s, and ␶2ϭ␪/␲ϭ0.003 s. HAϭ␶A/(1ϩ␶AS), organ afferents to force (F) ﬁtted Eq. 3. which produces the phase lead in the low-frequency Superior nerve activity (utricular nerve) was more band and produced dissociation from the theoretical sensitive to pitch than roll and showed directionality curve. A numerator ␶A is a time constant of the tem- and an increase of discharge in one direction and a de- poral change of adaptation and decreases gain in the crease in another. Many unit activities showed no such frequency range below 0.0125 Hz. HLϭ(1ϩ␶LS), characteristics. In regard to the otolith afferent re- reach the phase shift in the high-frequency range, and sponse to force, the force-discharge response was ap- produced a dissociation of the experimental from the proximated as a parabolic curve with a downward theoretical curves of the Bode diagram. However, convex; that is, characteristics differed greatly between the regular rϩ0.072ϭFϩ0.193F2 (6) and irregular units. Regular units had a larger dissoci- (26 utricular afferents) ation than irregular units did; the gain curve started to dissociate at 1.0 Hz, and the phase lag started at Moreover, d0ϭ0 for almost all canal and otolith af-

6 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology ferents. In contrast, central vestibular neuronal activi- (1) The superior and inferior nerve units were both ties coded position signals. Therefore central vesicular sensitive to small changes in angles from the resting neurons should code position signals in a population- position. Superior nerve units were particularly sensi- coding manner, supposedly by using phase signals tive from the zero-level position (corresponding to the [82]. More recently, a polar expression was proposed steepest point of the dynamic curve of frequency vs. for an otolith afferent response to explain directional tilt angle). (2) The sensitivity to tilt angle was greater specificity. According to the polar expression, utricu- for units discharging at a higher rather than a lower lar units were tuned to respond horizontally and sac- rate. For example, the sensitivity of a unit discharging cular units vertically [86]. When the function of neu- at 132.7 sps at rest was 62.2 sps/deg, and that of a unit ronal activities was considered on the basis of a vecto- with a resting discharge of 17.3 sps was 12.7 sps/deg. rial polar expression, the following results appeared (3) The units of the superior nerve had a higher dis- [82]. Units recorded in the superior nerve were of charge rate and thus a greater sensitivity to changes in utricular origin (23/30; 76.2%), and those in the infe- tilt angle than those of the inferior nerve with a lower rior nerve were of saccular origin (16/21; 76.2%). discharge rate. (4) The discharge of the otolith organs This means that each otolith nerve activity had its own was very regular. (5) Units with a higher discharge polarity, matching the same plane as that of the utricu- rate had a more regular discharge pattern; in other lar or saccular macula. When considered more in rela- words, they showed a smaller covariance (CV). Fol- tion to the X- and Y-axis (X or Y expressed the axis of lowing are numerical descriptions about the CV of the preferred direction of unit activity), many units semicircular and vestibular units classified into 4 significantly responded in a ϩX direction (the ipsilat- groups by sps and CV (sps/CV) from smaller to eral ear was to the down side). A similar analysis was larger. They were 7.5/0.063, 12.5/0.0798, 17.5/0.1057, conducted on units of inferior nerve afferents. When 22.5/0.1327, 27.5/0.1670, and 32.5/0.2045 for otolith considered in the Z direction, the response was almost units and, similarly, 7.5/0.1467, 12.5/0.1854, and the same in the ϩZ or ϪZ direction and in the ϩY or 17.5/0.3672 for semicircular canal units. This sug- ϪY direction. However, a preferred direction emerged gests that otolith units discharged more regularly than in the joint form of ϪZ and ϩY or ϩZ and ϪY when semicircular canal units did. It is also consistent with the Y- and Z-axis were to be considered in combina- the findings that otolith units discharge with a higher tion, indicating that the neurons responded in an an- frequency at rest than semicircular canal units do. (6) terodorsal to posteroventral direction. This can easily Units with regular discharge were more sensitive; an be understood in comparison with the polarity direc- index (ratio of sensitivity vs. resting discharge rate) tion of the sacculus. There was a difference of could be expressed as 0.51 for regular units and 1.19 30 degs, however, in the angle between the preferred for irregular units. direction and the main plane of the saccular macula, The characteristics of secondary vestibular neurons which also reflected the difference between the stan- have also been extensively studied. First, the charac- dard stereotaxic horizontal plane (defined by the infra- teristics of neuronal activity (unit) of the superior orbital margin and the openings of the meatus of both vestibular nucleus (briefly, superior nucleus) will be sides) and the saccular plane. described mainly on the studies of Goldberg and his The utricular and saccular nerve units both re- colleagues [87–93]. As described, the first order sponded to roll and pitch, but there were several dif- vestibular nerve units were categorized into two ferences between the two kinds of nerve activities. (1) groups, i.e., regular and irregular units. Therefore the Superior nerve units responded more in a differential question arises about how these two types of first- manner than inferior ones did, an increase in one di- order vestibular units physiologically connect to the rection (preferred direction) and a decrease in the op- second-order vestibular neurons (vestibular nuclear posite direction. (2) Superior nerve units showed a neurons). Electrical stimulation of the vestibular nerve different sensitivity to roll than to pitch, and inferior bundle at the threshold level (T) excited 10% of the nerve units responded equally to both. (3) Sensitivity vestibular nerve fibers. A stimulation at 4T excited al- was greater for superior nerve afferents, reflecting the most all fibers of irregular units. Using these criteria, frequency of resting discharge of nerve activity; the 115 units recorded from the vestibular nerve were sensitivity of the superior nerve afferents was 45.97Ϯ classified into 43 irregular (37%), 47 mixed (41%), 3.85 sps, vs. 26.26Ϯ2.98 sps for inferior nerve affer- and 25 regular (22%) units. Thus this stimulation ents. technique, could determine regular and irregular in- A more detailed description of the otolith unit ac- puts to individual secondary vestibular neurons in tivity (in the frequency range below 90 deg) follows. consideration of responses to horizontal sinusoidal ro-

Japanese Journal of Physiology Vol. 52, No. 1, 2002 7 K. MATSUNAMI tation with and without the anodal current stimulation vated 29.2% (type I) and 2.7% (type II) of the units, by eliminating the head-rotation signals in type I ir- stimulation of the posterior canal activated 31.7% regularly discharging vestibular-nerve afferents. It is (type I) and 1.4% (type II) of them, and stimulation of also revealed that the anodal current stimulation did the horizontal canal activated 10.9% (type I) and 3.3% not affect the mean vestibular gain or phase calculated (type II). Response to the stimulation of both canals from a population of type I position–vestibular-pause was noted in 9.5% of the units and to changes in posi- neurons or from a mixed population consisting of all tion (tilt) by 4.8%. Canal plugging did not modify type I units [90, 91]. Vestibular nerve stimulation these percentages. The localization of these neurons could also evoke monosynaptic EPSP for neurons in was studied in the superior nucleus. Units responding the vestibular nucleus with a latency of 0.7–1.4 ms. to the superior canal were recorded on the lateral side, Di-synaptic IPSP was recorded for half of these neu- and units responding to posterior canal stimulation rons. Contralateral vestibular nerve stimulation also were recorded on the medial side of the superior nu- evoked EPSP-IPSP sequences with a latency of cleus. Units responding to the horizontal canal were in 1.4–3.0 ms, probably through the commissural fibers. the lateral nuclei. The characteristics of neurons in the superior Neurons in the caudal part of the vestibular nuclei vestibular nucleus were investigated in conjunction (mostly dorsal and ventral areas of the lateral nucleus with fiber projection. Twenty-six neurons projected to and neighboring regions of the medial and descending the flocculus of the cerebellum, 27 to oculomotor nu- nucleus) were classified into several groups on the clei, 13 to the spinal cord, and 21 to both oculomotor basis of the targets of their axonal projection: medial nuclei and the spinal cord. An irregular index (I vestibulospinal tract (MVST) neurons, lateral vestibu- index) was developed to express the contribution of lospinal tract (LVST) neurons, neurons projecting primary vestibular nerve fibers. The I index was to the oculomotor nuclei and MVST relating to the 51.9% for those neurons projecting to the spinal cord, vestibulo-oculo-collic (VOC) reflex, and neurons and the floccular projecting neurons included I, M, projecting to both oculomotor nuclei involving the and R type neurons. vestibulo-ocular reflex (VOR). Most of these neurons As mentioned above, contralateral vestibular nerve were in the dorsal and lateral parts of the lateral nu- stimulation produced IPSPs in vestibular neurons. cleus, and some were in the medial and descending Upon HRP injection into the contralateral side, the nuclei. For these neurons, the ratio of regular and ir- vestibular neurons were retrogradely labeled 88% regular types of primary vestibular afferents was ex- (22/25 neurons) of neurons for the floccular group, pressed as the I index. VOR neurons received irregu- 37% (10/27) for the oculomotor group, and 42% lar afferents. MVST and LVST neurons projecting to (5/12) for the spinal group. Intracellular labeling by C1 and LVST neurons projecting down into C6 re- HRP revealed the morphologic characteristics of ceived irregular afferents. VOC neurons projecting to vestibular neurons for the soma and dendrites. Of the MVST received regular afferents. LVST neurons these neurons, 12 were at the center of the superior projecting down into the lumbar cord received regular nucleus, and 8 in the lateral nucleus. Four of the 8 and irregular afferents at various ratios. MVST and neurons were of mixed-type units and were in the me- LVST neurons had greater conduction velocity than dial part of the lateral nucleus; the other four were of VOC neurons, but most were under 75 m/s. This is irregular units and situated more ventrolaterally than consistent with the morphological characteristics re- the former. Concerning two of three neurons among vealed by the injection of biocytin into neurons 12 in the superior nucleus, the tracing of their axon [94–96]. was possible; two neurons projected to the ipsilateral Detailed electrophysiological studies were done for MLF, and the remaining one projected its axon to the two kinds of neurons in the superior nucleus, those brachium. The three neurons in the lateral nucleus projecting to the flocculus (FPN: floccular projection projected their axon into the lateral vestibulospinal neurons) and those receiving afferents from the floc- tract. culus (FTN: floccular target neurons) [97–99]. The Abend [87] conducted experiments revealing that anatomico-physiological characteristics of FTN were vestibular neurons (92.5%) responded bilaterally to a studied for vestibulo-visual stimulation. Briefly, FTN stimulation of the vestibular nerve. Moreover, re- had a higher spontaneous discharge rate (123Ϯ23 sps; sponses to rotatory stimulation were also examined nϭ45), received inhibitory inputs from the cerebel- for 147 units. Of these, 83.0% responded to stimula- lum, and had discharge rate modified by optokinetic tion in only one direction of the three canal planes. stimulation with a rotatory drum (0.5 Hz). The gain Stimulation in the direction of the superior canal acti- was 0.79 sps/deg/s; thus neurons (which were an-

8 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology tidromically activated by oculomotor nuclear electri- visual targets and to fixate a head stationary or earth cal stimulation) responded to VOR. This was in con- stationary target during passive whole body rotation trast to FPN, which did not respond to optokinetic (WBR). Half the units relating to eye movements were stimulation. Therefore it can be inferred that FTN related to eye velocity during smooth pursuit and combined two signals; a head velocity signal from the WBR. The sensitivity to eye velocity during WBR vestibular nerve and an optic velocity signal (in- was reduced when a visual target was absent. The re- hibitory) from the cerebellum. These FTNs can be sponse to unpredictable steps in WBR was also de- classified into three groups based on the ratio of the layed by 80–100 ms. These facts suggested that eye two signals. The first group had equal inputs of visual movement sensitivity depended on visual feedback. following and VOR signals. The second group re- The other half of the units were sensitive to eye veloc- ceived only visual following with an inhibition of ity during pursuit and to head velocity during VOR. VOR. The third group, though a minor one, received Furthermore, ocular pursuit velocity and the ability to different amounts of the two signals and responded to suppress the VOR by fixating a head stationary target all stimulus manipulation. were reduced by approximately 50%. These facts sug- When FTP neurons were considered in relation to gested that the flocculus was an essential neuronal eye movements, 30 responded to upward movements structure for both visual feedback–dependent and and 11 to downward movements. The sensitivity was nonvisual mechanisms for canceling the VOR during greater for the former than the latter. FTN were situ- passive head movements [105]. Floccular Purkinje ated more caudally than FPN in the superior nucleus. cell activity was also studied in the Japanese monkey When the flocculus was inactivated by the injection of in relation to a pursuit of eye movements and WBR GABA agonist (muscimol), the discharge of FTN [106]. Neuronal activity in relation to active head neurons increased and spontaneous nystagmus was movements were also studied in the vestibular nuclei produced in the upward or contralateral direction. The of squirrel monkeys [107–109]. characteristics of y group neurons were also investi- The input of semicircular canal interneurons encod- gated with a similar technique in relation to the floc- ing head-velocity to the y group was recently studied culus [100, 101], and a neuronal circuit was proposed [110]. The anterior and posterior semicircular canals to explain VOR induction, plasticity, and learning project to the y group via interneurons in the vestibu- [102]. lar nuclei in the rostrolateral corner of the SVN and in Hirata and Highstein proceeded further with these the caudal MVN (y-group projecting neurons studies [103, 104]. They investigated Purkinje cell ac- [YPNs]). YPNs in the SVN had a lower resting rate tivity in relation to vertical VOR (vVOR) in the floc- than FPNs, more irregular interspike intervals, and a culus and the ventral paraflocculus of squirrel mon- different phase and gain during VOR and were situ- keys by employing visual-vestibular mismatch stimuli ated differentially within the SVN [110]. [103]. They also proposed an elaborate mathematical model of the vertical optokinetic reflex (vOKR) and Motion Sickness or Space vVOR, incorporating floccular and nonfloccular sys- Motion Sickness tems divided into subsystems based on the known Several books and reviews on space motion sickness anatomy and input and output parameters. With this (SMS) or space adaptation syndromes (SAS) are model they concluded that parallel changes in identi- available [111–120]. SMS and SAS are considered to fied characteristics with vVOR adaptation were found have the same etiological origin as motion sickness in the prefloccular/floccular subsystem conveying (or seasickness [121]), though they are still thought by vestibular signals, and no change was found in other some to be different. I will take the former position in subsystems: that is, prefloccular/floccular subsystems this review. Abrupt vomiting without nausea is said to conveyed efference copy or visual signals, nonfloccu- be one of the unique symptoms of SAS. However, lar subsystems conveyed visual systems, and postfloc- abrupt vomiting is also observed in patients with a cular subsystems transformed Purkinje cell activity to cerebellar vermal tumor and in infants vomiting their eye movements. The result suggested that multiple milk. sites, including flocculus and nonflocculus pathways, Several hypotheses are proposed for the etiology of were involved for vVOR motor learning [104]. SAS: sensory conflict, a cephalad shift of body fluid, Furthermore, the role of the flocculus and ventral an asymmetry of otoliths between the left and right paraflocculus in the ability to voluntarily channel the sides, and a secretion of chemical substances into the VOR was investigated. Purkinje cell units were cerebrospinal fluid. The chemical substance theory recorded during the learned tasks to pursue moving fails to explain the discontinuation of symptoms (nau-

Japanese Journal of Physiology Vol. 52, No. 1, 2002 9 K. MATSUNAMI sea or vomiting) once the subject vomits, since such a substance must remain in the system for 5–30 min [122, 123]. In this article I will propose a hypothesis for the etiological origin of SAS on the basis of the hierarchical structure of the central nervous system (CNS), that is, the hierarchical model of SAS. As is shown in Fig. 2, SAS in space is not produced by a single cause, but is caused by several composed physiological mechanisms on internal and external inputs. External inputs are represented by vestibular, visual, and somatosensory (proprioceptive) sensory signals. Among them, vestibular input has the crucial role to cause SAS. Other sensory signals such as auditory, olfactory, and gustatory signals may have the ability to cause SAS, but they are usually not seriously considered; thus they are not illustrated in Fig. 2. The internal signal is the other major input to cause SAS. The typical inter- Fig. 2. The hierarchical model for the genesis of the nal signal is the cephalad shift of the body fluid, SAS. Inappropriate external and internal physiological sig- which has long been considered as one of the main nals cause spatial disorientation, disturbance of memory and emotion, hormo-immuno-humoral, autonomic, and/or factors that cause SAS. motor responses. The main responsible CNS structures for We proceed to consider the mechanisms in our the respective responses are demonstrated in rectangles. search to learn how the external and internal signals See text for further details. produce SAS. It has been known that even a weak autonomic signal, either peripheral or central, can cause phantom is another kind of expression of memory of the “syndrome d’irritation, or phenomene d’irritation the body image. When an abnormal change in gravita- (Reilly’s Phenomenon),” as far as the autonomic sig- tion or acceleration was introduced to the organism, a nal continues to work on an organism (Reilly, 1954 mismatch of the ongoing perceptional body image and [124]). The acute and chronic cephalad shift of the the body phantom is produced, which could cause body fluid produces the corresponding change of spatial disorientation, emotional change through the autonomic and hormo-humoral signals and could limbic system (amygdala), and the physiological func- evoke SAS. It is also well known that a stress signal tional changes in the hypothalamus, hypophysis, and causes the “general adaptation syndrome” (Selye, the lower CNS. In the latter structures, vestibular, vi- 1976 [125]). During the micro-g in space, organisms sual, and/or somatosensory signals work in concert to are exposed to stressful conditions of this kind, lead- produce the explicit SAS responses. ing to SAS. The two syndromes should be the major To evaluate the degree of SAS, several indexes contributors to causing most of the physiological and were developed. Among them, the rating score of biochemical SAS responses, that is, changes or distur- Graybiel and his colleagues [129] has been widely bances of hormo-immunohumoral response, auto- used for human subjects. Igarashi and his colleagues nomic response, and motor response. I would also like [130] modified this symptom rating score to evaluate to introduce one more concept to explain the physio- vestibular-visual conflict sickness in the squirrel mon- logical phenomenon of SAS: the concept of body key (Table 1). The rating score by Graybiel was devel- image, or in other words, the body phantom, which is oped on the basis of subjective symptoms; thus a de- well referred to in the books [126, 127]. The concept sire for objective scales developed. Igarashi et al. of the phantom in the brain could explain the etiologi- [131, 132] found that CV of the R-R interval of ECG cal origin of spatial disorientation in the hyper- or was a good index with which to evaluate SAS syn- hypo-acceleration condition. The phantom of the body drome. Since CV is easy to measure, it is widely used. (body image), particularly that in reference to the Igarashi and his colleagues also used an amount of gravitational axis, is firmly constructed during the salivary secretion for an evaluation of motion sickness course of the life of the organism. In that instance, the [131]. The autonomic balance in the squirrel monkey phantom is supposedly built in the cortex and/or in the was also studied in relation to life-style [133]. limbic system (especially in the hippocampus) in ref- Since the early 1960s, rotation stimulation has been erence to “memory” [128]. In this sense, the body the method of choice to induce motion sickness [134,

10 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology

Table 1. Vestibular-visual conflict sickness symptom ited after experiments in their home cages. In their ex- rating (Igarashi et al. [130]). periments, 16 black and white vertical strips (1.7 cm in width) were arranged on a drum (60 cm in diame- Rating Symptom ter), which was rotated at a speed of 0.25 Hz. Vertical 1 point salvation I (less than 100 mg*) motion was 0.25 Hz in frequency and 90 deg in ampli- sweating tude with a phase delay of 0.5 s in relation to visual 2 points salvation II (100–200 mg) stimulation. The common symptoms of motion sick- struggling ness in squirrel monkeys were as follows: salivary se- vocalization 4 points salvation III cretion, vocalization, micturition, defecation, move- (more than 300 mg; usually with foam) ments of the mouth, and vomiting (mostly autonomic urination nervous symptoms). The ratings of motion (sensory defecation conflict) sickness were evaluated based on these 8 points gagging symptoms (cf. Table 1). Eye movements were another retching kind of index, and nystagmus was usually used (OKN, chewing 16 points emesis optokinetic nystagmus; OKAN, optokinetic after nystagmus). The elongation of the time of poststimulus * By filter-paper method. after nystagmus was a particularly sensitive index. In sinusoidal vertical movements, the lag in the 135]. Five chimpanzees (?2, /3; 3.5–4.5 years, 16.4 slow phase of eye movements in VOR was larger and kg mean body weight) and 11 squirrel monkeys (Peru- more irregular for squirrel monkeys sensitive to mo- vian, ?5, /6; about 2 years; 500–700 g) were used. tion sickness than for those resistant to it. The irregu- Two female chimpanzees vomited upon rotatory stim- larity improved after the monkeys vomited. When ulation (5.4–10.0 and 10.0 rpm); so did 8 squirrel utriculotomy was performed on the sensitive squirrel monkeys (1.9, 2.6, 3.8, 10.0 rpm [134]). Caloric nys- monkeys, leaving their semicircular canals intact, the tagmus was observed. These experiments established vomiting subsided as a result of the same combined that the squirrel monkey was a good model for the in- stimulation. From these experiments, two important vestigation of SAS, opening the way to subsequent conclusions were deduced: (1) The otolith organs SAS experiments. But it must be kept in mind that were essential to evoke vomiting, and (2) the semicir- sensitivity to motion sickness differed by phenotype, cular canals alone could not induce vomiting [146]. sex, and age [136]. But when the otolith organ was destructed on only one Several experimental results of squirrel monkeys to side, sensitivity recovered 4.4 months after surgery, rotatory stimulation will be described. A combination suggesting that the reorganization occurred in the cen- of vertical movements (6 inches, 0.5 Hz) and horizon- tral nervous system. tal rotation (10, 25, 50 rpm) evoked motion sickness. Motion sickness can be evoked by eccentric rota- The respective percentage of SAS incidents was 21, tion [137, 139, 147–149]. The latencies from the stim- 89, and 71%, and latency was 44, 19, and 21 min. The ulus onset to vomiting formed a Poisson distribution males were more sensitive than the females (latency, with a median value of 32.25 min (nϭ29; Bolivian), 10.50 vs. 24.13 min) with significant individual differ- and 91% of the squirrel monkeys vomited in less than ences. Regional differences were observed: 59% in 130 min. Within 40 min, the monkeys showed some Bolivian, 29% in Colombian, but with no significant other symptoms: mouth movements (96%), nausea difference in latency [123, 137]. Habituation was ob- (85%), and vomiting (82%). No adaptation was observed when the horizontal rotation was repeated served for the combination of rotation with visual [138] stimulation applied once a day successively for 10 d. A combination of rotatory stimulation with visual However, a tendency toward increased nausea and a stimulation enhanced the incidence of motion sick- shortening of the latency to vomiting was observed, ness (53%, 48.1 min vs. 76%, 17.2 min). The inci- though without significance, suggesting an increase in dence was higher when the head and body were free sensitivity. If the visual signal was masked from squir- to move than when they were restrained [123, 137, rel monkeys by an eye patch, vomiting did not occur. 139]. With a combination of rotation with visual stim- In the observations of vomiting, however, at least two ulation, the vertical rotation was more effective than factors must be considered: (1) objective and observ- the horizontal rotation [140–145]; rating scores were able vomiting and (2) subjective nausea [150, 151]. 16.4Ϯ1.8 vs. 8.3Ϯ1.77 (cf. Table 1). This case to 50.0 vs. 13.3% when subjects were included that had vom-

Japanese Journal of Physiology Vol. 52, No. 1, 2002 11 K. MATSUNAMI of the head to the intact side, slight locomotor ataxia, Lesion Studies and irregular spontaneous nystagmus [141]. It is also 1. Lesion in labyrinth found that lesions of the posterior commissure dis- Johanson and his colleagues induced lesions of abled the vertical eye movements [159]. labyrinth in 6 squirrel monkeys (Peruvian; 3 males Even after surgery, peripheral neurons innervating and 3 females, 1.5–2 years old) [135]. After labyrinth semicircular canals were found to respond to constant destruction on the left side, all monkeys grew quiet linear acceleration. However, the response was artifa- and moved less than before the operation, when they cutual and arose from thermal gradients introduced by were alert and energetic. Lesioned monkeys tottered the surgical exposure. Otolith neurons did not respond or staggered and their movements were unsteady. Er- to even intense angular accelerations [78]. In this con- rors were observed in reaching movements or jump- nection, the readers should consult the elaborate ex- ing, but these symptoms disappeared after 1 month. periments of canal plugging in rhesus monkeys con- After 6 weeks, their coordination of movements was ducted by Cohen, Suzuki and their colleagues or completely restored so that the lesioned monkeys Highstein and his colleagues [160–162]. could not be differentiated from the sound ones. The The effects of the destruction of the saccular mac- threshold of a rotatory stimulation to evoke vomiting ula, the utricular nerve section, and the lateral am- was 2.6–3.8 rpm, only a little above the normal values. pullary nerve were quantitatively studied during the The second labyrinth destruction on the right side fol- behavior of squirrel monkeys. The utricular input was lowed at this time. The same symptoms (loss of bal- the most important for the maintenance of body equi- ance) observed after the first operation reappeared and librium, and slightly less equilibrium disturbance was remained for 3 months. The symptoms then improved found after the lateral ampullary nerve section [163]. after 4 months, but the coordination of movements The minimal effect for the maintenance of body equi- was not well organized. Caloric nystagmus was not librium was confirmed after unilateral saccular macula observed. Rotatory stimulation with 10.0 rpm pro- ablation. Spontaneous, positional, and paroxymal po- duced no salivary secretion, nausea or vomiting. Also, sitional nystagmus were observed after sectioning the unilateral destruction in the labyrinth was known to superior division of the vestibular nerve. In this in- reduce the CV of the heart rate [152]. Bilateral stance, a histological study revealed the degeneration labyrinthectomy abolished positional nystagmus, and of the macula utriculi with the release of statoconia. some changes occurred in positional nystagmus after The operated monkeys consistently demonstrated di- bilateral macular ablation, but the nystagmus did not rection-fixed spontaneous nystagmus over 5 months. completely disappear [153]. Positional tests could change the intensity of the spon- Ultrastructural changes were found after the taneous nystagmus, but they never elicited paroxysmal vestibular dendrites section peripheral to the vestibu- positional nystagmus. lar nerve ganglion. Some pericaria and some fibers of The horizontal angular VOR (aVOR) evoked by the vestibular nerve ganglion remained in the gan- high-frequency, high-acceleration rotations was stud- glionic matrix for up to 1,247 d. The surviving neu- ied in squirrel monkeys (nϭ4) after unilateral rons and fibers at first exhibited Wallerian-like degen- labyrinthectomy. The latency of the VOR measured eration with the retention of ultracellular organelles. from responses to steps of acceleration was The cross-sectional areas of the soma were signifi- 8.4Ϯ0.3 ms for ipsilesional rotations and 7.7Ϯ0.4 ms cantly smaller than those of normal neurons [154, for contralesional rotations. The gain of the VOR for 155]. The effects of a section of the superior vestibu- the step acceleration was 0.67Ϯ0.12 for contralesional lar nerve were also reported [156]. rotations and 0.39Ϯ0.04 for ipsilesional rotations (in Concerning vestibular compensation after unilat- darkness). Within 18–24 h after return to light, the eral labyrinthectomy, the cholinergic substance and VOR gain for contralesional rotations increased to polyamines were found to be involved. Atropine injec- 0.87Ϯ0.08 and for ipsilesional rotation, a slight in- tion reduced the slow-phase eye velocity of damped crease was noted, to 0.41Ϯ0.06. The VOR evoked by pendular rotation nystagmus, leading to the suggestion sinusoidal rotations of 2–15 Hz (Ϯ20 deg/s) was that the major site of atropine action was the vestibular found to recover better at lower (2–4 Hz) than at nuclei on the intact side [157, 158]. Vestibular com- higher (6–15 Hz) frequencies. At 0.5 Hz, the gain de- pensation (vestibulo-ocular and vestibulo-spinal bal- creased symmetrically when the peak amplitude was ance) was also studied after the destruction of the de- increased to 400 deg/s, from 20. A model incorporat- scending medial longitudinal fasciculus (MLF). Uni- ing linear and nonlinear pathways was proposed [164, lateral lesions on the MLF produced a slight deviation 165]

12 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology Following the unilateral destruction of the vestibu- slight reduction in OKAN was observed after unilat- lar organ, the amount of GABA increased among the eral macular ablation. Therefore it is concluded that a ipsilateral vestibular nuclei on the operated side, and significant reduction in OKN and an abolishment of it decreased on the contralateral side. The manner of OKAN were attributable to a deprivation of inputs change of the GABA contribution to post-operative from the ampulla of the semicircular canals and not compensation is of interest [36, 166]. from the otolith maculae [171]. The chronic toxic effects of methyl-mercurate were To understand lesion effects of the otolith organ, the induced in squirrel monkeys [167]. The results re- neuroanatomy of the otolith system is a prerequisite. vealed bubble formations or degenerative changes in The author suggests that the reader consult figures in the supporting cells of the cristae and maculae, and the papers published by Uchino and Isu [20, 21], the function of sensory hair cells was completely pre- Gresty et al. [172], and Büttner-Ennever [48], where served. OKN, OKAN, and caloric nystagmus were the wiring diagrams of the cat or human otolith- normal, though the threshold for cold caloric nystag- vestibular system is illustrated. mus with cold water or air decreased. The presence of spontaneous nystagmus and positional nystagmus sug- 3. Lesions in area postrema gested cerebellar dysfunction, but no degeneration The area postrema is considered to be the chemore- was found in the cerebellum itself; glial changes were ception center of vomiting [173]. A lesion study was observed in the cerebral cortex and subcortical nuclei, made with Bolivian squirrel monkeys (nϭ12; ?, 4–6 including the vestibular nuclei. It is also of interest years, 531–675 g bw [174]). A combined stimulation that the effects of rapid decompression produced inner of sinusoidal vertical movement (6 inches in ampli- ear pathological changes and related dysfunctions tude) with horizontal rotation (25 rpm) was applied [168]. for 2 h to squirrel monkeys in an unrestrained condition. Vomiting did not occur in 5 of 8 monkeys after a 2. Lesions in the otolith organs lesion of the area postrema. The mean incidence of It is commonly acknowledged that the semicircular vomiting decreased 2.2 to 0.45 times. However, the la- canal organs are essential to evoke motion sickness, tency of vomiting did not significantly change in the but it has long been controversial whether the otolith three monkeys that suffered from vomiting, from organs are also involved in the genesis of that malaise. 33 min (nϭ8) to 29 min (nϭ3). It is concluded from Igarashi and his colleagues elegantly addressed this these experiments that the area postrema has an essen- problem [132, 169, 170]. Eleven squirrel monkeys tial role in triggering vomiting. The results of another were used (2–3 years; 2 Bolivian, 1 Guinean, 8 Peru- study, however, argued for the opposite conclusion Colombian). Optokinetic stimulation was combined because a lesion restricted to the area postrema with a with sinusoidal movements in an anteroposterior di- CO2 laser changed the mode of vomiting, but did not rection (0.25 Hz, 90 deg in amplitude and 141 deg/s of abolish it [151]. There is also a unique lesion study of maximum velocity). Optokinetic stimulation was de- a human. A resection of the area postrema was per- livered by a rotatory drum (60 cm in diameter) with formed to suppress persistent vomiting [175]. Ten black and white vertical strips 1.7 cm in width. With days after the resection, the patient neither vomited this combined stimulation, motion sickness was in- nor felt nausea upon an injection of apomorphine duced in squirrel monkeys and evaluated by use of the (4 mg, I.V.). Twelve days after the surgery he felt only rating score already described (Table 1). The score slight nausea upon an intravenous injection of even up was significantly reduced after a unilateral or bilateral to 12 mg of apomorphine. No vomiting was observed ablation of the otolith macula. There were also signifi- during a follow-up survey of 4 years. Because an- cant differences between the monkeys thus ablated timuscarinic drugs have depressant effects of space and the monkeys before ablation. However, no signifi- motion sickness [176], it is noteworthy that mus- cant difference could be detected in squirrel monkeys, carinic cholinergic receptors existed in area postrema which showed low sensitivity before the ablation. A [121]. small ablation of the saccular macula reduced the score, without nausea. The score, however, regained Behavioral and Psychological Studies the preoperation level after 4.5 months, suggesting the Sensitivity and adaptation to motion sickness were presence of reorganization of the nervous system. The studied in relation to age. No difference was observed effects of macular ablation on horizontal OKN and in the rating score across various ages of adult squirrel OKAN were studied. A bilateral ablation of maculae monkeys [15, 176]. Another study was performed on reduced OKN, but OKAN was not affected, though a the adaptation of Bolivian squirrel monkeys to motion

Japanese Journal of Physiology Vol. 52, No. 1, 2002 13 K. MATSUNAMI sickness [149, 150]. Horizontal rotatory stimulation the hippocampus and the hypothalamus was of great (30.5 rpm, 1–2 h/d) applied every day lengthened the interest [181, 182]. latency to vomiting in more than half the squirrel A vasopressin (AVP) V1 antagonist is another kind monkeys tested. Some showed a decrease in latency, of drug to suppress the development SAS [176], and however, particularly monkeys that showed latency in the intravenous application of d (CH2) 5Tyr (Me) AVP the initial state. A shortening of the latency period completely blocked emesis and other significant was distinct in the first 2 d. Thereafter the incidence of symptoms in squirrel monkeys (nϭ6) [180]. Readers vomiting decreased and leveled off after 5 d of train- should also consult the experiments of 2-deoxy-D-glu- ing. This type of adaptation was transient and disap- cose uptake into brain-stem nuclei of squirrel mon- peared after 1 week if training was stopped. Food keys exposed to rotation [53, 54]. In this connection, aversion was observed when motion sickness was in- it is also desired that in the future a change of cate- duced in squirrel monkeys [177]. cholamine substances in the brain be done, as it was in the based ganglion by microdialysis [183]. Prevention and Medication of Motion Sickness Caloric Nystagmus Several kinds of medicine for motion sickness or An infusion of warm or cold water into the meatus space motion sickness were developed [114, acusticus, or blowing with warm or cold air, evokes 178–180]. Scopolamine did not prevent motion sick- nystagmus (caloric nystagmus), the main cause of ness in cats or dogs, though it was very effective in which is convectional expansion of the endolymph man. The following premedications were found to fluid in the semicircular canals (Bárány, 1906). If be effective to suppress the incidence of motion sick- Bárány’s theory is right, the amplitude of caloric nys- ness in human subjects: (1) scopolamine (100 ␮g), tagmus must be the same irrespective of a prone or a (2) dexedrine (140 ␮g), (3) scopolamine (50 ␮g)ϩ supine position. However, caloric nystagmus was 4 dexedrine (70 ␮g), (4) prometazine (3 mg), and (5) times greater for the prone than for the supine posi- promethazine (3 mg)ϩ ephedrine (3 mg). Ephedrine tion, and it followed the cosine function [184]: (adrenaline: 0.3–6.0 mg) alone was ineffective [169]. ϭ This is consistent with another study [121] in which Ga Gv·Tvor scopolamine was the most effective drug in cases Gvϭgv·cos(xϩdx) where only a single drug was applied. It also proved to be most effective drug for human subjects. These facts Ga, gain of VOR acceleration; Gv, gain of velocity; confirmed that muscarinic receptors were involved in Tokan, time constant of OKAN; Tvor, time constant of the etiology of motion sickness. Atropine, propranol, VOR; gv, constant. isoproterenol, and carbachol reduced CV of the heart Ga took different values for the prone or supine po- rate [152]. sition, i.e., it was two times larger for the supine posi- The distribution of acetylcholine receptors was in- tion. Tvor showed a similar type of asymmetry, and Tvor vestigated in the brain stem of the squirrel monkeys and Tokan behave in a similar manner. It was then pro- by the use of 3H-1-quinucldinyl benzilate (3H-QNB; posed that two-time constants were affected by way of a muscarinic receptor antagonist). The scatchard the velocity storage. Evidence was also provided that method was employed to evaluate the affinity of the the otolith organs affected caloric nystagmus. From tracer to receptor sites [121]. The following results these facts it was suggested that caloric nystagmus is were obtained: the vagal nerve nuclear complex composed of 75% convectional components and 25% (VNC, 1,048Ϯ139 fmol/mg protein), followed by area nonconvectional components. The two types of com- postrema (1,023Ϯ243), the nucleus reticularis parvo- ponents were position-dependent. cellularis (719.2Ϯ67.0), the nucleus reticularis gi- It is also known that in caloric nystagmus, heat di- ganto-cellularis (646.8Ϯ81.5), and the vestibular nu- rectly affects hair cells and the ends of nerve termi- clei (393.3Ϯ26.7). nals, or it produces changes in the cupula because of In this connection, it is noteworthy that efferent an expansion of endolymph in the labyrinth. The nicotinic innervation at the primary sensory hair cells change in spike discharge (dD) as it relates to the and the medial vestibular nuclei were supposed to be change in temperature was expressed as follows: sites for a beneficial influence by cholinergic drugs dDϭ2g ·N /g ·k·dT [115]. The importance of the limbic system in the AFF c v genesis of SMS is also suggested ([116], Fig. 2). When each term was substituted with the respective Therefore the presence of the vestibular activation of appropriate values, dDϭ10 sps/deg (Q10ϭ2.6). It is

14 Japanese Journal of Physiology Vol. 52, No. 1, 2002 Squirrel Monkey in Space Physiology further supposed that a nonconvectional but thermal mates, Academic Press, London and New York, 1967 factor could induce caloric nystagmus in space or 13. Stephan H: Data on size of the brain and of various upon canal plugging [185], and this has induced brain parts in insectivores and primates. In: The Pri- mate Brain, ed. Noback CR and Montagna W, Apple- asymmetry of carolic nystagmus in the prone and ton-Century-Crofts, New York, pp 289–297, 1970 supine positions. 14. Baron G, Frahm H, and Stephan H: Comparison of brain structure volumes in insectivore and primates. Concluding Remarks III. Vestibular complex. J Hirnforsch 29: 509–523, A description was made on the studies of the squirrel 1988 15. Cheung BS and Money KE: The inﬂuence of age on monkey vestibular system in consideration of SAS. susceptibility to motion sickness in monkeys. 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