Cerebellum in Levodopa-Induced Dyskinesias: The Unusual Suspect in the Motor Network

Abstract

The exact mechanisms that generate levodopa-induced dyskinesias (LID) during chronic levodopa therapy for Parkinson’s disease (PD) are not yet fully established. The most widely accepted theories incriminate the non-physiological synthesis, release and reuptake of dopamine generated by exogenously administered levodopa in the striatum, and the aberrant plasticity in the cortico-striatal loops. However, normal motor performance requires the correct recruitment of motor maps. This depends on a high level of synergy within the primary motor cortex (M1) as well as between M1 and other cortical and subcortical areas, for which dopamine is necessary. The plastic mechanisms within M1, which are crucial for the maintenance of this synergy, are disrupted both during “OFF” and dyskinetic states in PD. When tested without levodopa, dyskinetic patients show loss of treatment benefits on long-term potentiation and long-term depression-like plasticity of the intracortical circuits. When tested with the regular pulsatile levodopa doses, they show further impairment of the M1 plasticity, such as inability to depotentiate an already facilitated synapse and paradoxical facilitation in response to afferent input aimed at synaptic inhibition. Dyskinetic patients have also severe impairment of the associative, sensorimotor plasticity of M1 attributed to deficient cerebellar modulation of sensory afferents to M1. Here, we review the anatomical and functional studies, including the recently described bidirectional connections between the cerebellum and the basal ganglia that support a key role of the cerebellum in the generation of LID. This model stipulates that aberrant neuronal synchrony in PD with LID may propagate from the subthalamic nucleus to the cerebellum and “lock” the cerebellar cortex in a hyperactive state. This could affect critical cerebellar functions such as the dynamic and discrete modulation of M1 plasticity and the matching of motor commands with sensory information from the environment during motor performance. We propose that in dyskinesias, M1 neurons have lost the ability to depotentiate an activated synapse when exposed to acute pulsatile, non-physiological, dopaminergic surges and become abnormally receptive to unfiltered, aberrant, and non-salient afferent inputs from the environment. The motor program selection in response to such non-salient and behaviorally irrelevant afferent inputs would be abnormal and involuntary. The motor responses are worsened by the lack of normal subcortico–cortical inputs from cerebellum and basal ganglia, because of the aberrant plasticity at their own synapses. Artificial cerebellar stimulation might help re-establish the cerebellar and basal ganglia control over the non-salient inputs to the motor areas during synaptic dopaminergic surges.

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

“…This includes the cortex, with LIDs correlating with supersensitive excitatory transmission at corticostriatal synapses (Ueno et al, 2014) and high-frequency cortical oscillations (Richter et al, 2013). The cerebellum also plays a role in LIDs possibly via the primary motor cortex (Kishore and Popa, 2014; Kishore et al, 2014). Overall, LIDs appear to be complex in origin with the involvement of numerous brain circuits (Engeln et al, 2015), one of which is the cholinergic system.…”

Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex

“…At this moment, both hypotheses are equally plausible and not mutually exclusive: such a state of imbalance in the cerebellum could affect basal ganglia functions and generate dyskinesias just as in the rat model [167], or the aberrant basal ganglia activity in advanced PD could affect the bidirectional cerebellar modulation of M1 plasticity [179]. Based on the indirect evidence of cerebellar involvement in advanced PD and the state of cerebellar hyperexcitation in the levodopa-naïve, MPTP-treated primates [181], a model was recently proposed [182] that considers cerebellar, basal ganglia, and motor cortical networks as interlinked and their abnormal interactions as central to the generation of abnormal movements in both parkinsonism and levodopa-induced dyskinesias (Fig. 9).…”

Activation of V2 vasopressin receptors induces recovery of motor function in patients with stroke, Parkinson’s disease and parkinsonism of different nature

“…На супрасегментарном уровне в регуляции мышечного тонуса задействованы ретикулярная формация мозгового ствола, мозжечок, ганглии экстрапирамидной системы, пирамидная система [20,21]. В организации сложно координированных движений, таких как ходьба и поддержание позы, кро-ме спинальных механизмов, задействован мозжечок [20,21,43]. Произвольные движения осуществляют-ся при сокращении мышц-агонистов и расслабле-нии мышц-антагонистов и обеспечиваются пере-крещенным кортикоспинальным путем [20,21,43].…”

“…В организации сложно координированных движений, таких как ходьба и поддержание позы, кро-ме спинальных механизмов, задействован мозжечок [20,21,43]. Произвольные движения осуществляют-ся при сокращении мышц-агонистов и расслабле-нии мышц-антагонистов и обеспечиваются пере-крещенным кортикоспинальным путем [20,21,43]. С нейрохимической точки зрения двигательная функция реализуется при участии нейромедиаторов: ацетилхолина, дофамина, глутамата, ГАМК, в извест-ной степени норадреналина и серотонина [27,32,43,48,53].…”

“…Произвольные движения осуществляют-ся при сокращении мышц-агонистов и расслабле-нии мышц-антагонистов и обеспечиваются пере-крещенным кортикоспинальным путем [20,21,43]. С нейрохимической точки зрения двигательная функция реализуется при участии нейромедиаторов: ацетилхолина, дофамина, глутамата, ГАМК, в извест-ной степени норадреналина и серотонина [27,32,43,48,53]. Поддержание определенного соотношения уровней медиаторов в структурах мозга, связанных с двигательной активностью, обес печивает высокую пластичность ее организации.…”