LOCEN Research Focus: Bio-constrained models of the basal ganglia-cortex-cerebellum system: applications to the study of Parkinson and other diseases



Authors: Daniele Caligiore, Francesco Mannella, Gianluca Baldassarre

Topic and its relevance. The basal ganglia and cortex forms re-entrant loops through which basal ganglia contribute to select the contents of cortex. Also cerebellum forms re-entrant loops with motor cortex subserving both motor and cognitive functions. Recent evidence has also shown the existence of important cerebellum-basal ganglia anatomical bidirectional links. Basal-ganglia, cortex, and cerebellum thus form a whole system and closely cooperate to implement a large number of brain functions subserving adaptive behaviour. The specific brain mechanisms underlying these functions are only in part known. Computational models can play a key role in understanding them given the highly-dynamical complex-system nature of the basal ganglia-cortex-cerebellum system. The study of this system is also important for understanding and treating neurodegenerative diseases, such as Parkinson caused by the progressive death of dopaminergic neurons. Indeed, the system-level model-based study empowers the tracing of the effects that the Parkinson dopaminergic disregulation causes onto the whole basal ganglia-cortex-cerebellum system, thus helping to understand the multifaceted sympthoms of the diseases expressed in different patients sub-types (e.g., tremor vs. akinetic). 

Questions and goals. How does dopamine decrease produce the main sympthoms of Parkinson? What are the different underlying causes of different typologies of sympthoms manifested by Parkinson patients? Which guidelines do computational models give to therapy?
Methods. We build detailed system-level computational models of the classic brain system affected by the decrease of dopamine (striatum, globus pallidus, subthalamic nucleus, D1 and D2 receptors, substantia nigra, motor cortex) but also of their interaction with cerebellum, recently shown to have important connections with cortex and basal ganglia.

Results. System-levels computational models are integrating and accounting for apparently separated empirical results. The models are for example being used to account for the different types of patient groups exhibiting different sympthoms. This has the potential to give suggestions on how to differentiate therapeutic treatments depending on the patient sympthoms.

Conclusions. System-level computational modelling allows the account for aspects of Parkinson that cannot be account for by approaches studing basal ganglia, cortex, or cerebellum in isolation.