Fast Intracortical Sensory-Motor Integration: A Window Into the Pathophysiology of Parkinson's Disease.

Raffaele Dubbioso,Fiore Manganelli,Vincenzo Di Lazzaro,Hartwig Roman Siebner

doi:10.3389/fnhum.2019.00111

Abstract

Parkinson’s Disease (PD) is a prototypical basal ganglia disorder. Nigrostriatal dopaminergic denervation leads to progressive dysfunction of the cortico-basal ganglia-thalamo-cortical sensorimotor loops, causing the classical motor symptoms. Although the basal ganglia do not receive direct sensory input, they are important for sensorimotor integration. Therefore, the basal ganglia dysfunction in PD may profoundly affect sensory-motor interaction in the cortex. Cortical sensorimotor integration can be probed with transcranial magnetic stimulation (TMS) using a well-established conditioning-test paradigm, called short-latency afferent inhibition (SAI). SAI probes the fast-inhibitory effect of a conditioning peripheral electrical stimulus on the motor response evoked by a TMS test pulse given to the contralateral primary motor cortex (M1). Since SAI occurs at latencies that match the peaks of early cortical somatosensory potentials, the cortical circuitry generating SAI may play an important role in rapid online adjustments of cortical motor output to changes in somatosensory inputs. Here we review the existing studies that have used SAI to examine how PD affects fast cortical sensory-motor integration. Studies of SAI in PD have yielded variable results, showing reduced, normal or even enhanced levels of SAI. This variability may be attributed to the fact that the strength of SAI is influenced by several factors, such as differences in dopaminergic treatment or the clinical phenotype of PD. Inter-individual differences in the expression of SAI has been shown to scale with individual motor impairment as revealed by UPDRS motor score and thus, may reflect the magnitude of dopaminergic neurodegeneration. The magnitude of SAI has also been linked to cognitive dysfunction, and it has been suggested that SAI also reflects cholinergic denervation at the cortical level. Together, the results indicate that SAI is a useful marker of disease-related alterations in fast cortical sensory-motor integration driven by subcortical changes in the dopaminergic and cholinergic system. Since a multitude of neurobiological factors contribute to the magnitude of inhibition, any mechanistic interpretation of SAI changes in PD needs to consider the group characteristics in terms of phenotypical spectrum, disease stage, and medication.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder affecting multiple neuromodulatory transmitter systems (Barone, 2010)
The results suggest that the attenuating effect of medication state on short-latency afferent inhibition’’ (SAI) is more pronounced in patients in whom dopamine replacement therapy shows limited efficacy to normalize parkinsonian motor symptoms as indicated by high UPDRS scores in the on-medication state
We concluded that PD-related changes in SAI are most likely caused at the cortical level, where sensory input is rapidly integrated into a motor output

Summary

INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative disorder affecting multiple neuromodulatory transmitter systems (Barone, 2010). The TMS-evoked excitation of the corticomotor projections produced an increased, prolonged and less synchronized excitation of the target muscle (Kleine et al, 2001) This converging evidence shows that anatomical and functional impairment of the cortico-basal ganglia-thalamocortical loop in PD profoundly affects sensory-motor integration in the cortex. KEY CONCEPT 2 | Short-latency afferent inhibition (SAI) Fast component of sensorimotor integration can be studied in vivo by examining the effects of sensory input on the motor output at the cortical level. The most direct evidence that peripheral somatosensory input modulates the TMS-induced motor output at the cortical level comes from invasive recordings of corticospinal volleys in patients with implanted electrodes in the cervical epidural space (Tokimura et al, 2000) These studies showed that later I-waves (I2 and I3 waves) were reduced at an interval appropriate for SAI, whereas the early I-wave (I1 wave) remained unchanged. PD-ON hyposmia (18.96 ± 1.31) PD-ON anosmia (21.67 ± 2.27) PD-ON normosmia (14.94 ± 2.3)

12 CONDITIONS

Findings

CONCLUSION AND OUTLOOK