Transcranial Non-Invasive Brain Stimulation in Parkinson's Disease Patients with Dyskinesias. Where is the Optimal Target?

Dear Editor, The treatment of secondary effects of levodopa treatments in Parkinson’s disease (PD) patients is an actual necessity and priority in clinical practice. The paper made by Ferrucci et al. [1] represents an additional confirmation that levodopainduced dyskinesias (LIDs) are potentially treatable by neuromodulation techniques. Differently from previous literature, this is the first study using transcranial direct current stimulation (tDCS) to reduce dyskinetic movements in PD. Indeed, until now, nine papers had provided evidence on the effectiveness of non-invasive brain stimulation (NIBS) administered as repetitive transcranial magnetic stimulation (rTMS). However, despite methodological and technical differences (tDCS vs. rTMS; single vs. prolonged stimulation sessions; inhibitory vs. excitatory; and unilateral vs. bilateral) what merits to be focused after the current article is where stimulation should be applied. In other words, which is the main brain region to be targeted in LIDs patients: the Motor Cortex? Supplementary Motor Area (SMA)? Cerebellum? Or Inferior Frontal Cortex (IFC)? The target location problem in LIDs is strongly dependent upon the current pathophysiological model. In the last few years, a considerable effort has been made to understand the neurobiological basis of this motor complication. LIDs are classically ascribed to the degree of nigrostriatal neurodegeneration and striatal changes associated with chronic levodopa therapy [2]. These interact to induce maladaptive striatal plasticity, which has the effect of altering neuronal activity in striatopallidal circuits. The first step in imaging of LIDs was made by Rascol [3] and Brooks [4], who demonstrated that these abnormal neuronal firing patterns extended on the brain cortex mainly including the sensorimotor areas of the corticobasal ganglia loop. Guided by these first neurofunctional results, neuromodulation over regions showing functional overactivity in LIDs was tested either for the primary motor cortex (M1) [4–10] or for the SMA [11, 12]. Although, Ferrucci et al. [1] demonstrated that noninvasive brain stimulation over the M1 improved LIDs, the present literature is characterized by conflicting findings. First of all, Wagle-Shukla et al. [5], by using a prolonged session (2 weeks) of low frequency (1HZ) rTMS, reported no evident clinical improvements in six PD patients with LIDs. This preliminary lack of significant effects has also been confirmed in two recent studies [6, 10], despite the employment of different rTMS protocols. Otherwise, three additional studies demonstratedmoderate evidence about the role of theM1 as potential stimulation site for LIDs treatment. First, Filipovic et al. [7], using low-frequency rTMS (1 Hz) for 4 consecutive days in ten PD patients with LIDs, reported residual beneficial clinical effects in dyskinesia severity. With the same TMS protocol, these authors found an increased beneficial effect also in one PD patient with diphasic dyskinesia [8]. Finally, in another case report, rTMS over the M1 significantly reduced the painful dystonia and walking disturbances in one dyskinetic patient with painful off-period dystonia [9]. Despite these conflicting findings, a central role of M1 in the genesis of LIDs may be hypothesized since it has been * Antonio Cerasa a.cerasa@unicz.it