LAUSR

We read with interest the response letter “Does Motor Cortex Plasticity Depend on the Type of Mutation in the LRRK2 Gene?” by Dubbioso and colleagues. The authors investigated motor cortex excitability and plasticity in LRRK2-PD patients with R1441C mutation. In our recent work, we observed that LRRK2-PD patients with the G2019S mutation showed remarkable increase of Long Term Potentiation (LTP)-like cortical plasticity as well as a pronounced deficit of short intracortical inhibition. In contrast with our data, Dubbioso and colleagues did not find differences between LRRK2-PD patients and idiopathic PD patients for both intermittent Theta Burst Stimulation (iTBS)-induced cortical plasticity and intracortical circuits as assessed by short intracortical inhibition and facilitation (SICI/ICF) protocol. Therefore, taken together these findings provide novel evidence that a different mutation within the same LRRK2 gene may differently affect motor cortical response to Transcranial Magnetic Stimulation (TMS) in PD patients. Dubbioso and colleagues suggest that these opposite effects might involve a different modulation of the protein kinase activity in cortico-striatal circuits. Although this could be an interesting hypothesis, it has to be noted that TMS protocols investigate the neuronal activity of the primary motor cortex. Therefore, these modifications could not necessarily imply cortico-striatal circuits activation but also involve local changes in motor cortical interneurons, such as those mediating Gamma-aminobutyric acid (GABA(A)) activity. Apart from these pathophysiological considerations, we noticed that the groups of PD patients with R1441C mutation and idiopathic PD patients enrolled in the study by Dubbioso and colleagues were clinically more impaired in terms of UPDRS in comparison with our samples. They also required higher doses of L-dopa, thereby indicating a more severe course of the disease. This is relevant in light of a recent work showing that mechanisms of LTPlike cortical plasticity strictly depend on the stage of the disease. Moreover, in contrast to our study, PD patients with an R1441C mutation were recorded only in the ON L-dopa condition. At this regard, it would be interesting to further investigate whether L-dopa withdrawal could reveal underlying abnormalities eventually modified by L-dopa administration in PD patients with the R1441C mutation. This is important becasue L-dopa is a key neuromodulator of cortical plasticity assessed by means of TMS in different physiological and pathological conditions. Finally, other TMS paired-pulse protocols, such as long intracortical inhibition, should be investigated to better characterize other circuits not tested in PD patients with both G2019S and R1441C LRRK2 mutations. Nevertheless, taken together both studies indicate that TMS is a sensible tool able to detect subtle neurophysiological abnormalities associated with different mutations of the same gene in PD patients.