Neuroanatomical studies using transneuronal virus tracers in macaque monkeys recently demonstrated that substantial interactions exist between basal ganglia and the cerebellum. To what extent these interactions are present in the human brain remains unclear; however, these connections are thought to provide an important framework for understanding cerebellar contributions to the manifestation of basal ganglia disorders, especially with respect to tremor genesis in movement disorders such as Parkinson's disease. Here, we tested the feasibility of assessing these connections in vivo and non-invasively in the human brain with diffusion magnetic resonance imaging and tractography. After developing a standardized protocol for manual segmentation of basal ganglia and cerebellar structures, masks for diffusion tractography were defined based on structural magnetic resonance images. We tested intra- and inter-observer stability and carried out tractography for dentato-pallidal and subthalamo-cerebellar projections. After robustly achieving connection probabilities per tract, the connectivity values and connectional fingerprints were calculated in a group of healthy volunteers. Probabilistic diffusion tractography was applicable to probe the inter-connection of the cerebellum and basal ganglia. Our data confirmed that dentato-thalamo-striato-pallidal and subthalamo-cerebellar connections also exist in the human brain at a level similar to those that were recently suggested by transneuronal tracing studies in non-human primates. Standardized segmentation protocols made these findings reproducible with high stability. We have demonstrated that diffusion tractography in humans in vivo is capable of revealing the structural bases of cerebellar networks with the basal ganglia. These findings support the role of the cerebellum as a satellite system of established cortico-basal ganglia networks in humans.

Cerebellum and basal ganglia are reciprocally interconnected with the neocortex via oligosynaptic loops. The signal pathways of these loops predominantly converge in motor areas of the frontal cortex and are mainly segregated on subcortical level. Recent evidence, however, indicates subcortical interaction of these systems. We have reviewed literature that addresses the question whether, and to what extent, projections of main output nuclei of basal ganglia (reticular part of the substantia nigra, internal segment of the globus pallidus) and cerebellum (deep cerebellar nuclei) interact with each other in the thalamus. To this end, we compiled data from electrophysiological and anatomical studies in rats, cats, dogs, and non-human primates. Evidence suggests the existence of convergence of thalamic projections originating in basal ganglia and cerebellum, albeit sparse and restricted to certain regions. Four regions come into question to contain converging inputs: (1) lateral parts of medial dorsal nucleus (MD); (2) parts of anterior intralaminar nuclei and centromedian and parafascicular nuclei (CM/Pf); (3) ventromedial nucleus (VM); and (4) border regions of cerebellar and ganglia terminal territories in ventral anterior and ventral lateral nuclei (VA-VL). The amount of convergences was found to exhibit marked interspecies differences. To explain the rather sparse convergences of projection territories and to estimate their physiological relevance, we present two conceivable principles of anatomical organization: (1) a "core-and-shell" organization, in which a central core is exclusive to one projection system, while peripheral shell regions intermingle and occasionally converge with other projection systems and (2) convergences that are characteristic to distinct functional networks. The physiological relevance of these convergences is not yet clear. An oculomotor network proposed in this work is an interesting candidate to examine potential ganglia and cerebellar subcortical interactions.

The interaction of basal ganglia and other brain regions is more complex regarding anatomic and functional perspectives than previously assumed. Hence, the classical basal ganglia model has to be extended to at least four satellite systems modulating motor-executive, associative and limbic-motivational brain regions: (i) an indirect projection system, (ii) a striato-nigro-striatal loop, (iii) a "hyperdirect" projection system as well as additional projections to the subthalamic nucleus and (iv) multisynaptic connections from the cerebellum exerting influence on the indirect projection system. The investigation of these satellite systems would be invaluable to foster our understanding of basal ganglia circuitries and may yield a better appreciation of largely opaque symptoms like resting tremor in Parkinson's disease; analysis of these anatomic pathways and functional implications may facilitate explanatory model approaches to side effects due to dopaminergic therapy and deep brain stimulation in humans and thereby offer the possibility for new therapeutic approaches in movement disorders.

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