Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition

Abstract

Following the fundamental recognition of its involvement in sensory-motor coordination and learning, the cerebellum is now also believed to take part in the processing of cognition and emotion. This hypothesis is recurrent in numerous papers reporting anatomical and functional observations, and it requires an explanation. We argue that a similar circuit structure in all cerebellar areas may carry out various operations using a common computational scheme. On the basis of a broad review of anatomical data, it is conceivable that the different roles of the cerebellum lie in the specific connectivity of the cerebellar modules, with motor, cognitive, and emotional functions (at least partially) segregated into different cerebro-cerebellar loops. We here develop a conceptual and operational framework based on multiple interconnected levels (a meta-levels hypothesis): from cellular/molecular to network mechanisms leading to generation of computational primitives, thence to high-level cognitive/emotional processing, and finally to the sphere of mental function and dysfunction. The main concept explored is that of intimate interplay between timing and learning (reminiscent of the "timing and learning machine" capabilities long attributed to the cerebellum), which reverberates from cellular to circuit mechanisms. Subsequently, integration within large-scale brain loops could generate the disparate cognitive/emotional and mental functions in which the cerebellum has been implicated. We propose, therefore, that the cerebellum operates as a general-purpose co-processor, whose effects depend on the specific brain centers to which individual modules are connected. Abnormal functioning in these loops could eventually contribute to the pathogenesis of major brain pathologies including not just ataxia but also dyslexia, autism, schizophrenia, and depression.

Keywords: autism; cerebellum; cognition; dyslexia; motor control; prediction; schizophrenia; timing.

Figure 1

Schematic representation of the cerebellar circuit. The cerebellar circuit consists of cortical and subcortical sections. At subcortical level, the afferent fibers activate DCN cells (DCN-C) and IO cells (IO-C). The DCN emits the output and at the same time inhibits the IO. In the cerebellar cortex, there are different types of neurons including granule cells (GrC), Golgi cells (GoC), Purkinje cells (PC), stellate and basket cells (SC, BC), Lugaro cells, and unipolar brush cells (not shown). The two main inputs are represented by mossy fibers (mf) originating in various brain stem and spinal cord nuclei, and by climbing fibers (cf) originating from the IO. Signals conveyed through the mossy fibers diverge to DCN and activate the granular layer (containing GrC and GoC). The ascending axon of the GrC bifurcates in the molecular layer (containing PC, SC, and BC) forming the parallel fibers (pf). The cerebellar cortical circuit is organized as a feedforward excitatory chain assisted by inhibitory loops: mfs excite GrCs, which activate all the other cortical elements. In the granular layer, inhibition is provided by GoC, in the molecular layer by SC and BC. Finally, PC inhibit DCN. The IO, which is also activated by brain stem and spinal cord nuclei, controls PC activity though a single powerful synapse. Thus, the whole system can be seen as a complex mechanism controlling the DCN output.

Figure 2

The modular organization of the cerebellum. The picture shows a flattened view of the cerebellum. Four ideal zones are shown in color, each one containing microzones forming a multizonal microcomplex. The microzones have the basic structure reported in the expansion on the right (same symbols as in Figure 1, inhibitory interneurons are overlaid in blue). A microzone is defined as a group of the order of 1000 Purkinje cells all having the same somatotopic receptive field. These Purkinje cells are arranged in a long, narrow strip, oriented perpendicular to the cortical folds, so that Purkinje cell dendrites are flattened in the same direction as the microzones extend and are crossed by parallel fibers at right angles. The climbing fibers branches (about 10) usually innervate Purkinje cells belonging to the same microzone and the olivary neurons generating such climbing fibers tend to be coupled by gap junctions. This helps synchronizing Purkinje cells within a microzone on a millisecond time scale. The Purkinje cells belonging to a microzone all send their axons to the same small cluster of output cells within the deep cerebellar nuclei. Finally, the axons of basket cells are much longer in the longitudinal direction than in the mediolateral direction (not shown), causing them to be confined largely to a single microzone. Thus, cellular interactions within a microzone are much stronger than those between different microzones.

Figure 3

The cerebello-thalamo-cerebro-cortical circuits (CTCCs). The figure represents schematically the bidirectional connectivity between the cerebellum and the telencephalon, in particular with the cereberal cortex. Telencephalic projections from the cortex and basal ganglia (through the subthalamic nucleus, STN) and limbic areas are relayed to the cerebellum through the anterior pontine nuclei (APN). The cerebellum in turn sends its output through the deep cerebellar nuclei (DCN), red nucleus (RN), and anterior thalamic nucleus (ATN) to various telencephalic areas including the motor cortex (MC), the prefrontal cortex (PFC), the parietal cortex (PC), and the temporal cortex (TC). These connections, which are supported by anatomical and functional data, forming several bidirectional cerebello-thalamo-cerebro-cortical circuits (CTCCs).

Figure 4

The meta-levels of cerebellar activity. The figure depicts the causal relationships between the functions that the cerebellum is thought to play at different operative levels (meta-levels hypothesis) and between these same functions and brain pathologies. The neuron and network level lays in the blue box and is normally investigate using electrophysiological and imaging techniques. These combined with mathematical models, allow to infer the computational functions of the circuit (forward model, various parameter transformation and detection of discrepancies between predicted and actual signal patterns). Once integrated into the large-sale connectivity of the CTCC loops, circuit computations lead to emerging functions. At low-level (yellow boxes), these include learning, prediction, and timing (cerebellar processing primitives), which can implement structured cerebellar operations including forms of working memory, error/novelty detection, and mental object manipulation. The low-level functions lay at the basis of more complex high-level functions (green box) including motor control, attention switching, language processing, imagery and visuospatial processing, decision-making, and reasoning. Major aspects of brain pathology (red box) can be predicted on the basis of the low- and high-level functions. Emerging functions and dysfunctions are usually investigated using non-invasive recordings (fMRI, DTI, TMS etc.), neuropsychological and clinical assessments. As a whole, the cerebellar function can contribute to global brain operations not just of motricity but also of learning and memory, cognition, emotion, attention, and even awareness.