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The human cerebellum
Journal of Chemical Neuroanatomy 26 (2003) 243–252
Review
The human cerebellum Jan Voogd∗ Department of Neuroscience, Erasmus MC, Box 1738, 3000 DR Rotterdam, The Netherlands Received 17 April 2003; received in revised form 8 July 2003; accepted 20 July 2003
Abstract This short review deals with observations on the gross morphology and internal structure of the human cerebellum, and with studies of cerebellar fiber connections in non-human primates. Attention is focussed on its gross anatomy, the zonal organization of the primate cerebellum, the brain stem, thalamic and cortical connections of the cerebellar nuclei and on the cortico-ponto-cerebellar pathway. The presence of important reciprocal nucleo-mesencephalo-olivary loops as part of the circuitry of the dentate and globose (posterior interposed) nuclei and their absence among the connections of other cerebellar nuclei is emphasized. © 2003 Published by Elsevier B.V. Keywords: Cerebellar zones; Cerebellar nuclei; Cerebellar circuitry; Pontocerebellar pathway; Central tegmental tract; Red nucleus
Apart from its appearance in numerous imaging studies and the publication of an MRI atlas (Schmahmann et al., 2000, see also Schmahmann et al., 1999), the human cerebellum has received little attention in the recent past. This short review will deal, therefore, with old observations on its gross morphology and internal structure and on studies of cerebellar fiber connections in non-human primates. References and a full documentation of the subjects treated in this review can be found in my chapter on the cerebellum in the forthcoming second edition of Paxinos and Mai ‘The Human Nervous System’. The nomenclature of the lobules and fissures of the human cerebellum has confused many of its students. The classical nomenclature, introduced by Malacarne, Reil and Burdach in the 18th and early 19th century, is still the most commonly used for the human cerebellum. Other influential nomenclatures, rooted in the comparative anatomy of the mammalian cerebellum, were published by Bolk (1906) and Larsell (1952) (see also Larsell and Jansen (1972)). Different nomenclatures of the cerebellum were reviewed by Angevine et al. (1961) and tabulated by Schmahmann et al. (1999). The latter author used a mixture of Larsell’s roman numbering system and Bolk’s nomenclature in his recent MRI atlas (Schmahmann et al., 2000), completely discarding
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the classical nomenclature. Time shall learn whether the use of Larsell’s number IX for the uvula and the tonsilla and X for the nodulus and the flocculus, really is an improvement. There is a rationale behind most nomenclatures. The classical nomenclature of the human cerebellum used similarities in shape or appearance (Malacarne (1776) cat’s tongue: the lingula). The Bolk (1906) nomenclature accentuated the different degrees of continuity between the lobules of vermis and hemispheres; Larsell (1952) stressed the continuity of each (sub)lobule of the vermis with a (sub)lobule in the hemisphere. With respect to the homology of the major lobules of the human cerebellum, Bolk and Larsell came to the same conclusions, but Bolk clearly had priority. In Fig. 1, I have shown how Bolk’s nomenclature can be applied to the human cerebellum. The classical names are given in parenthesis. The human cerebellum is large, in particular the great width of the folia of the hemispheres is one of its distinguishing features. A faint depression on the superior surface marks the border between vermis and hemispheres. Schmahmann et al. (1999) were probably right when they concluded that this border is indistinct. This superior surface of the cerebellum consists of the anterior lobe and Bolk’s lobulus simplex. Bolk coined this name because the lack of a clear border between vermis and hemispheres imparts a uniform appearence to this lobule. Both in the anterior lobe and the lobulus simplex, the transverse fissures run uninnerruptedly from the vermis into the hemispheres.
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Fig. 1. Three diagrams of the human cerebellum. The grey bands indicate the direction of the folial chains of vermis and hemispheres. The two loops in the folial chain of the hemisphere are indicated as 1 and 2. Insets show the wire diagram of the fundamental structure of the mammalian cerebellum of Bolk (1906) and a photograph of the folial loop of the tonsilla, reproduced from Rohen and Yokochi (1988). Bolk’s terms for the lobules are used, with the classical names in parenthesis. Abbreviations: ANS, ansiform lobule; ANT, anterior lobe; BI, biventral lobule; fH, horizontal fissure; fI, primary fissure; FLO, flocculus; fPS, posterior superior fissure; GR, gracile lobule; Ped, cerebellar peduncles; PM, paramedian lobule; PFL, paraflcculus; QUa, anterior quadrangular lobule; QUp, posterior quadrangular lobule; SEM, semilunar lobules; SI, lobulus simplex; TO, tonsilla; VE, vermis.
Anterior lobe and lobulus simplex, therefore, constitute a single morphological entity. Bolk observed the same features: an indistinct vermis and the continuity of the fissures accross the entire width of the cerebellum, in the anterior portion of most mammalian cerebella. In his wire diagram of the fundamental structure of the mammalian cerebellum (Fig. 1, inset) this region was indicated with a single line.
Caudal to the lobulus simplex the cerebellum splits into a distinct vermis and the two hemispheres. This split and the direction of the folial chains of vermis and hemispheres is indicated with the grey bands in Fig. 1. The chain of parallel folia of the hemisphere contains two loops. The first loop (Fig. 1: 1) is located on the posterior surface, in the region of the ansiform lobule (the semilunar lobules of the classical nomenclature), where the folia fan out from a common stalk (the horizontal fissure), like the feathers from a wing. The anterior and posterior limbs of this loop are known as the crus I and the crus II of the ansiform lobule and correspond to the superior semilunar lobule and to the inferior semilunar lobule with the lobulus gracilis, respectively. The second loop (2) is made up of the folia of the paraflocculus (the human tonsilla) and is located on the ventral surface. This loop terminates in the flocculus. The folial loop of the tonsilla is rarely illustrated in textbooks on the brain. Rohen and Yokoshi’s (1988) outstanding photographic atlas of the human body, from which the inset in Fig. 1 is reproduced, is an exception. The segment of the folial chain of the hemisphere located between the ansiform lobule and the paraflocculus is known as the paramedian lobule. It corresponds to the biventral lobule of the classical nomenclature. Bolk also indicated the two loops, which are a general feature of the mammalian cerebellum, in his wire diagram. The homology of the mammalian paraflocculus with the human tonsilla, which is mainly based on the development of their limiting fissures, receives support from the presence of a folial loop in this region. The human cerebellum, therefore, conforms to the general mammalian pattern, as established by Bolk. Detailed homologies of the lobules of the human cerebellum with lower mammals were established by Bolk, Larsell (1952), Larsell and Jansen (1972) and others. Larsell’s comparative anatomical nomenclature, which divides the cerebellum in ten lobules—indicated with roman numerals—became popular for its simplicity. Its implications for the homology of these lobules, however, should be viewed with some circumspection. His conclusions, for instance, on the homology of the medial belly of the biventral lobule (HVIIIB) with the mammalian ventral paraflocculus and of the tonsilla (HIX) with the ventral paraflocculus (Larsell and Jansen, 1972) are untenable because the location of the border between dorsal and ventral limbs of the paraflocculus varies greatly among different mammalian species (Voogd, 2003). The entire cerebellum is covered by a uniformly structured cortex. Due to the transverse fissures, the lengh of the cortical sheet greatly exceeds its width. The cortex is continuous between the succesive segments (lobules) of the folial chains of vermis and hemispheres, with the exception of the cortex of the flocculus, which is not continuous with the tonsilla. Between caudal vermis and hemispheres the cortex is usually interrupted (Fig. 4, *). The cerebellar nuclei are located within the central white matter. Stilling (1864) was the first to distinguish the four cerebellar nuclei of the human cerebellum: the fastigial,
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Fig. 3. The high iron-content of the caudal and lateral, macrogyric portion of the dentate nucleus. One of the first exemples of a neurochemical characterization of a brain nucleus. From Gans (1924).
Fig. 2. The four cerebellar nuclei of the human cerebellum. Relabeled lithograph from Stilling (1864). The subdivision of the dentate nucleus in microgyric and macrogyric portions is shown.
globose, emboliform and dentate nuclei. Fig. 2 is reproduced from one of his lithographs. Inspection of the dentate nucleus in Fig. 2 indicates that it is composed of two parts: a dorsomedial and rostral region with narrow dentations (microgyric dentate) and a ventrolateral and caudal portion with wide and subdivided gyrations (macrogyric dentate). The two parts of the dentate were illustrated but not recognized by Stilling as such. This distinction was made in the early 20th century by several authors on the basis of differences in cell-size between the two parts, the late development of the macrogyric dentate, its selective vulnerability in cases of ‘neocerebellar’ atrophy and its high iron content (Gans, 1924; Fig. 3).
Comparative anatomists have attributed different names to the cerebellar nuclei: the globose and emboliform nuclei became known as the posterior and anterior interposed nucleus, and the fastigial and dentate nuclei as the medial and lateral cerebellar nuclei. The rostro-medial and caudolateral portions of the lateral cerebellar nuclei differ in their connections, but a clear homology between these parts and the microgyric and macrogyric dentate of the human cerebellum has not been substantiated. In the rat, Buisseret-Delmas et al. (1993) described a fifth cerebellar nucleus, the ‘interstitial cell groups’, located between the medial and posterior interposed nuclei. A similar cell group appears to be present in monkeys and carnivores. The connections between the cortex and the cerebellar nuclei have been studied extensively since the appearance of Klimoff’s thesis on the corticonuclear projection in the rabbit, written under the supervision of Darkschewitsch in Kazan (Klimoff, 1897) and summarized by Klimoff (1899). A diagram of the corticonuclear projection, based on more recent studies in carnivores and monkeys, is illustrated in Fig. 4. The Purkinje cells, the only output element of the cerebellar cortex, are responsible for this projection. Purkinje cells projecting to a particular cerebellar or vestibular nucleus are arranged in discrete parallel longitudinal zones which, generally, are continuous from one lobule to the next.
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Fig. 4. Diagram of the zonal organization in the corticonuclear and olivocerebellar projections in the cat. Modified from Groenewegen et al. (1979). (A) Diagram of the flattened cerebellar cortex. (B) Diagram of the cerebellar and vestibular nuclei. (C) Diagram of a projection of the monkey inferior olive in the horizontal plane, constructed according to Brodal (1940). The longitudinal corticonuclear and olivocerebellar projection zones are indicated with capitals (A, X, B, C1–3 , D1,2 ). The zones, their target nuclei and the subnuclei of the inferior olive which project to these zones are indicated with the same colors. The diagram applies equally to the monkey cerebellum, with the exception of the floccular zones, the most medial one of which is lacking in the monkey (for details see Voogd et al., 1987). Asterisks: areas without cortex. The two squares refer to the position of Fig. 5(A, B). Abbreviations: A, A zone; Ans, ansiform lobule; B, B zone; C1–3, C1–3 zones; D1,2, D1,2 zones; DAOc, caudal dorsal accessory olive; DAOr, rostral dorsal accessory olive; DC, dorsal cap; DEIT, lateral vestibular nucleus of Deiters; DENTc, caudal part of dentate nucleus; DENTr, rostral part of dentate nucleus; dl, dorsal lamina of the principal olive; DMCC, dorsomedial cell column; EMB, emboliform nucleus; FAST, fastigial nucleus; FLO, flocculus; GLOB, globose nucleus MAOr, rostral medial accessory olive; MAOc, caudal medial accessory olive; NOD, nodulus; PFL paraflocculus; PFld, dorsal paraflocculus; PMD, paramedian lobule; PO, principal nucleus of the inferior olive; vl, ventral leaf of principal olive.
Three Purkinje cell zones, A, X and B, can be distinguished in the anterior vermis. A projects to the fastigial nucleus, X to the interstitial cell groups and B to the lateral vestibular nucleus of Deiters. X and B are lacking in the caudal vermis. The most caudal part of the vermis (the nodulus) mainly projects to the vestibular nuclei, other than Deiters’ nucleus. This projection is organized in four or more zones. In the anterior hemisphere, five zones are present: C1–3 , D1 and D2 . C1 and C3 both project to the emboliform nucleus, C2 to the globose nucleus and D1 and D2 to caudal and rostral portions of the dentate nucleus, respectively. C1 and C3 are absent from the two loops of the folial chain of the hemisphere at the level of the ansiform lobule and the paraflocculus, but they are present again in the intermediate segment of the hemisphere, located between the two loops: the paramedian lobule. C2 , D1 and D2 continue uninterruptedly from the anterior cerebellum into the paraflocculus and the flocculus. In the flocculus, the D zones are replaced by four zones, which project to the vestibular nuclei. The most medial one of these four zones is lacking in monkeys. Exactly the same zonal arrangement is found for the olivocerebellar climbing fiber projection to the Purkinje cells. This crossed projection is illustrated in panel C of Fig. 4 for the monkey inferior olive. Olivocerebellar fibers, terminating on the Purkinje cells of a particular zone, moreover, emit collaterals terminating in the target nucleus of these Purkinje cells (Ruigrok and Voogd, 2000). Finally, a GABAergic inhibitory pathway connects the cerebellar nuclei with the contralateral inferior olive (Kalil, 1979; Mugnaini and Oertel, 1985; Ruigrok and Voogd, 1990) This nucleo-olivary projection is organized in same topical fashion (Fig. 7). The zonal organization of the cerebellum is a highly concerved feature of the cerebellum of vertebrates. Recently, the four floccular zones were also found to be present in birds (Winship and Wylie, 2003). It seems likely, therefore that they should have emerged as early as in the reptilian ancestor of mammals and birds. From the point of view of its connections, the cortex appears to be less uniform than stated in one of the previous paragraphs. In rodents, zebrin-immunoreactive and non-reactive Purkinje cells are distributed in a pattern of alternating longitudinal zones (Hawkes and Leclerc, 1987). A very similar distribution has been observed for a variety of substances, including enzymes, protein kinases, growth factor receptors, neurotransmitter splice variants and glutamate transporters (see Voogd et al., 1996 and Voogd, in press for reviews). In the rat there is a close correspondance between the zebrin pattern and the projection zones A–D (Voogd et al., 2003), in other words, Purkinje cells of a projection zone are characterized by their connections, but also share a particular chemical identity. Thus far, the zebrin pattern in primates has only been substantiated for the vermis of the squirrel monkey (Leclerc et al., 1990). I was unable to observe such a pattern in the rhesus monkey, where all Purkinje cells are zebrin-positive (Voogd, unpublished
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observations). The distribution of zebrin-positive and negative Purkinje cells in the human cerebellum is unknown (Plioplys et al., 1985). Why should we be so confident that zonal arrangement, depicted in Fig. 4 is valid for primates? Certainly not because of the scarce experimental evidence. Convincing, structural evidence, however, is available from studies of the compartmentation of the cerebellar white matter. In the white matter, each Purkinje cell zone corresponds with a particular white matter compartment, which contains the Purkinje cell axons and the olivocerebellar climbing fiber afferents of that particular zone. The borders of these compartments strongly stain for acetylcholinesterase (AchE; Hess and Voogd, 1986). In Fig. 5, two AchE-sections through the monkey cerebellum are depicted. Fig. 5(A), shows the anterior lobe of the rhesus monkey (boxed area in Fig. 4), with the A, X, B, C1–3 , D1 and D2 compartments. The C1 and C3 compartments converge upon their target nucleus, the anterior interposed (emboliform) nucleus. The target nuclei of the other compartments cannot be seen at this level. Fig. 5(B) shows the transitional region of the paramedian lobule into the paraflocculus (boxed area in Fig. 4). The C1 and C3 compartments terminate in this region; C2 , D1 and D2 turn laterally to enter the folial loop of the paraflocculus. The caudal pole of the posterior interposed nucleus is located within the C2 compartment, the caudal pole of the lateral cerebellar nucleus occupies D1 .
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Our knowledge of the zonal organization of the primate cerebellum is still very incomplete. Notably, information is lacking on the precise corticonuclear and the climbing fiber connections of the D1 and D2 zones and on the precise delimitation of their target nuclei: the rostral and caudal dentate. Precise data on this subject are important because the great width of the primate cerebellar hemisphere, probably, is due to the width of the D2 zone. In monkeys, the paraflocculus is still a relatively narrow band of folia.The folia of it human counterpart, the tonsilla, are much wider. It is possible that this increased width is caused by the D1 zone; this would explain the large size of the macrogyric dentate. Data on the zonal organization of the human cerebellum are almost completely lacking. Evidence of the presence of a zonal arrangement of the Purkinje cells of the human cerebellum mainly rests on preliminary studies of the development of the Purkinje cell zones in human fetuses from a series of primordial Purkinje cell clusters, a developmental process which has been traced in more detail in monkeys (Kappel, 1981) and rats (Korneliussen, 1968). The borders between the white matter compartments, each containing the axons of a Purkinje cell cluster destined for a particular cerebellar nucleus alluded to in the previous paragraphs, already exist at these fetal stages. The cerebellar nuclei are the gateway of the cerebellum to other parts of the brain. There is strong evidence in
Fig. 5. Two photographs of acetylcholinesterase-stained transverse sections through white matter of the monkey cerebellum. For approximate location see insets Fig. 4. (A) Rhesus monkey anterior lobe. (B) Transitional region of the paramedian lobule into the paraflocculus in Saimiri sciurus. Abbreviations: A–D, white matter compartments A–D; bc, brachium conjunctivum; cr, restiform body; IntA, anterior interposed (emboliform) nucleus; IntP, posterior interposed (globose) nucleus; Lat, lateral (dentate) nucleus; m, midline; PFLd, dorsal paraflocculus
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rodents and carnivores that the axons of the main relay cells of the nuclei collateralize to different parts of the brain stem, the cord and the thalamus (Bharos et al., 1981; Bentivoglio and Kuypers, 1982; Teune, 1999; Teune et al., 2000). The target, or the combination of targets supplied by the different nuclei differ considerably. The target nuclei of the Purkinje cell zones of the vermis, the fastigial nucleus and Deiters’ nucleus, monitor descending vestibulo-spinal and reticulospinal pathways. Cells of the interstital cell groups collateralize to the spinal cord, the superior colliculus and the thalamus (Bentivoglio and Kuypers, 1982). The target nucleus of the C1 and C3 zones, the emboliform (anterior interposed) nucleus projects to the contralateral magnocellular red nucleus and via the thalamus to the primary motor cortex (Figs. 6 and 7D).Via the magnocellular red nucleus, it monitors the rubrobulbar and spinal tract and via the motor cortex, the pyramidal tract.
Fig. 6. Diagram of the nucleo-thalamo-cortical projections from the individual cerebellar Purkinje cell zones in primates. Subdivision of the thalamic motor nuclei according to Percheron (in press). The thalamic projection area of the intermediate cell groups is not known. From Voogd (2003). Abbreviations: A–D, zones A–D; Mot, primary motor cortex; Olsz, Olszewski; Pariet, parietal lobe; Prearc, prearcuate area; Premot, premotor area; SM(A), supplementary motor area; VLc, caudal part of the ventrolateral nucleus; Vlo, oral part of the ventrolateral nucleus; VLps, posterior part of ventrolateral nucleus; VPLo, oral part of the lateral ventroposterior nucleus.
Fig. 7. Diagrams of brain stem, thalamic and cortical connections of the D and C zones. The D1 , D2 and C2 zones and their target nuclei give rise to a mesencephalo-olivary reciprocal circuit. These circuits are topically organized, and include a cortico-rubral (-Darkschewitsch) projection from their cortical target area (for references see text). A similar reciprocal circuit does not exist for the C1 and C3 zones and their target nucleus. Based on data from the literature. For references see Voogd (2003). Abbreviations: (pre)mot, (pre)motor area; C, D, C, D zones; ctt, central tegmental tract; DAOr, rostral part of the dorsal accessory olive; DARK, Darkschewitsch nucleus; Dentc, caudal dentate nucleus; Dentr, rostral denate nucleus; EMB, emboliform (anterior interposed) nucleus; GLOB, globose (posterior interposed) nucleus; M1, primary motor cortex; MAOr, rostral part of the medial accessory olive; mtt, medial tegmental tract; no, nucleo-olivary pathway; POdl, dorsal lamina of the principal olive; POvl, ventral lamina of the principal olive; prefront, prefrontal cortex; rs, rubrospian tract; RUdm, dorsomedial subnucleus of the parvocellular red nucleus; RUlc, latero-caudal part of the parvocellular red nucleus; RUmc, magnocellular red nucleus; THAL, thalamus.
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The brain stem connections from the target nuclei of the C2 , D1 and D2 zones are quite different. The globose (posterior interposed) nucleus projects to Darkschewitsch’ nucleus, located in the central grey at the junction of the mesencephalon and the diencephalon. Its fibers proceed to the thalamus, where they terminate on nuclei projecting to a large, but insufficiently characterized region of the frontal lobe, including the frontal eye field (Kievit, 1979). Darkschewitsch nucleus gives rise to an ipsilaterally descending pathway (medial tegmental tract), which terminates on the rostral half of the medial accessory olive (for references see Voogd, 2003). This olivary subnucleus provides climbing fibers to the C2 zone and its target nucleus, the globose (Fig. 7C). Similar closed, reciprocally organized mesencephalo-olivary-cerebellar circuits exist for the the dentate. In the case of the rostral dentate, this circuit includes the lateral and caudal parvocellular red nucleus and the dorsal lamina of the principal olive, and the D2 zone (Fig. 7A), in the case of the caudal dentate it includes the dorsomedial parvocellular red nucleus, the ventral lamina of the principal olive and the D1 zone (Fig. 7D). The pathway connecting the parvocellular red nucleus with the principal olive is known as the central tegmental tract. The thalamic and cortical targets of the rostral and caudal dentate also differ. The rostral dentate projects to motor and premotor regions via the lateral (VImL) subpart of the nucleus ventralis intermedius of Percheron (in press). The correspondence of Percheron’s lateral and medial subdivisions of his nucleus ventralis intermedius to the Olszewski (1952) nomenclature is indicated in Fig. 6. The caudal dentate projects to more rostral and dorsal regions of the frontal lobe, including the frontal eye fields, and the areas 9 and 46, and the inferior parietal cortex, via the medial subpart of the nucleus ventralis intermedius (VImM). The thalamic projections of the individual cerebellar nuclei and their ultimate cortical target areas are a complicated subject for the non-initiated. Fig. 6, taken from Voogd (2003) summarizes these connections, but Fig. 6 clearly is a simplification and the single question mark underestimates the number of open questions which still confront us. The studies of the cerebello-cerebral relations of Wiesendanger and Wiesendanger (1985) and Strick et al. (see Middleton and Strick (1997) for a review and Clower et al. (2001) for more recent references) used retrograde transneuronal labeling from small tracer injections of the cerebral cortex to circumvent the problem of the cerebellar relay nuclei of the thalamus. The data on the cortical projections of the caudal and rostral dentate from Fig. 6, where they were transposed to the human cerebral hemisphere, were derived from these studies. Cortical areas in the frontal lobe which receive cerebellar projections from the thalamus give origin to corticorubral projections (Kuypers and Lawrence, 1967; Hartmann-von Monakow et al., 1979). These projections are independent from the corticospinal and corticopontine projections which arise from the same cortical areas, but from different sublay-
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ers of layer V (Catsman-Berrevoets et al., 1979; Humphrey et al., 1984; Kuypers, 1987). The corticorubral projection is topically organized: the lateral and caudal parvocellular red nucleus, which is involved in the reciprocal loop from the rostral dentate, receives a projection from motor and premotor cortex, the dorsomedial parvocellular red nucleus, involved in the loop from the caudal dentate receive a projection from prefrontal areas and the frontal eye field (Fig. 7). Contrary to the corticorubral projection to the parvocellular red nucleus, the projection to the magnocellular red nucleus originates as a collateral system from the corticospinal tract. The presence of strong reciprocal nucleo-mesencephaloolivary circuits distinguishes the brain stem circuitry of the target nuclei of the C2 , D1 and D2 zones from the brain stem circuitry of the target nuclei of the zones of the vermis and the C1 and C3 zones. Most studies of the physiology of the cerebellum, implicitly or explicitly, concern functions subserved by the circuitry of the vermis, the C1 and C3 zones and the vestibulocerebellum. These functions mostly concern the coordination or long-term adaptation of motor behaviour, which employ the long descending vestibulo-spinal, reticulospinal, rubrospinal and corticospinal tracts or the oculomotor system as their final paths. The functional significance of the reciprocal nucleo-mesencephalo-olivary loop, which is an essential feature of the efferents pathways from the C2 and the D zones rarely has been considered. The D zones of the cerebellar hemispheres and the dentate nucleus account for the major part of the human cerebellum. These regions of the cerebellar hemisphere, probably, are responsible for the important functions of the cerebellum in cognition, sensation and the adaptation of motor behaviour, which received so much recent attention (Leiner et al., 1986; Schmahmann, 1997; Bower, 1997). However, the brain stem circuitry used by these systems has never been systematically studied with appropriate electrophysiological techniques. The importance of the dentato-rubro-olivary loop can be judged from the size of the central tegmental tract, one of the largest brain stem pathways known. It was illustrated as early as 1846 by Stilling (1846), in one of his atlases of serial sections of the human brain (Fig. 8). von Bechterew (1885) gave it its name and defined its origin as the principal nucleus of the inferior olive. Its true origin from the parvocellular red nucleus was established in a long series of studies, summarized by Voogd (2003). Reciprocal cerebro-cerebellar loops were studied by Allen and Tsukahara (1974) and more recently by Houk et al. (1993) and Houk and Wise (1995). However, the loops studied by these authors did not involve the inferior olive, but the reticular nuclei which are a link in reciprocal mossy fiber pathways. The application of modeling techniques, as exemplified in Houk’s studies, would be a means to increase our knowledge of this system and the putative role of the cerebellum in cognition. Mossy fiber systems and connections are a blank area in our knowledge of the primate cerebellum. The last paper tracing a mossy fiber system in the human cerebellum was a paper published by Brodal and Jansen (1941) on the
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Fig. 8. Part of a lithograph illustrating the tegmentum pontis from the Stilling (1846) atlas of serial sections through the human brain stem. The central tegmental tract (ctt) and the medial longitudinal fascicle (mlf), which contains the medial tegmental tract, were labeled.
spinocerebellar tracts. Several retrograde labeling studies on mossy fiber pathways in monkeys are available, but these generally provide little information on their intracerebellar topography. Fortunately, more is known about the first link in the major afferent mossy fiber pathway which connects the cortex of the cerebral hemisphere with the contralateral cerebellum through the pons. The corticopontine system takes its origin from layer V pyramidal cells in extensive regions of the cortex, including the motor, sensory, striatal, peristriatal, parietal and prefrontal cortices, as established by Beck (1950) for the human brain and by Glickstein et al. (1985) (Fig. 9) and Schmahmann and Pandya (1995, 1997) in monkeys. The corticopontine projection arises as a collateral system from the corticospinal and bulbar fibers (Ugolini and Kuypers, 1986) and from the corticotectal system (Baker et al., 1976; Keizer et al., 1987). It seems likely, therefore, that ponto-cerebellar pathway supplies the cerebellum with an efferent copy of signals from cortical origin. In the frontal lobe, its origin from motor, premotor and dorsal prefrontal areas corresponds remarkably well with the cortical areas targeted by the cerebellar nuclei and the origin of the cortico-rubral projection to the parvocellular red nucleus. This correspondence does not hold for the parietal and peristriatal cortex, however, which supplies an important contingent to the corticopontine system but, thus far, only has been found to receive a minor, thalamus-relayed projection from the dentate nucleus (Clower et al., 2001). It has been pointed out that the origin of the corticopontine system corresponds with the cortical areas belonging to the dorsal visual steam, of Mishkin and Ungerleider (1982) of visual and visually related cortical areas, which contain representations of speed and direction of stimuli in the peripheral visual field and are concerned with the visual guidance of movements. Areas belonging to the ‘ventral visual stream’,
Fig. 9. Distribution of retrogradely labeled corticopontine neurons after a large, almost complete injection with a retrograde axonal tracer of the pontine nuclei in a macaque monkey. (A) Distribution of retrogradely labeled neurons in the left cerebral hemisphere from a complete wheat germ agglutinin-coupled horseradish peroxidase filling of the pontine nuclei. (B) Bargraphs illustrating the numbers of retrogradely labeled neurons in different cortical areas. From Glickstein et al. (1985). Abbreviations: ai, ansate sulcus, inferior limb; as, ansate sulcus superior ilmb; ccs, calcarine fissure; cs, central sulcus; ios, inferior occipital sulcus; ips, intraparietal sulcus; lf, lateral fissure; ots occipitotemporal sulcus; pps, postparietal sulcus; ps, principal sulcus; ts, superior temporal sulcus.
directed at the temporal lobe, which are concerned with object recognition, do not project to the pons. Prefrontal corticopontine connections are limited to dorsolateral and medial areas, related to kinesthetic, motivational and spatially related functions, including spatial memory. Inferior and orbital prefrontal areas, related to autonomic and emotional response inhibition, stimulus significance and object recognition, do not project to the pons (Glickstein et al., 1985; Schmahmann and Pandya, 1995, 1997). Little information is available on the pontocerebellar projection in primates. Of the two papers using antegrade tracing of pontocerebellar mossy fibers, one dates from
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1907 (Spitzer and Karplus, 1907) and only one other paper on visually-related pontocerebellar projections to the flocculus-paraflocculus region was published more recently by Glickstein et al. (1995). Data obtained by retrograde labeling in monkeys were summarized by Brodal and Bjaalie (1992). However, the precise distribution of pontocerebellar fibers, the topical relations between the cerebral cortex and the cerebellum, its zonal organization (Serapide et al., 2001) and the topographical interrelations of the pontocerebellar system with other systems terminating as mossy fibers remain mostly unknown. This review focussed on the early roots of our knowledge of the human cerebellum and tried to point out the main areas were our anatomical knowledge is still insufficient to explain the role of the cerebellum in motor behavious and cognition. The circumstances to undertake the necessary anatomical and physiological experiments in non-human primates to fill these gaps have changed for the worse. The focus in research has shifted away from systems neuroscience. Moreover, primate studies are costly and have been curtailed by government measures. Still, there is hope. Increasing the resolution in functional MRI studies, in humans and experimental animals to the level of brain stem nuclei like the red nucleus and the inferior olive, and the development of methods to trace connections in the living brain, may bring the anatomy of the human cerebellum again to the focus of attention.
Acknowledgements I would like to express my gratitude to the organizers of the conference on The Human Brain in Rome in 2002, especially to Professor J. Mai and Benigna Malebrein, for the opportunity to collect my thoughts on the human cerebellum.
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Review
The human cerebellum Jan Voogd∗ Department of Neuroscience, Erasmus MC, Box 1738, 3000 DR Rotterdam, The Netherlands Received 17 April 2003; received in revised form 8 July 2003; accepted 20 July 2003
Abstract This short review deals with observations on the gross morphology and internal structure of the human cerebellum, and with studies of cerebellar fiber connections in non-human primates. Attention is focussed on its gross anatomy, the zonal organization of the primate cerebellum, the brain stem, thalamic and cortical connections of the cerebellar nuclei and on the cortico-ponto-cerebellar pathway. The presence of important reciprocal nucleo-mesencephalo-olivary loops as part of the circuitry of the dentate and globose (posterior interposed) nuclei and their absence among the connections of other cerebellar nuclei is emphasized. © 2003 Published by Elsevier B.V. Keywords: Cerebellar zones; Cerebellar nuclei; Cerebellar circuitry; Pontocerebellar pathway; Central tegmental tract; Red nucleus
Apart from its appearance in numerous imaging studies and the publication of an MRI atlas (Schmahmann et al., 2000, see also Schmahmann et al., 1999), the human cerebellum has received little attention in the recent past. This short review will deal, therefore, with old observations on its gross morphology and internal structure and on studies of cerebellar fiber connections in non-human primates. References and a full documentation of the subjects treated in this review can be found in my chapter on the cerebellum in the forthcoming second edition of Paxinos and Mai ‘The Human Nervous System’. The nomenclature of the lobules and fissures of the human cerebellum has confused many of its students. The classical nomenclature, introduced by Malacarne, Reil and Burdach in the 18th and early 19th century, is still the most commonly used for the human cerebellum. Other influential nomenclatures, rooted in the comparative anatomy of the mammalian cerebellum, were published by Bolk (1906) and Larsell (1952) (see also Larsell and Jansen (1972)). Different nomenclatures of the cerebellum were reviewed by Angevine et al. (1961) and tabulated by Schmahmann et al. (1999). The latter author used a mixture of Larsell’s roman numbering system and Bolk’s nomenclature in his recent MRI atlas (Schmahmann et al., 2000), completely discarding
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the classical nomenclature. Time shall learn whether the use of Larsell’s number IX for the uvula and the tonsilla and X for the nodulus and the flocculus, really is an improvement. There is a rationale behind most nomenclatures. The classical nomenclature of the human cerebellum used similarities in shape or appearance (Malacarne (1776) cat’s tongue: the lingula). The Bolk (1906) nomenclature accentuated the different degrees of continuity between the lobules of vermis and hemispheres; Larsell (1952) stressed the continuity of each (sub)lobule of the vermis with a (sub)lobule in the hemisphere. With respect to the homology of the major lobules of the human cerebellum, Bolk and Larsell came to the same conclusions, but Bolk clearly had priority. In Fig. 1, I have shown how Bolk’s nomenclature can be applied to the human cerebellum. The classical names are given in parenthesis. The human cerebellum is large, in particular the great width of the folia of the hemispheres is one of its distinguishing features. A faint depression on the superior surface marks the border between vermis and hemispheres. Schmahmann et al. (1999) were probably right when they concluded that this border is indistinct. This superior surface of the cerebellum consists of the anterior lobe and Bolk’s lobulus simplex. Bolk coined this name because the lack of a clear border between vermis and hemispheres imparts a uniform appearence to this lobule. Both in the anterior lobe and the lobulus simplex, the transverse fissures run uninnerruptedly from the vermis into the hemispheres.
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Fig. 1. Three diagrams of the human cerebellum. The grey bands indicate the direction of the folial chains of vermis and hemispheres. The two loops in the folial chain of the hemisphere are indicated as 1 and 2. Insets show the wire diagram of the fundamental structure of the mammalian cerebellum of Bolk (1906) and a photograph of the folial loop of the tonsilla, reproduced from Rohen and Yokochi (1988). Bolk’s terms for the lobules are used, with the classical names in parenthesis. Abbreviations: ANS, ansiform lobule; ANT, anterior lobe; BI, biventral lobule; fH, horizontal fissure; fI, primary fissure; FLO, flocculus; fPS, posterior superior fissure; GR, gracile lobule; Ped, cerebellar peduncles; PM, paramedian lobule; PFL, paraflcculus; QUa, anterior quadrangular lobule; QUp, posterior quadrangular lobule; SEM, semilunar lobules; SI, lobulus simplex; TO, tonsilla; VE, vermis.
Anterior lobe and lobulus simplex, therefore, constitute a single morphological entity. Bolk observed the same features: an indistinct vermis and the continuity of the fissures accross the entire width of the cerebellum, in the anterior portion of most mammalian cerebella. In his wire diagram of the fundamental structure of the mammalian cerebellum (Fig. 1, inset) this region was indicated with a single line.
Caudal to the lobulus simplex the cerebellum splits into a distinct vermis and the two hemispheres. This split and the direction of the folial chains of vermis and hemispheres is indicated with the grey bands in Fig. 1. The chain of parallel folia of the hemisphere contains two loops. The first loop (Fig. 1: 1) is located on the posterior surface, in the region of the ansiform lobule (the semilunar lobules of the classical nomenclature), where the folia fan out from a common stalk (the horizontal fissure), like the feathers from a wing. The anterior and posterior limbs of this loop are known as the crus I and the crus II of the ansiform lobule and correspond to the superior semilunar lobule and to the inferior semilunar lobule with the lobulus gracilis, respectively. The second loop (2) is made up of the folia of the paraflocculus (the human tonsilla) and is located on the ventral surface. This loop terminates in the flocculus. The folial loop of the tonsilla is rarely illustrated in textbooks on the brain. Rohen and Yokoshi’s (1988) outstanding photographic atlas of the human body, from which the inset in Fig. 1 is reproduced, is an exception. The segment of the folial chain of the hemisphere located between the ansiform lobule and the paraflocculus is known as the paramedian lobule. It corresponds to the biventral lobule of the classical nomenclature. Bolk also indicated the two loops, which are a general feature of the mammalian cerebellum, in his wire diagram. The homology of the mammalian paraflocculus with the human tonsilla, which is mainly based on the development of their limiting fissures, receives support from the presence of a folial loop in this region. The human cerebellum, therefore, conforms to the general mammalian pattern, as established by Bolk. Detailed homologies of the lobules of the human cerebellum with lower mammals were established by Bolk, Larsell (1952), Larsell and Jansen (1972) and others. Larsell’s comparative anatomical nomenclature, which divides the cerebellum in ten lobules—indicated with roman numerals—became popular for its simplicity. Its implications for the homology of these lobules, however, should be viewed with some circumspection. His conclusions, for instance, on the homology of the medial belly of the biventral lobule (HVIIIB) with the mammalian ventral paraflocculus and of the tonsilla (HIX) with the ventral paraflocculus (Larsell and Jansen, 1972) are untenable because the location of the border between dorsal and ventral limbs of the paraflocculus varies greatly among different mammalian species (Voogd, 2003). The entire cerebellum is covered by a uniformly structured cortex. Due to the transverse fissures, the lengh of the cortical sheet greatly exceeds its width. The cortex is continuous between the succesive segments (lobules) of the folial chains of vermis and hemispheres, with the exception of the cortex of the flocculus, which is not continuous with the tonsilla. Between caudal vermis and hemispheres the cortex is usually interrupted (Fig. 4, *). The cerebellar nuclei are located within the central white matter. Stilling (1864) was the first to distinguish the four cerebellar nuclei of the human cerebellum: the fastigial,
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Fig. 3. The high iron-content of the caudal and lateral, macrogyric portion of the dentate nucleus. One of the first exemples of a neurochemical characterization of a brain nucleus. From Gans (1924).
Fig. 2. The four cerebellar nuclei of the human cerebellum. Relabeled lithograph from Stilling (1864). The subdivision of the dentate nucleus in microgyric and macrogyric portions is shown.
globose, emboliform and dentate nuclei. Fig. 2 is reproduced from one of his lithographs. Inspection of the dentate nucleus in Fig. 2 indicates that it is composed of two parts: a dorsomedial and rostral region with narrow dentations (microgyric dentate) and a ventrolateral and caudal portion with wide and subdivided gyrations (macrogyric dentate). The two parts of the dentate were illustrated but not recognized by Stilling as such. This distinction was made in the early 20th century by several authors on the basis of differences in cell-size between the two parts, the late development of the macrogyric dentate, its selective vulnerability in cases of ‘neocerebellar’ atrophy and its high iron content (Gans, 1924; Fig. 3).
Comparative anatomists have attributed different names to the cerebellar nuclei: the globose and emboliform nuclei became known as the posterior and anterior interposed nucleus, and the fastigial and dentate nuclei as the medial and lateral cerebellar nuclei. The rostro-medial and caudolateral portions of the lateral cerebellar nuclei differ in their connections, but a clear homology between these parts and the microgyric and macrogyric dentate of the human cerebellum has not been substantiated. In the rat, Buisseret-Delmas et al. (1993) described a fifth cerebellar nucleus, the ‘interstitial cell groups’, located between the medial and posterior interposed nuclei. A similar cell group appears to be present in monkeys and carnivores. The connections between the cortex and the cerebellar nuclei have been studied extensively since the appearance of Klimoff’s thesis on the corticonuclear projection in the rabbit, written under the supervision of Darkschewitsch in Kazan (Klimoff, 1897) and summarized by Klimoff (1899). A diagram of the corticonuclear projection, based on more recent studies in carnivores and monkeys, is illustrated in Fig. 4. The Purkinje cells, the only output element of the cerebellar cortex, are responsible for this projection. Purkinje cells projecting to a particular cerebellar or vestibular nucleus are arranged in discrete parallel longitudinal zones which, generally, are continuous from one lobule to the next.
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Fig. 4. Diagram of the zonal organization in the corticonuclear and olivocerebellar projections in the cat. Modified from Groenewegen et al. (1979). (A) Diagram of the flattened cerebellar cortex. (B) Diagram of the cerebellar and vestibular nuclei. (C) Diagram of a projection of the monkey inferior olive in the horizontal plane, constructed according to Brodal (1940). The longitudinal corticonuclear and olivocerebellar projection zones are indicated with capitals (A, X, B, C1–3 , D1,2 ). The zones, their target nuclei and the subnuclei of the inferior olive which project to these zones are indicated with the same colors. The diagram applies equally to the monkey cerebellum, with the exception of the floccular zones, the most medial one of which is lacking in the monkey (for details see Voogd et al., 1987). Asterisks: areas without cortex. The two squares refer to the position of Fig. 5(A, B). Abbreviations: A, A zone; Ans, ansiform lobule; B, B zone; C1–3, C1–3 zones; D1,2, D1,2 zones; DAOc, caudal dorsal accessory olive; DAOr, rostral dorsal accessory olive; DC, dorsal cap; DEIT, lateral vestibular nucleus of Deiters; DENTc, caudal part of dentate nucleus; DENTr, rostral part of dentate nucleus; dl, dorsal lamina of the principal olive; DMCC, dorsomedial cell column; EMB, emboliform nucleus; FAST, fastigial nucleus; FLO, flocculus; GLOB, globose nucleus MAOr, rostral medial accessory olive; MAOc, caudal medial accessory olive; NOD, nodulus; PFL paraflocculus; PFld, dorsal paraflocculus; PMD, paramedian lobule; PO, principal nucleus of the inferior olive; vl, ventral leaf of principal olive.
Three Purkinje cell zones, A, X and B, can be distinguished in the anterior vermis. A projects to the fastigial nucleus, X to the interstitial cell groups and B to the lateral vestibular nucleus of Deiters. X and B are lacking in the caudal vermis. The most caudal part of the vermis (the nodulus) mainly projects to the vestibular nuclei, other than Deiters’ nucleus. This projection is organized in four or more zones. In the anterior hemisphere, five zones are present: C1–3 , D1 and D2 . C1 and C3 both project to the emboliform nucleus, C2 to the globose nucleus and D1 and D2 to caudal and rostral portions of the dentate nucleus, respectively. C1 and C3 are absent from the two loops of the folial chain of the hemisphere at the level of the ansiform lobule and the paraflocculus, but they are present again in the intermediate segment of the hemisphere, located between the two loops: the paramedian lobule. C2 , D1 and D2 continue uninterruptedly from the anterior cerebellum into the paraflocculus and the flocculus. In the flocculus, the D zones are replaced by four zones, which project to the vestibular nuclei. The most medial one of these four zones is lacking in monkeys. Exactly the same zonal arrangement is found for the olivocerebellar climbing fiber projection to the Purkinje cells. This crossed projection is illustrated in panel C of Fig. 4 for the monkey inferior olive. Olivocerebellar fibers, terminating on the Purkinje cells of a particular zone, moreover, emit collaterals terminating in the target nucleus of these Purkinje cells (Ruigrok and Voogd, 2000). Finally, a GABAergic inhibitory pathway connects the cerebellar nuclei with the contralateral inferior olive (Kalil, 1979; Mugnaini and Oertel, 1985; Ruigrok and Voogd, 1990) This nucleo-olivary projection is organized in same topical fashion (Fig. 7). The zonal organization of the cerebellum is a highly concerved feature of the cerebellum of vertebrates. Recently, the four floccular zones were also found to be present in birds (Winship and Wylie, 2003). It seems likely, therefore that they should have emerged as early as in the reptilian ancestor of mammals and birds. From the point of view of its connections, the cortex appears to be less uniform than stated in one of the previous paragraphs. In rodents, zebrin-immunoreactive and non-reactive Purkinje cells are distributed in a pattern of alternating longitudinal zones (Hawkes and Leclerc, 1987). A very similar distribution has been observed for a variety of substances, including enzymes, protein kinases, growth factor receptors, neurotransmitter splice variants and glutamate transporters (see Voogd et al., 1996 and Voogd, in press for reviews). In the rat there is a close correspondance between the zebrin pattern and the projection zones A–D (Voogd et al., 2003), in other words, Purkinje cells of a projection zone are characterized by their connections, but also share a particular chemical identity. Thus far, the zebrin pattern in primates has only been substantiated for the vermis of the squirrel monkey (Leclerc et al., 1990). I was unable to observe such a pattern in the rhesus monkey, where all Purkinje cells are zebrin-positive (Voogd, unpublished
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observations). The distribution of zebrin-positive and negative Purkinje cells in the human cerebellum is unknown (Plioplys et al., 1985). Why should we be so confident that zonal arrangement, depicted in Fig. 4 is valid for primates? Certainly not because of the scarce experimental evidence. Convincing, structural evidence, however, is available from studies of the compartmentation of the cerebellar white matter. In the white matter, each Purkinje cell zone corresponds with a particular white matter compartment, which contains the Purkinje cell axons and the olivocerebellar climbing fiber afferents of that particular zone. The borders of these compartments strongly stain for acetylcholinesterase (AchE; Hess and Voogd, 1986). In Fig. 5, two AchE-sections through the monkey cerebellum are depicted. Fig. 5(A), shows the anterior lobe of the rhesus monkey (boxed area in Fig. 4), with the A, X, B, C1–3 , D1 and D2 compartments. The C1 and C3 compartments converge upon their target nucleus, the anterior interposed (emboliform) nucleus. The target nuclei of the other compartments cannot be seen at this level. Fig. 5(B) shows the transitional region of the paramedian lobule into the paraflocculus (boxed area in Fig. 4). The C1 and C3 compartments terminate in this region; C2 , D1 and D2 turn laterally to enter the folial loop of the paraflocculus. The caudal pole of the posterior interposed nucleus is located within the C2 compartment, the caudal pole of the lateral cerebellar nucleus occupies D1 .
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Our knowledge of the zonal organization of the primate cerebellum is still very incomplete. Notably, information is lacking on the precise corticonuclear and the climbing fiber connections of the D1 and D2 zones and on the precise delimitation of their target nuclei: the rostral and caudal dentate. Precise data on this subject are important because the great width of the primate cerebellar hemisphere, probably, is due to the width of the D2 zone. In monkeys, the paraflocculus is still a relatively narrow band of folia.The folia of it human counterpart, the tonsilla, are much wider. It is possible that this increased width is caused by the D1 zone; this would explain the large size of the macrogyric dentate. Data on the zonal organization of the human cerebellum are almost completely lacking. Evidence of the presence of a zonal arrangement of the Purkinje cells of the human cerebellum mainly rests on preliminary studies of the development of the Purkinje cell zones in human fetuses from a series of primordial Purkinje cell clusters, a developmental process which has been traced in more detail in monkeys (Kappel, 1981) and rats (Korneliussen, 1968). The borders between the white matter compartments, each containing the axons of a Purkinje cell cluster destined for a particular cerebellar nucleus alluded to in the previous paragraphs, already exist at these fetal stages. The cerebellar nuclei are the gateway of the cerebellum to other parts of the brain. There is strong evidence in
Fig. 5. Two photographs of acetylcholinesterase-stained transverse sections through white matter of the monkey cerebellum. For approximate location see insets Fig. 4. (A) Rhesus monkey anterior lobe. (B) Transitional region of the paramedian lobule into the paraflocculus in Saimiri sciurus. Abbreviations: A–D, white matter compartments A–D; bc, brachium conjunctivum; cr, restiform body; IntA, anterior interposed (emboliform) nucleus; IntP, posterior interposed (globose) nucleus; Lat, lateral (dentate) nucleus; m, midline; PFLd, dorsal paraflocculus
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rodents and carnivores that the axons of the main relay cells of the nuclei collateralize to different parts of the brain stem, the cord and the thalamus (Bharos et al., 1981; Bentivoglio and Kuypers, 1982; Teune, 1999; Teune et al., 2000). The target, or the combination of targets supplied by the different nuclei differ considerably. The target nuclei of the Purkinje cell zones of the vermis, the fastigial nucleus and Deiters’ nucleus, monitor descending vestibulo-spinal and reticulospinal pathways. Cells of the interstital cell groups collateralize to the spinal cord, the superior colliculus and the thalamus (Bentivoglio and Kuypers, 1982). The target nucleus of the C1 and C3 zones, the emboliform (anterior interposed) nucleus projects to the contralateral magnocellular red nucleus and via the thalamus to the primary motor cortex (Figs. 6 and 7D).Via the magnocellular red nucleus, it monitors the rubrobulbar and spinal tract and via the motor cortex, the pyramidal tract.
Fig. 6. Diagram of the nucleo-thalamo-cortical projections from the individual cerebellar Purkinje cell zones in primates. Subdivision of the thalamic motor nuclei according to Percheron (in press). The thalamic projection area of the intermediate cell groups is not known. From Voogd (2003). Abbreviations: A–D, zones A–D; Mot, primary motor cortex; Olsz, Olszewski; Pariet, parietal lobe; Prearc, prearcuate area; Premot, premotor area; SM(A), supplementary motor area; VLc, caudal part of the ventrolateral nucleus; Vlo, oral part of the ventrolateral nucleus; VLps, posterior part of ventrolateral nucleus; VPLo, oral part of the lateral ventroposterior nucleus.
Fig. 7. Diagrams of brain stem, thalamic and cortical connections of the D and C zones. The D1 , D2 and C2 zones and their target nuclei give rise to a mesencephalo-olivary reciprocal circuit. These circuits are topically organized, and include a cortico-rubral (-Darkschewitsch) projection from their cortical target area (for references see text). A similar reciprocal circuit does not exist for the C1 and C3 zones and their target nucleus. Based on data from the literature. For references see Voogd (2003). Abbreviations: (pre)mot, (pre)motor area; C, D, C, D zones; ctt, central tegmental tract; DAOr, rostral part of the dorsal accessory olive; DARK, Darkschewitsch nucleus; Dentc, caudal dentate nucleus; Dentr, rostral denate nucleus; EMB, emboliform (anterior interposed) nucleus; GLOB, globose (posterior interposed) nucleus; M1, primary motor cortex; MAOr, rostral part of the medial accessory olive; mtt, medial tegmental tract; no, nucleo-olivary pathway; POdl, dorsal lamina of the principal olive; POvl, ventral lamina of the principal olive; prefront, prefrontal cortex; rs, rubrospian tract; RUdm, dorsomedial subnucleus of the parvocellular red nucleus; RUlc, latero-caudal part of the parvocellular red nucleus; RUmc, magnocellular red nucleus; THAL, thalamus.
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The brain stem connections from the target nuclei of the C2 , D1 and D2 zones are quite different. The globose (posterior interposed) nucleus projects to Darkschewitsch’ nucleus, located in the central grey at the junction of the mesencephalon and the diencephalon. Its fibers proceed to the thalamus, where they terminate on nuclei projecting to a large, but insufficiently characterized region of the frontal lobe, including the frontal eye field (Kievit, 1979). Darkschewitsch nucleus gives rise to an ipsilaterally descending pathway (medial tegmental tract), which terminates on the rostral half of the medial accessory olive (for references see Voogd, 2003). This olivary subnucleus provides climbing fibers to the C2 zone and its target nucleus, the globose (Fig. 7C). Similar closed, reciprocally organized mesencephalo-olivary-cerebellar circuits exist for the the dentate. In the case of the rostral dentate, this circuit includes the lateral and caudal parvocellular red nucleus and the dorsal lamina of the principal olive, and the D2 zone (Fig. 7A), in the case of the caudal dentate it includes the dorsomedial parvocellular red nucleus, the ventral lamina of the principal olive and the D1 zone (Fig. 7D). The pathway connecting the parvocellular red nucleus with the principal olive is known as the central tegmental tract. The thalamic and cortical targets of the rostral and caudal dentate also differ. The rostral dentate projects to motor and premotor regions via the lateral (VImL) subpart of the nucleus ventralis intermedius of Percheron (in press). The correspondence of Percheron’s lateral and medial subdivisions of his nucleus ventralis intermedius to the Olszewski (1952) nomenclature is indicated in Fig. 6. The caudal dentate projects to more rostral and dorsal regions of the frontal lobe, including the frontal eye fields, and the areas 9 and 46, and the inferior parietal cortex, via the medial subpart of the nucleus ventralis intermedius (VImM). The thalamic projections of the individual cerebellar nuclei and their ultimate cortical target areas are a complicated subject for the non-initiated. Fig. 6, taken from Voogd (2003) summarizes these connections, but Fig. 6 clearly is a simplification and the single question mark underestimates the number of open questions which still confront us. The studies of the cerebello-cerebral relations of Wiesendanger and Wiesendanger (1985) and Strick et al. (see Middleton and Strick (1997) for a review and Clower et al. (2001) for more recent references) used retrograde transneuronal labeling from small tracer injections of the cerebral cortex to circumvent the problem of the cerebellar relay nuclei of the thalamus. The data on the cortical projections of the caudal and rostral dentate from Fig. 6, where they were transposed to the human cerebral hemisphere, were derived from these studies. Cortical areas in the frontal lobe which receive cerebellar projections from the thalamus give origin to corticorubral projections (Kuypers and Lawrence, 1967; Hartmann-von Monakow et al., 1979). These projections are independent from the corticospinal and corticopontine projections which arise from the same cortical areas, but from different sublay-
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ers of layer V (Catsman-Berrevoets et al., 1979; Humphrey et al., 1984; Kuypers, 1987). The corticorubral projection is topically organized: the lateral and caudal parvocellular red nucleus, which is involved in the reciprocal loop from the rostral dentate, receives a projection from motor and premotor cortex, the dorsomedial parvocellular red nucleus, involved in the loop from the caudal dentate receive a projection from prefrontal areas and the frontal eye field (Fig. 7). Contrary to the corticorubral projection to the parvocellular red nucleus, the projection to the magnocellular red nucleus originates as a collateral system from the corticospinal tract. The presence of strong reciprocal nucleo-mesencephaloolivary circuits distinguishes the brain stem circuitry of the target nuclei of the C2 , D1 and D2 zones from the brain stem circuitry of the target nuclei of the zones of the vermis and the C1 and C3 zones. Most studies of the physiology of the cerebellum, implicitly or explicitly, concern functions subserved by the circuitry of the vermis, the C1 and C3 zones and the vestibulocerebellum. These functions mostly concern the coordination or long-term adaptation of motor behaviour, which employ the long descending vestibulo-spinal, reticulospinal, rubrospinal and corticospinal tracts or the oculomotor system as their final paths. The functional significance of the reciprocal nucleo-mesencephalo-olivary loop, which is an essential feature of the efferents pathways from the C2 and the D zones rarely has been considered. The D zones of the cerebellar hemispheres and the dentate nucleus account for the major part of the human cerebellum. These regions of the cerebellar hemisphere, probably, are responsible for the important functions of the cerebellum in cognition, sensation and the adaptation of motor behaviour, which received so much recent attention (Leiner et al., 1986; Schmahmann, 1997; Bower, 1997). However, the brain stem circuitry used by these systems has never been systematically studied with appropriate electrophysiological techniques. The importance of the dentato-rubro-olivary loop can be judged from the size of the central tegmental tract, one of the largest brain stem pathways known. It was illustrated as early as 1846 by Stilling (1846), in one of his atlases of serial sections of the human brain (Fig. 8). von Bechterew (1885) gave it its name and defined its origin as the principal nucleus of the inferior olive. Its true origin from the parvocellular red nucleus was established in a long series of studies, summarized by Voogd (2003). Reciprocal cerebro-cerebellar loops were studied by Allen and Tsukahara (1974) and more recently by Houk et al. (1993) and Houk and Wise (1995). However, the loops studied by these authors did not involve the inferior olive, but the reticular nuclei which are a link in reciprocal mossy fiber pathways. The application of modeling techniques, as exemplified in Houk’s studies, would be a means to increase our knowledge of this system and the putative role of the cerebellum in cognition. Mossy fiber systems and connections are a blank area in our knowledge of the primate cerebellum. The last paper tracing a mossy fiber system in the human cerebellum was a paper published by Brodal and Jansen (1941) on the
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Fig. 8. Part of a lithograph illustrating the tegmentum pontis from the Stilling (1846) atlas of serial sections through the human brain stem. The central tegmental tract (ctt) and the medial longitudinal fascicle (mlf), which contains the medial tegmental tract, were labeled.
spinocerebellar tracts. Several retrograde labeling studies on mossy fiber pathways in monkeys are available, but these generally provide little information on their intracerebellar topography. Fortunately, more is known about the first link in the major afferent mossy fiber pathway which connects the cortex of the cerebral hemisphere with the contralateral cerebellum through the pons. The corticopontine system takes its origin from layer V pyramidal cells in extensive regions of the cortex, including the motor, sensory, striatal, peristriatal, parietal and prefrontal cortices, as established by Beck (1950) for the human brain and by Glickstein et al. (1985) (Fig. 9) and Schmahmann and Pandya (1995, 1997) in monkeys. The corticopontine projection arises as a collateral system from the corticospinal and bulbar fibers (Ugolini and Kuypers, 1986) and from the corticotectal system (Baker et al., 1976; Keizer et al., 1987). It seems likely, therefore, that ponto-cerebellar pathway supplies the cerebellum with an efferent copy of signals from cortical origin. In the frontal lobe, its origin from motor, premotor and dorsal prefrontal areas corresponds remarkably well with the cortical areas targeted by the cerebellar nuclei and the origin of the cortico-rubral projection to the parvocellular red nucleus. This correspondence does not hold for the parietal and peristriatal cortex, however, which supplies an important contingent to the corticopontine system but, thus far, only has been found to receive a minor, thalamus-relayed projection from the dentate nucleus (Clower et al., 2001). It has been pointed out that the origin of the corticopontine system corresponds with the cortical areas belonging to the dorsal visual steam, of Mishkin and Ungerleider (1982) of visual and visually related cortical areas, which contain representations of speed and direction of stimuli in the peripheral visual field and are concerned with the visual guidance of movements. Areas belonging to the ‘ventral visual stream’,
Fig. 9. Distribution of retrogradely labeled corticopontine neurons after a large, almost complete injection with a retrograde axonal tracer of the pontine nuclei in a macaque monkey. (A) Distribution of retrogradely labeled neurons in the left cerebral hemisphere from a complete wheat germ agglutinin-coupled horseradish peroxidase filling of the pontine nuclei. (B) Bargraphs illustrating the numbers of retrogradely labeled neurons in different cortical areas. From Glickstein et al. (1985). Abbreviations: ai, ansate sulcus, inferior limb; as, ansate sulcus superior ilmb; ccs, calcarine fissure; cs, central sulcus; ios, inferior occipital sulcus; ips, intraparietal sulcus; lf, lateral fissure; ots occipitotemporal sulcus; pps, postparietal sulcus; ps, principal sulcus; ts, superior temporal sulcus.
directed at the temporal lobe, which are concerned with object recognition, do not project to the pons. Prefrontal corticopontine connections are limited to dorsolateral and medial areas, related to kinesthetic, motivational and spatially related functions, including spatial memory. Inferior and orbital prefrontal areas, related to autonomic and emotional response inhibition, stimulus significance and object recognition, do not project to the pons (Glickstein et al., 1985; Schmahmann and Pandya, 1995, 1997). Little information is available on the pontocerebellar projection in primates. Of the two papers using antegrade tracing of pontocerebellar mossy fibers, one dates from
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1907 (Spitzer and Karplus, 1907) and only one other paper on visually-related pontocerebellar projections to the flocculus-paraflocculus region was published more recently by Glickstein et al. (1995). Data obtained by retrograde labeling in monkeys were summarized by Brodal and Bjaalie (1992). However, the precise distribution of pontocerebellar fibers, the topical relations between the cerebral cortex and the cerebellum, its zonal organization (Serapide et al., 2001) and the topographical interrelations of the pontocerebellar system with other systems terminating as mossy fibers remain mostly unknown. This review focussed on the early roots of our knowledge of the human cerebellum and tried to point out the main areas were our anatomical knowledge is still insufficient to explain the role of the cerebellum in motor behavious and cognition. The circumstances to undertake the necessary anatomical and physiological experiments in non-human primates to fill these gaps have changed for the worse. The focus in research has shifted away from systems neuroscience. Moreover, primate studies are costly and have been curtailed by government measures. Still, there is hope. Increasing the resolution in functional MRI studies, in humans and experimental animals to the level of brain stem nuclei like the red nucleus and the inferior olive, and the development of methods to trace connections in the living brain, may bring the anatomy of the human cerebellum again to the focus of attention.
Acknowledgements I would like to express my gratitude to the organizers of the conference on The Human Brain in Rome in 2002, especially to Professor J. Mai and Benigna Malebrein, for the opportunity to collect my thoughts on the human cerebellum.
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