The Cerebellum and Cognition - The Autism Treatment
THE CEREBELLUM AND COGNITION
The most recent research in the cognitive neuroscience literature shows the significant
involvement of the cerebellum in a diverse range of cognitive functions. The term cognition
usually refers to thought processes such as executive function, learning, memory, visual
analysis and language. This research is showing that the cerebellum is actively involved in
processing in all these areas of cognition. Also, researchers are finding the cerebellum is
intricately linked with emotion, personality and behaviour as well as autonomic and vascular
Connectional neuro-anatomy has provided a wealth of information concerning the anatomic
substrates that may support the cerebellar contribution to cognition. Functional neuro-
imaging has also provided much of the impetus for the exploration of the hypotheses and
concepts derived from systems neuroanatomy, theoretical modelling, and experimental
observations. The demonstration of cerebellar activation by non-motor tasks, first noted
incidentally and then studied as a specific entity in its own right, has essentially validated
the new questions “why is the cerebellum being activated, where and under what
The first decade of research utilising this methodology has revealed insights and posed new
questions about the cerebellum. An entirely separate long-standing view of cerebellar
function has been overshadowed by its role in the motor systemfrom the earliest days of
clinical case reporting. Instances of mental and intellectual dysfunction were described in
the settings of cerebellar pathology.
Investigators at that time lacked the necessary clinical and pathological tools to provide a
clear understanding of their patients’ lesions and psychiatric and cognitive disturbances.
Consequently, their anecdotal reports have been essentially ignored. The result has been
that the possibility of a causal relationship between cerebellar dysfunction and cognitive
and psychiatric pathology, has either been summarily dismissed or not considered for lack
of awareness of the question having been posed.
In addition to this clinical background, the substantial body of experimental evidence dating
back to the early part of the nineteenth century indicates that the cerebellum is involved in
a number of non-motor functions. The motor bias with respect to the study of the
cerebellum has been so overwhelming that this work, albeit conducted by eminent neuro-
physiologists, has been omitted from mainstream thinking about the functions of the
Early work has shown a close relationship between the cerebellum and the autonomic
nervous system(vegetative phenomena). Stimulation of the fastigial nucleus (by Moruzzi
and Magoun, 1949), and of the cortex of the cerebellar anterior lobe, produced generalised
arousal of the EEG, and Snider et al, (1949), demonstrated an inhibitory influence of the
cerebellum on the inhibitory part of the brain stem reticular formation. Fastigial nucleus
ablation produced a state of constant hyperactivity both in the monkey and the cat, (see
Carpenter, 1959 and Sprague and Chambers, 1959), and the role of the fastigial nucleus and
regulation of the sleep/awake cycle, was shown by Manzoni et al, 1968.
Later, anatomic investigations confirmed physiological data showing connections between
the cerebellum and reticular hypothalamic and limbic structures. Andrew Arthur Abbie in
1934 studied the cerebro-cerebellar system, focusing on the anatomy of the cortico-pontine
pathway. He observed degeneration in the cerebral peduncle and basis pontis of the human
brain following large lesions involving the parietal, temporal and occipital lobes. He was
intrigued by the existence of this tract connecting non-motor areas of the cerebral
hemisphere with the pons. He suggested that this pathway “weaves all sensory impulses
into a homologous fabric and translates the resultant in muscular response, which is
accurately co-ordinated and acutely adapted to the requirements of the situation as a
whole. To it, man owes the possibility of his highest powers as expressed in his work, in
sport, and in art.
Robert S Dow in 1942 and 1974 determined that the dentate nucleus of the cerebellum
could be divided into two components, on the basis of differential staining properties and
microscopic anatomy. The lateral part of the dentate (the neodentate) is phylogenetically
and more recently developed that the medial part (Dow 1942). The coincidence in evolution
of the appearance of the neodentate and the expanded lateral cerebellar hemisphere with
the expansion of the frontal and temporal association areas, later lead Dow (1974 and 1978)
to postulate that the cerebral and cerebellar regions were anatomically interconnected, and
therefore functionally relevant.
THE OUTPUT CHANNELS OF THE DENTATE.
Peripheral sensory afferents to the cerebellum have been shown from early works of
Sherrington in 1906, who showed that the cerebellum receives afferents from the
proprioceptive system. Dow in 1939 demonstrated that the stimulation of the sciatic and
saphenous nerves in the cat, resulted in cerebellar sensory potentials and in the rat he
showed (Dow and Anderson, 1942) that both proprioceptive and cutaneous stimulation also
resulted in cerebellar action potentials.
Dow and Moruzzi in 1958, in their book on the cerebellum, reached the conclusion that the
arrival of splanchnic or vagal volleys, and of the auditory or visual impulses to the cerebellar
cortex and the possible modification of the reflex activity of vasomotor centres by
cerebellifugal volleys, justify the hypothesis that a hitherto unknown control may be exerted
by the cerebellum in the sensory sphere and on autonomic functions. Unfortunately no
adequate tests were performed at the time to analyse this data.
Sensory, visual and auditory connections in the cerebellum were shown by Snider and
Wolsey. Snider and Stowell, 1944, showed that there are topographically organised
cerebellar tactile receiving areas responsive to both proprioceptive input and cutaneous
stimulation. Snider and Eldred, 1948, and Snider and Stowell, 1942, also demonstrated
visual and auditory projections to the cerebellar vermis and that visual projections are
conveyed via the tectum (Snider, 1945).
Anatomical studies (Sunderland, 1940, Brodel and Jansen, 1946) of the feed-forward loop of
the cerebro-cerebellar systemand electrophysiological experiments (Henneman et al, 1948)
of the feed-back limb, were also influential in shaping Snider’s conclusions. He found that
there are dual projections to the cerebellum, one from end organs and one from related
sensory and motor areas of the cerebral hemispheres. Snider saw the cerebellum as the
great modulator of neurologic function and predicted for it a role not only in the field of
neurology, but also in psychiatry.
In later work on connections linking the cerebellum with the locus ceruleus and limbic
structures, hippocampus, septum, and amygdala (Snider, 1975 and 1976) supported his
contention in the notion of cerebellar function needing to be revised.
Snider also noticed that not all lesions produce ataxia. He noted that one could remove
considerable masses of cerebellar tissue without producing any apparent deficits. This
conclusion was also apparent to Dow in 1974, who commented that it was particularly true
for the lateral cerebellar cortex and the dentate nucleus. He posed the question that if
lesions or cooling of the dentate nucleus alone are not productive of the classical signs of
cerebellar ataxia, what methods can one employ to unravel the functions of this part of the
cerebellum, which is so large in man and so selectively related to the association areas of
the cerebral cortex (Dow, 1974, page 115).
In the 1970s there was an increased interest in non-motor functions of the cerebellum and a
number of studies addressed different aspects. James Prescott, 1971, presented views
which are similar to those of early developmental psychologists, most notably Jean Piaget.
He felt that movement is intricately bound with sensation and with intellectual and
emotional growth, and Prescott reached the conclusion that the cerebellum participates in
the emotional development and that it is a master integrating and regulatory systemfor
sensory, emotional and motor processes. He asserted that maternal social deprivation of
neonatal animals (the Harlow monkeys, 1971) is fundamentally a form of somatosensory
input deficit. He theorises that the physiological effect of this deprivation would be a
reduction in the number of cerebellar neurones, and those neurones that survived would
operate under a condition of denervation supersensitivity.
He reasoned that the psycho-pathological characteristics that the animals tested manifested
(rhythmic rocking, head-banging) reflects the effects of sensory de-afferentation at a critical
period. He postulates that hyper-reactive cerebellar neurones generate unusual movement
patterns. Compare this to similar behaviours in patients with autism.
Heath and colleagues in 1972 studied the relationship between the cerebellum and
psychopathology, and used electrophysiology recordings. He demonstrated fastigial nucleus
connections with the septum, as well as with the hippocampus and amygdala. Reciprocal
cerebellar connections with the hypothalamus and mamillary bodies were to be
convincingly shown anatomically in later studies. A cerebellar influence on human
emotional experience has been shown when the dentate nucleus and the superior
cerebellar peduncle were stimulated (Nashold and Slaughter, 1969).
In 1977 Heath produced amelioration of aggression in ten out of eleven patients with severe
emotional dyscontrol by chronically stimulating the cerebellar vermis through subdurally
implanted electrodes. Following up six and sixteen months later, ten out of the eleven
patients were reported to be markedly improved. He ascribed these behavioural effects to
cerebellar connections with the limbic system. Heath concluded that the cerebellum
operates as an emotional pacemaker, necessary for the modulation of normal behaviour.
Berman et al, 1978, concluded that the vermis and archicerebellum are concerned with
aggression. Cooper and colleagues in 1974 and 1978, demonstrated that cerebellar cortical
stimulation achieved seizure control in his patients, but also had the unexpected side-effect
of improving aggression, anxiety and depression.
A number of experimental observations in the 1980s in the many disciplines within the
neurosciences helped anchor the role of the cerebellum in non-motor and cognitive
processes. Classically conditioned learning was shown to be dependent on the cerebellum
by Thompson in 1988 with his rabbit nictitating response. Leaton and Supple, 1986, showed
the cerebellar involvement in the acoustic startle response of the rat and visual spatial
navigational skills were impaired in the mutant mouse model by Lalonde and Botez, 1986.
Anatomic substrates for the cerebellum’s modulation of cognitive processing began to be
demonstrated by the findings of organised projections from associative and paralimbic
cerebral areas, to the feed-forward limb of the cerebro-cerebellar system (Schmahmann
and Pandya, 1987, 1989). Dow, 1974, demonstrated a relationship between the neodentate
nucleus and the prefrontal cortex during his collaboration with Leiner et al in 1986 and 198.
A neuropathologic study, Bauman and Kenper, 1985, and neuroimaging (Courchesne et al,
1988) of patients with early infantile autism, revealed abnormalities in the cerebellum, and
these anatomic correlations and their clinical relevance remains the subject of ongoing
The cerebro-cerebellar system fits in with electro-cerebellar function and cognition. If there
is a cerebellar contribution to non-motor function and particularly to cognitive abilities and
effective states, then there must be a corresponding anatomic substrate that supports this:
this is the cerebro-cerebellar circuit.
This circuit consists of a feed-forward or afferent limb and feed-back, or efferent limb. The
feed-forward limb to the cerebellum is composed of cortico-pontine and ponto-cerebellar
mossy fibre projections.
The feed-back loop is the cerebello-thalamic and thalamo-cortical pathways linking the
cerebellum to the cortex. Schmahmann in 1991, developed a conceptual approach stating
that the cerebellum modifies behaviourally relevant information that it has received from
the cerebral cortex via the cortico-pontine pathways. It then re-distributes this cerebellar-
processed information back to the cerebral hemispheres, and therefore both limbs are
essential for discussion of cognitive and non-motor processing.
There is a second feed-forward systemlinking the cerebral cortex with the red nucleus, from
where the central tegmental tract leads to the inferior olivary nucleus, and then through the
climbing fibre systemto the cerebellar cortex. This second afferent arc has more restricted
relevance to the discussion of the relationship between the cerebellum and cognition.
The feed-forward limb of the cerebro-cerebellar system consists of the cortico-pontine
projections. These projections come from several areas of the cortex into the basilar pons
and are the obligatory first stage in the feed-forward limb of the cerebro-cerebellar loop.
These cortico-pontine pathways originate in neurones in layers Vb of the cerebral cortex.
The axons enter the internal capsule and descend into the cerebral peduncle and terminate
around neurones that occupy the ventral half of the pons.
THE FEEDBACK LIMB OF THE CEREBROCEREBELLAR CIRCUIT.
The basilar pons appears to be parcelated into different nuclear groups, (see Schmahmann
and Pandya, 1989 and 199)1, and appears to indicate different areas of cerebral projection.
These projections appear to inter-digitate with each other, but do not overlap. Motor, pre-
motor and supplementary motor regions, as well as primary somatosensory cortices have
been shown to send their efferents to the cerebellum via this route. However, the origins of
the cortico-pontine pathway are not limited to the sensory motor cortices. The cerebral
cortex areas of interest in regard to cognitive ability are areas of the association cortex of
the parietal, temporal and frontal lobes, which are responsible for highly complex cognitive
operations and when lesioned in humans, result in clinical syndromes which are now part of
classicalneurological teaching. Also, the paralimbic areas of the para-hippocampal gyrus
and cingulate cortices, are concerned with motivation and drive, and are thought to play a
role in emotionally relevant memory (Nadel, 1991).
These connections are critical for directed attention, visio-spatial analysis and vigilance in
the contra-lateral hemi-space and lesions are associated with disturbances of complex visio-
spatial integration, trimodal neglect of the contra-lateral body and extra-personal space.
ALIEN HAND SYNDROME, IMPAIRED LANGUAGE, APRAXIA AND AGNOSIA
The superior parietal lobule (SPL) and the inferior parietal lobule (IPL) are thought to be
involved in the sequential processing of somatotopically organised information received
from adjacent primary somatosensory cortices and this includes somatosensory as well as
visual and vestibular information.
MULTIPLE JOINT POSITION, SENSE, TOUCH AND PROPRIOCEPTION
These areas have connections with the prefrontal cortex and the cingular gyrus as well as
paralimbic cortices and other multi-modal zones in the temporal and frontal lobes. Recent
studies (Glickstein et al, 1985, May and Anderson, 1986, Schmahmann and Pandya, 1989)
have shown that there are consistent pontine projections from these regions. These
projections are directed most heavily towards the peri-peduncular and lateral nuclei.
The role of the temporal lobe with respect to language, memory and complex behaviour has
been well established and confusional states, highly structured visual hallucinations and the
Cluver-Bucy syndrome, consequent upon lesions in this area, are also recognised. The
cortex in the upper bank of the superior temporal sulcus (STS) has been shown to be
concerned with multiple sensory modalities; vision, somatic sensation and audition. It has
connections with association areas of the frontal and parietal cortices, as well as with limbic
related structures at the medial and inferior frontal convexity and para-hippocampal and
The superior temporal gyrus appears to be an association area confined to the auditory
realm and the deep area of the STS is the important association area for the somatosensory
modality. The extreme dorso-lateral and lateral pontine nuclei are the major recipients of
efferents from each of the sub-divisions of the upper bank of the STS. The inferior temporal
region and the lower bank of the STS, which are strongly interconnected, contain neurones
that are functionally unimodal within the visual system. They subserve mainly central vision
and seem to be involved in object recognition. They appear to contribute no projections to
the basis pontes and it appears that visual projection to the pons is derived exclusively from
areas devoted to the peripheral visual field rather than from areas subserving central or
PARA-STRIATE, OCCIPITO-TEMPORAL AND PARA-HIPPOCAMPAL PROJECTIONS TO THE
The dichotomy in the pontine connectivity between the visual motion “where” versus visual
feature “what” system is also observed in the para-striate and occipito-temporal pontine
system. The pons receives the dorsal visual stream responsible for spatial features of
objects or events in the periphery of the visual field and these are distributed in the lateral
peri-peduncular and dorso-lateral pontine nuclei. The ventral stream, which deals with
form, colour and orientation and with the stimuli occurring in the central part of the visual
field, does not project to the pons.
It also appears that only the posterior para-hippocampal regions project to the pons and
these are concerned again with the peripheral rather than central visual field and are
concerned with the spatial aspects of memory. These afferents appear to facilitate a
cerebellar contribution to visual spatial memory, particularly when invested with
The prefrontal cortex has repeatedly been shown in both humans and non-human primates
to be an essential component in the normal integration of higher order behaviour. This
includes such functions as planning, foresight, judgement, attention, language and working
memory. Different functional attributes have been ascribed to different regions, but also
lateral and medial convexities are important for kinesthetic, motivational and spatially
related functions, including spatial memory, whereas inferior prefrontal and orbital areas
are more related to autonomic and emotional response; inhibition, stimulus significance and
object recognition and memory. Schmahmann and Pandya in 1995 and 1997, demonstrated
that connectional heterogeneity of the prefrontal cortex also exists in the cortico-pontine
The dorsal lateral convexity and the medial prefrontal cortex provide the majority of the
pontine efferents. The projections are most prominent and occupy the rostro-caudal extent
of the pons when derived from dorsal area 46 (9/46d), areas 8a,d and 9 at the dorso-lateral
convexity and area 10 at the dorso-lateral and medial convexities.
The topographic organisation within this general framework of projection is discernible.
More medial prefrontal areas send projections to the most medial pontine regions, whereas
pontine terminations tend to shift away from the midline following lateral prefrontal
projections. Furthermore, each cortical area appears to have a unique complement of
pontine nuclei with which it is connected.
The fronto-pontine connections are concerned with attention as well as with conjugate eye
movements (area 8a), the spatial attributes of memory and working memory (area 46),
planning, foresight and judgement (area 10), motivational behaviour and decision-making
capabilities (area 9 and 32), and from areas considered to be homogenous to the language
area in a human (area 45b).
Not all regions of the prefrontal cortex project to the pons. These areas resemble the
infero-temporal region and the ventral bank of the superior temporal sulcus with which they
are interconnected. They are concerned with object memory, feature discrimination and
certain aspects of motivation. The dichotomy in the spatial (where) versus object (what)
which are apparent in the cortico-pontine projections from other associated areas, appear
to be conserved to the prefrontal areas as well.
PARA-LIMBIC AND AUTONOMIC CONNECTIONS WITH THE PONS
A direct and reciprocal hypothalamo-cerebellar projection has been identified in the
monkey. The ansiform and paramedian lobules and the paraflocculus are connected with
the lateral and posterior hypothalamic areas. The anterior lobe is connected with these as
well as the ventro-medial and dorso-medial and dorsal hypothalamic nuclei and deep
cerebellar nuclei project to the contra-lateral posterior and lateral hypothalamic nuclei.
HYPOTHALAMIC PROJECTIONS TO THE CEREBELLUM.
Also the mamillary and super-mamillary nuclei project to the cerebellar ansiform and
paramedian lobules, paraflocculus and anterior lobe. Schmahmann and Pandya in 1993,
demonstrated projections to the pons from the posterior para-hippocampal regions, which
have been implicated in the spatial aspects of memory.
It is therefore apparent that the ponto-cerebellar system indeed receives a sizeable input
from limbic related cortices and these findings may help explain the autonomic phenomena
produced in animals by cerebellar stimulation, and also provide a plausible anatomic
substrate for a cerebellar role in modulation of affect. The course of these fibre pathways
to the pons appear to consist of segregated and partially overlapping pathways, which are
to some extent distinguishable anatomically at each stage of their trajectory from their
origin to destination.
There is only limited information about the exact connections between the ponto-cerebellar
projections. Nevertheless, it has been established, for example, from physiological studies,
that the parietal and prefrontal cortices are functionally related to the neocerebellar
hemispheres and auditory and visual inputs are received in vermal lobules 6 and 7.
Anatomic and physiological studies in the monkey indicate that the dorsal paraflocculus, the
uvula and the vermal visual area (vermal lobule 7) receive information from visually
responsive neurones in the dorso-lateral pontine region and the nucleus reticularis
In 1979 Brodel performed horseradish peroxidase (HRP) retrograde labelling on the ponto-
cerebellar projections in the monkey. He found that the anterior lobe (lobe 5) receives
input from medial parts of the caudal pons and the vermal visual area (lobules 7 and 8a),
from two cell groups located in the dorso-medial and dorso-lateral pons. Vermal lobules
(8b) receive input from the intrapeduncular nucleus, crus 1 from medial parts of the rostral
pons and crus 2 from the medial, ventral and lateral pons.
The hemispheres have relatively greater pontine input than the rostral vermis. Brodel
concluded that the anterior lobe and lobulus simplex (lobes 1 to 6) receive afferents from
the motor and pre-motor cortices and, to a small extent, from the parietal lobe. The pre-
motor and prefrontal cerebral regions are linked with crus 1 (lobule 7 and 8). The motor
cortex is linked with crus 2 and somatosensory and parietal association areas are linked with
the paramedian lobule.
Brodel concluded that there was a high degree of order with each cerebellar sub-division
receiving input, at least partly, from its own pontine territory. One small part of the
cerebellum receiving input from several discrete pontine cell groups situated far apart and
Brodel concluded that information from one small part of the cerebral cortex is distributed
to numerous discrete sites in the cerebellar cortex, where it is combined with other specific
kinds of information. However, overall, detailed understanding of the ponto-cerebellar
system is still not available.
Much remains to be elucidated regarding the details of the pontine afferents to defined
regions of the cerebellum and with respect to the cerebral and cerebellar connections of
individual basilar pontine regions. There is not yet any information regarding the transfer of
associated information from the pons to the cerebellum. Higher order information is
distributed in complex but specific patterns throughout the basilar pons, but the manner in
which this information is conveyed to the cerebellum and the corresponding organisation
within the cerebellum have not yet been studied. Also, the fractured somatotopy that has
been discerned in the sensory afferents to the cerebellum may apply also to the associative
THE FEED-BACK LIMB OF THE CEREBRO-CEREBELLAR SYSTEM
This consists of cerebellar cortico-nuclear projections, efferents from deep cerebellar nuclei
en passant through the red nucleus to the thalamus and the thalamo-cortical relay. Despite
the homogenous appearance of the cerebellum, there is increasing evidence that there are
neurotransmitter/modulator/peptide differences in neuronal sub-types of cerebellar cortex
There is a mediolateral zonal pattern of organisation of the cortex that correlates with
connectional specificity in the olivary projections to the cerebellum, and this suggests that
the otherwise homogenous appearing cortex can be sub-divided by methods other than
gross anatomic descriptions and topographically organised connectional relationships. The
cortico-nuclear projection consists of axons of the cerebellar Purkinje cells being the only
neurone responsible for efferents from the cerebellar cortex that traverse the cerebellar
white matter and terminate in the deep cerebellar nuclei.
The topographic arrangement of the cortico-nuclear projection is such that the midline
cortex projects to the medial nuclear regions (fastigial), lateral hemispheres project to the
dentate and the intervening cortex corresponds with the interposed nuclei in a predictable
mediolateral pattern. The flocculonodular lobe additionally has direct connections with the
vestibular nuclei and the anterior interpositus with the red nucleus. It is thought that
thalamic projections from the cerebellum, which traditionally were thought to come purely
from the dentate nucleus, are now thought to be assisted by efferents from the fastigial and
More detailed understanding is needed regarding the precise topographical relationships
between each cerebellar nucleus and its corresponding complement of thalamic
terminations. Certain principles of organisation of the cerebello-thalamic projections have
been defined however. There appear to be differential anterior versus posterior dentate
nucleus projections to the thalamus and each cerebellar nuclear region projects a few
(between three and seven) rostro-caudally orientated rod-like aggregates situated within a
dorso-ventral curved lamella in the thalamus.
Classic cerebellar recipient motor thalamic nuclei are not alone in receiving input from the
cerebellum. Non-motor nuclei have a considerable cerebellar input as well. These include
the intralaminar nuclei, particularly centralis lateralis (CL) as well as the paracentralis (PCN)
and the centromedian-parafascicular (CM-PF) complex and the medial dorsal nucleus. The
CL nucleus appears to project in a widespread fashion as many other intralaminar nuclei do,
to areas of the posterior parietal cortex (PPC), the upper bank of the superior temporal
sulcus (STS), the prefrontal cortex (PFC), the cingular gyrus and the primary motor cortex.
The PCN nucleus projects to the parahippocampal gyrus. The medial dorsal thalamic
nucleus, which is the major site of thalamic connections with the frontal lobe, also receives
Also traditionally motor thalamic nuclei have projections to regions of the cerebral cortex
outside the primary and the supplementary motor areas, including the prefrontal peri-
arcuate cortex, see later notes regarding area 46 of the prefrontal lobe by Middleton and
Strick in 1994.
DENTATE NUCLEUS PROJECTIONS
Further research in the use of direct trans-neuronal techniques remain to show how much
of the cerebellar input to the thalamus is conveyed to association cortices. Nevertheless, it
would appear from available anatomic evidence that the cerebellar recipient ‘motor
thalamic nuclei’ project not only to the motor cortices, but also to the associative areas in
the posterior, parietal, superior, temporal and prefrontal cortices. Furthermore, the
intralaminar nuclei which are themselves the recipient of cerebellar efferents and are non-
motor, project widely throughout the cerebral cortex, including the motor, associative and
A CLIMBING FIBRE SYSTEM AND COGNITION
A central feature of the Marr, 1969 and Albus, 1971, theory of motor learning, is the
interaction between mossy fibre and climbing fibre systems. It has been suggested that
learning is an important mechanism whereby the cerebellum also modulates non-motor
behaviour. Mossy fibres to the cerebellum arise largely from neurones in the basilar pons.
The inferior olive is the sole source of the climbing fibres input to the cerebellum. The
cerebral afferents of the pontine (mossy fibre) and olivary (climbing fibre systems) are
The pontine system input is derived in a large part from the cerebral hemispheres including
the association areas. In the non-human primate the inferior olive receives much of its
descending input from the parvicellular red nucleus. Afferents of the parvicellular red
nucleus are derived most heavily from motor, pre-motor and supplementary motor cortices,
and to some extent from the post-central gyrus and area 5 in the superior parietal lobule.
They are not derived to any convincing degree (at least in studies to the present date) from
the associative or para-limbic cortices.
The zona incerta, which projects to the inferior olive has been reported to receive
projections from prefrontal cortices, suggesting there maybe some indirect prefrontal input
to the olivary systemof climbing fibres. Schmahmann and Pandya have investigated this
and performed a review of previously performed anterograde trace experiments in the
monkey, and this reveals there are prominent and topographically organised projections
from the pre-central motor cortex to the parvicellular and magnocellular divisions of the red
Additionally, there is substantial input from the supplementary motor area to the
parvicellular division. However, no projections to the red nucleus were seen to arise from
associative or para-limbic cerebral cortices. Significant projections to the zona incerta were
observed from the cingulate cortex, as well as from the posterior parietal, prefrontal and
para-striate association areas.
Additionally, prefrontal cortex projections to the zona incerta arose from areas 9/46d, as
well as from area 9 and medial convexity. Therefore, the possibility of interaction between
mossy fibre and climbing fibre systems in learning non-motor tasks is therefore maintained
by virtue of the associative projections to the zona incerta, which in turn projects to the
inferior olivary nucleus.
CEREBELLAR OUTPUT CHANNELS
Middleton and Strick have been investigating the cerebellar output channels using
retrograde trans-neuronal transport of herpes simplex virus type 1 (HSV1). Two strains used
interestingly show anterograde and retrograde transport. Strain H129 shows an
anterograde trans-neuronal transport and McIntyre-B strain shows retrograde trans-
neuronal transport. Their results suggest that the cerebellar output projects via the
thalamus to multiple cortical areas, including pre-motor and prefrontal cortex, as well as the
primary motor cortex.
In addition, the projections to different cortical areas appear to originate from distinct
regions of the deep cerebellar nuclei and their observations lead them to propose that this
cerebellar output is composed of a number of separate output channels. In the past a
number of technical limitations have made it difficult to define cerebello-thalamo-cortical
circuits. For example, most studies that examined the pattern of cerebellar terminations in
the thalamus did not determine the cortical targets of these thalamic nuclei.
In addition, the lack of standard criteria for defining thalamic borders and confusing
thalamic nomenclature have made comparison of the results from different studies difficult.
Middleton and Strick developed a tracing technique with trans-neuronal transport of herpes
simplex virus type 1. Their results indicate that cerebellar output targets not only the
primary motor cortex, but also several areas of pre-motor, ocular motor and prefrontal
cortices. They propose that the output from the cerebellum and specifically that from the
dentate nucleus contains multiple output channels, each projecting to a distinct cortical
area, see Strick, 1993, Middleton and Strick, 1994 and 1996.
Trans-neuronal transport of HSV1 provides a novel method for labelling a chain of
synaptically linked neurones and the technique is capable of identifying circuits of at least
three neurones in length.
They tested the virus originally by injecting the arm area (M1 of the motor cortex) in Cebus
monkeys. After three days the virus had migrated to second order neurones in regions of
the pontine nuclei known to receive input from the arm. Five days after the injection
multiple patches of third order neurones were found in the cerebellar cortex. These
patches were located in the granular layer and contain two types of labelled neurone
granule and Golgi cells. Both these cell types are known to be contacted via mossy fibre
afferents that project to the cerebellar cortex from the pontine nuclei. The majority of the
labelled patches were located in the vermal and hemispheric lobules of 5 and 6, in and
adjacent to the primary fissure.
Separate labelled patches were found posteriorly in the paramedian lobule 8a and laterally
in lobule 7b. Also some neurones were found in portions of the dentate and interpositus
nuclei. These areas corresponded to sites where evoked potentials have been recorded
after stimulation of the arm area of the primary motor cortex using McIntyre-B strain
retrograde analysis of the cerebello-thalamo-cortical tracts. Using this type of tracking,
Middleton and Strick have observed cerebellar projections to the primary motor cortex,
ventral pre-motor area (area 6), the frontal eye field, FEF (area 8) and two regions in the
prefrontal cortex (area 9 and 46).
CEREBELLAR OUTPUT TO PREFRONTAL CORTEX
Middleton and Strick have looked at Brodmann areas BA9 and BA 46. These areas have
been reported to be involved in working memory and in the guidance of behaviour based on
transiently stored information rather than immediate external cues. Both have been shown
to project to regions of the pontine nuclei and to receive input from sub-divisions of the
ventro-lateral thalamus. Viral injections into prefrontal cortex labelled many neurones in
the dentate nucleus. These neurones were confined to the most ventral portions of the
dentate and were concentrated rostro-caudally in the middle third of the nucleus.
Therefore, these regions of the dentate clearly differ from the more dorsal regions that
were labelled by virus injections into the motor cortex and also the more caudal regions of
the dentate labelled by injections in the frontal eye fields.
Two conclusions arise from these results. Firstly the output of the cerebellum can influence
skeletal motor, ocular motor and prefrontal regions of the cerebral cortex. Secondly, each
of these different cortical regions receive input from a different region of the dentate, and
therefore the dentate appears to contain a number of distinct output channels, which
project via the thalamus to specific areas of the cerebral cortex. Middleton and Strick also
performed physiological studies examining the function of the dentate nucleus during a
learned behaviour mechanism in monkeys. They were able to analyse activity in the motor
and supplementary motor and prefrontal areas separately by analysing a sequence of
learned tasks. They were able to discriminate between purely motor function,
supplementary motor function involved in more complex higher order aspects of motor
behaviour, such as the generation of sequential movements based on external cues, and
also output channels that influence the prefrontal cortex involved in cognitive aspects of
behaviour, such as working memory. These systems seemto have separate output channels
in different areas of the dentate nucleus.
All these studies were performed on human subjects using magnetic resonance imaging
(MRI). There were two tasks; one using a visual guided motor task using the dominant hand
to move pegs from one hole to another. Another task required cognitive involvement using
rules for moving pegs around on the board. In the visually guided task there was minimal
activation only on the ipsilateral dentate nucleus. In the cognitively determined test, both
dentate nuclei were activated bilaterally and the degree of activation was three to four
times larger than during the visually guided task. Additionally the ventral portions of the
dentate activated by the cognitive task appeared to differ in the location from the portions
of this nucleus activated during the visually guided task.
The conclusion to this experiment is that the cognitive demands associated with attempts to
solve the cognitive task lead to dentate activation. Secondly, the ventral regions of the
dentate involved in cognitive processing are distinct from the dentate regions involved in
the control of eye and limb movements and are potentially within an output channel that
innervates prefrontal cortex.