The basal ganglia and the cerebellum: nodes in an integrated network

Abstract

The basal ganglia and the cerebellum are considered to be distinct subcortical systems that perform unique functional operations. The outputs of the basal ganglia and the cerebellum influence many of the same cortical areas but do so by projecting to distinct thalamic nuclei. As a consequence, the two subcortical systems were thought to be independent and to communicate only at the level of the cerebral cortex. Here, we review recent data showing that the basal ganglia and the cerebellum are interconnected at the subcortical level. The subthalamic nucleus in the basal ganglia is the source of a dense disynaptic projection to the cerebellar cortex. Similarly, the dentate nucleus in the cerebellum is the source of a dense disynaptic projection to the striatum. These observations lead to a new functional perspective that the basal ganglia, the cerebellum and the cerebral cortex form an integrated network. This network is topographically organized so that the motor, cognitive and affective territories of each node in the network are interconnected. This perspective explains how synaptic modifications or abnormal activity at one node can have network-wide effects. A future challenge is to define how the unique learning mechanisms at each network node interact to improve performance.

Fig. 1 |. Organization of basal ganglia and cerebellar outputs to the cerebral cortex.

a | The cortical targets of basal ganglia and cerebellar outputs are indicated on medial and lateral views of the Cebus monkey brain. b,c | These panels show summary maps of topography in the basal ganglia (part b) and cerebellar (part c) output nuclei on the basis of their cortical targets. The division between motor and non-motor areas of the internal segment of the globus pallidus (GPi) and the dentate nucleus is indicated by the dashed lines. In all panels, orange labels indicate areas of the cerebral cortex that are the targets of both basal ganglia and cerebellar outputs, whereas blue labels indicate areas of the cerebral cortex that are the targets of basal ganglia, but not cerebellar, output. The numbers refer to cytoarchitectonic areas. AIP, anterior intraparietal area; AS, arcuate sulcus; C, caudal; CC, corpus callosum; CgS, cingulate sulcus; CS, central sulcus; D and d, dorsal; FEF, frontal eye field; i, the inner portion of the internal segment of the globus pallidus; IPS, intraparietal sulcus; LS, lateral sulcus; M and m, medial; M1, primary motor cortex; M1 arm, arm area of M1; M1 face, face area of M1; M1 leg; leg area of M1; o, the outer portion of the internal segment of the globus pallidus; pc, pars compacta; PMd arm, arm area of the dorsal premotor area; PMv arm, arm area of the ventral premotor area; pr, pars reticulata; Pre-PMd, predorsal premotor area; Pre-SMA, presupplementary motor area; PS, principal sulcus; SMA arm, arm area of the supplementary motor area; STS, superior temporal sulcus; TE, area of inferotemporal cortex. Based on data from REFS^,,–.

Fig. 2 |. Anatomical connections.

a | A study using retrograde transneuronai transport of rabies virus in monkeys revealed a disynaptic pathway from the dentate nucleus (DN) to the putamen. Rabies virus was injected into the putamen and underwent retrograde transport to first-order neurons that project to the striatum (for example, neurons in the intralaminar thalamic nuclei) and then retrograde transneuronal transport to second-order neurons that innervate the first-order neurons. The second-order neurons in the cerebellum were located primarily in the DN. b | A study using retrograde transneuronal transport of rabies virus in monkeys revealed a disynaptic pathway from the subthalamic nucleus (STN) to the cerebellar cortex. Rabies virus was injected into the lateral cerebellar cortex and underwent retrograde transport to first-order neurons that project to the cerebellar cortex (for example, neurons in the pontine nuclei (PN)) and then retrograde transneuronal transport to second-order neurons that innervate the first-order neurons. The study revealed second-order neurons labelled in the basal ganglia, primarily in the STN. CL, central lateral thalamic nucleus; CM, central medial thalamic nucleus; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; MD, medial dorsal thalamic nucleus; Pf, parafascicular thalamic nucleus; VL, ventral lateral thalamic nucleus.

Fig. 3 |. Neuroimaging evidence for basal ganglia and cerebellar interactions in disease.

Findings from neuroimaging studies of several disorders provide evidence for interactions between the basal ganglia and cerebellum. Indeed, abnormal structure, connectivity and activity in both the basal ganglia and the cerebellum have been reported in several debilitating disorders. Note that in this figure, orange arrows point to sites in the cerebellum, blue arrows point to sites in the basal ganglia and white arrows point to sites in the thalamus and/or the cerebral cortex. a | Analysis of ¹⁸F-fluorodeoxyglucose (FDC) positron emission tomography (PET) scans indicated that brain metabolism in individuals with Parkinson disease (PD), relative to age-matched controls, is characterized by co-varying pallido-thalamic, pontine and cerebellar hypermetabolism. The metabolic pattern associated with PD is illustrated on two axial sections in which marked metabolic increases and decreases are shown on red to yellow and blue to purple colour scales, respectively. b | In individuals with obsessive-compulsive disorder (OCD), relative to healthy control subjects, regions within both the basal ganglia and the cerebellum demonstrated increased whole-brain connectivity. Clusters in which individuals with OCD showed markedly increased whole-brain connectivity in the putamen and cerebellar cortex are illustrated on two coronal sections on a red to yellow colour scale. c | Analysis of FDC-PET scans indicated that brain metabolism in individuals with Tourette syndrome (TS), relative to healthy controls, is characterized by hypometabolism in the striatum that co-varies with hypermetabolism in the cerebellum. The metabolic pattern associated withTS is illustrated on axial and sagittal sections in which notable metabolic increases and decreases are shown in red and blue, respectively. d | A similar metabolic pattern was identified in Huntington disease (HD) gene carriers, relative to healthy controls. The metabolic pattern associated with HD is illustrated on axial sections, and marked metabolic increases and decreases are shown on red to yellow and blue to purple colour scales, respectively. e | Finally, analysis of FDC-PET scans in non-manifesting carriers of dystonia-associated mutations in torsin 1A (TOR1A; also known as DYT1), relative to healthy controls, revealed co-varying hypermetabolism (red) in the striatum and the cerebellar cortex. GP, globus pallidus; L, left; R, right. Part a is adapted with permission from REF., John Wiley and Sons. Part b is adapted with permission from REF., Elsevier. Parte c is adapted with permission from REF., American Academy of Neurology. Part d is adapted from Feigin, A et al. Thalamic metabolism and sympton onset in preclinical Huntington’s disease. Brain (2007) 130, 2858–2867, by permission of Oxford University Press, REF.. Part e is adapted with permission from REF., John Wiley and Sons.

Fig. 4 |. Neuroimaging evidence for basal ganglia and cerebellar interactions in normal function.

Findings from neuroimaging studies in heaithy individuals have shown co-activations in the basal ganglia and cerebellum in various tasks. Event-related functional MRI (fMRI) studies revealed that activity in both regions of the basal ganglia and the cerebellum is correlated with temporal difference prediction error during appetitive conditioning with a pleasant taste reward (part a) and during higher-order aversive conditioning (part b). A positron emission tomography (PET) study demonstrated that movement vigour (that is, extent and speed) is associated with regional cerebral blood flow increases in regions of both the basal ganglia (putamen and globus pallidus) and the cerebellum (part c). An fMRI study of healthy subjects adapting to visuomotor rotations, in the context of a joystick aiming task, indicated that sensorimotor adaptation is associated with increased activity in both the basal ganglia and the cerebellum (part d). Finally, early stages of sequence learning are associated with activation of both the subthalamic nucleus (STN) and the cerebellum (part e). Note that orange arrows in this figure point to activation sites in the cerebellum and blue arrows point to activation sites in the basal ganglia. DN, dentate nucleus. Part a is adapted with permission from REF., Elsevier. Part b is adapted from REF., Macmillan Publishers Limited. Part c is adapted with permission from REF., American Physiological Society. Part d is adapted from REF., Macmillan Publishers Limited. Part e is adapted with permission from REF., Proceedings of the National Academy of Sciences.

Fig. 5 |. Learning specializations of cortico–basal ganglia and cortico–cerebellar loops.

a | The cerebral cortex, basal ganglia and cerebellum are thought to implement distinct learning algorithms. According to this view, the cerebral cortex is specialized for unsupervised learning based on Hebbian plasticity The basal ganglia are specialized for reinforcement (reward-based) learning, guided by the reward signals from midbrain dopaminergic neurons. The cerebellum is specialized for supervised (error-based) learning, guided by error signals from the inferior olive. The interconnections between these structures are illustrated by large arrows. Outputs from the cerebral cortex are depicted as large dark grey arrows. Outputs from the basal ganglia are depicted as large blue arrows. Outputs from the cerebellum are depicted as large orange arrows. The asterisk emphasizes the newly discovered connections between the basal ganglia and cerebellum that are the subject of this Review^,. b | An example of learning in the motor domain. Within the basal ganglia, only the input stage of basal ganglia processing (putamen) is included for simplicity. Labelling next to the interconnection arrows identifies the intermediary structure for the connection. CL, central lateral nucleus; PN, pontine nuclei; VLo, ventral lateral nucleus, pars oralis; VPLo, ventral posterior lateral nucleus, pars oralis. Part a is adapted with permission from REF., Elsevier.

Fig. 6 |. Action planning.

Functionally related corticai, basal ganglia and cerebellar sites within interconnected networks participate in progressive stages of action planning. On the basis of these results, learning through exploration involves a limbic network, including the ventromedial prefrontal cortex (PFC), ventromedial striatum and posterior cerebellum. Model-based learning involves an associative (cognitive) network, including the dorsolateral PFC, dorsomedial striatum and lateral posterior cerebellum. Performance based on motor memory involves a motor network , including the supplementary motor area, putamen and anterior cerebellum. The authors’ imaging data suggest that as learning progresses, the sites of activation shift in a topographically organized fashion. Our interpretation of these data is that each stage of the learning progress involves a different set of interconnected basal ganglia, cerebellar and cerebral cortical regions.