Long-term changes in short-interval intracortical facilitation modulate motor cortex plasticity and L-dopa-induced dyskinesia in Parkinson's disease

Guerra, Andrea; Asci, Francesco; Zampogna, Alessandro; D'Onofrio, Valentina; Suppa, Antonio; Fabbrini, Giovanni; Berardelli, A.

doi:10.1016/j.brs.2021.11.016

Cited by 16 publications

(6 citation statements)

References 52 publications

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“…Safinamide has non-dopaminergic actions, such as its action as a sodium channel blocker, and it has been reported to suppress changes in the GluN2A/GluN2B ratio caused by chronic levodopa administration (Gardoni et al 2018). Patients with LID have abnormal cortical facilitation, suggesting overactive glutamatergic neurotransmission in the cortex, and this dysfunction was restored via modulation of synaptic plasticity mechanisms by the long-term safinamide effect (Guerra et al 2019(Guerra et al , 2021. It is not clear whether this action of safinamide is mediated by blocking sodium channels; however, safinamide may affect dyskinesia.…”

Section: Completer Without Any Changes In Dose Of Levodopa Combinatio...mentioning

confidence: 99%

Long-term effects of safinamide adjunct therapy on levodopa-induced dyskinesia in Parkinson’s disease: post-hoc analysis of a Japanese phase III study

et al. 2022

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This post-hoc analysis investigated the long-term effects of safinamide on the course of dyskinesia and efficacy outcomes using data from a phase III, open-label 52-week study of safinamide 50 or 100 mg/day in Japanese patients with Parkinson’s disease (PD) with wearing-off. Patients (N = 194) were grouped using the UPDRS Part IV item 32: with and without pre-existing dyskinesia (pre-D subgroup; item 32 > 0 at baseline [n = 81], without pre-D subgroup; item 32 = 0 at baseline [n = 113]). ON-time with troublesome dyskinesia (ON-TD) increased significantly from baseline to Week 4 in the pre-D subgroup (+ 0.25 ± 0.11 h [mean ± SE], p = 0.0355) but gradually decreased up to Week 52 (change from baseline: − 0.08 ± 0.17 h, p = 0.6224); ON-TD did not change significantly in the Without pre-D subgroup. UPDRS Part IV item 32 score increased significantly at Week 52 compared with baseline in the Without pre-D subgroup, but no UPDRS Part IV dyskinesia related-domains changed in the pre-D subgroup. Both subgroups improved in ON-time without TD, UPDRS Part III, and Part II [OFF-phase] scores. The cumulative incidence of new or worsening dyskinesia (adverse drug reaction) at Week 52 was 32.5 and 5.0% in the pre-D and Without pre-D subgroups, respectively. This study suggested that safinamide led to short-term increasing dyskinesia but may be not associated with marked dyskinesia at 1-year follow-up in patients with pre-existing dyskinesia, and that it improved motor symptoms regardless of the presence or absence of dyskinesia at baseline. Further studies are warranted to investigate this association in more details.Trial registration: JapicCTI-153057 (Registered: 2015/11/02).

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Section: Completer Without Any Changes In Dose Of Levodopa Combinatio...mentioning

confidence: 99%

Long-term effects of safinamide adjunct therapy on levodopa-induced dyskinesia in Parkinson’s disease: post-hoc analysis of a Japanese phase III study

et al. 2022

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“…Moreover, we enrolled patients in early-to-intermediate disease stages, and none had tremor-dominant PD or LID. Since previous studies have shown specific differences in cortical excitability between akinetic-rigid and tremor-dominant PD and differential effects of L-dopa on neurophysiological measures depending on LID presence (Barbin et al, 2013;Guerra, Asci, et al, 2022;Khedr et al, 2021;, our iTBS-γ tACS results cannot be generalized to all PD subtypes and disease stages.…”

Section: Discussionmentioning

confidence: 94%

Assessing the interaction between L‐dopa and γ‐transcranial alternating current stimulation effects on primary motor cortex plasticity in Parkinson's disease

Guerra

D'Onofrio

Asci

et al. 2022

Eur J of Neuroscience

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L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients OFF dopaminergic medication, impaired M1 plasticity and defective GABA-A-ergic inhibition can be restored by boosting gamma (γ) oscillations via transcranial alternating current stimulation (tACS) during intermittent theta-burst stimulation (iTBS). However, it is unknown whether L-dopa modifies the beneficial effects of iTBS-γ-tACS on M1 in PD. In this study, a PD patients group underwent combined iTBS-γ-tACS and iTBS-sham-tACS, each performed both OFF and ON dopaminergic therapy (four sessions in total). Motor evoked potentials (MEPs) elicited by single TMS pulses and short-interval intracortical inhibition (SICI) were assessed before and after iTBS-tACS. We also evaluated possible SICI changes during γ-tACS delivered alone in OFF and ON conditions. The amplitude of MEP elicited by single TMS pulses and the degree of SICI inhibition significantly increased after iTBS-γ-tACS. The amount of change produced by iTBS-γ-tACS was similar in patients OFF and ON therapy. Finally, γ-tACS (delivered alone) modulated SICI during stimulation and this effect did not depend on the dopaminergic condition of patients. In conclusion, boosting cortical γ oscillatory activity via tACS during iTBS improved M1 plasticity and enhanced GABA-A-ergic transmission in PD patients to the same extent regardless of dopaminergic state.These results suggest a lack of interaction between L-dopa and γ-tACS effects at the M1 level. The possible neural substrate underlying iTBS-γ tACS effects,

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“…Excessive glutamate signaling has been suggested in dyskinesia pathophysiology ( 31 , 32 ), and abnormal cortical facilitation, which indicates hyperactive glutamatergic neurotransmission, was reported in patients with levodopa-induced dyskinesia ( 33 ). Guerra et al have shown that long-term safinamide treatment ameliorated cortical facilitation, and the change in cortical facilitation and the change in dyskinesia severity were positively correlated ( 34 ). Although it is not clear that the non-dopaminergic action of safinamide was involved in the decrease in cortical facilitation, this suggests that inhibition of glutamatergic neurotransmission may lead to dyskinesia alleviation.…”

Section: Discussionmentioning

confidence: 99%

Sustained response in early responders to safinamide in patients with Parkinson's disease and motor fluctuations: A post hoc analysis of the SETTLE study

et al. 2023

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Safinamide is a selective, reversible, monoamine oxidase B inhibitor for the treatment of patients with Parkinson's disease (PD) and motor fluctuations. This was a post hoc analysis of the SETTLE study, in which patients with PD and motor fluctuations were randomly assigned to 24-week treatment with safinamide (50 mg/day for 2 weeks, increased to 100 mg/day if tolerated) or placebo. In the present analysis, responders were defined according to their treatment responses at Week 2 and Week 24 based on changes in ON-time without troublesome dyskinesia from baseline with cutoffs of 1 hour. It was found that 81% (103/127) of the responders at Week 2 maintained the response through Week 24 in the safinamide group. Other outcomes did not necessarily coincide with the ON-time response; however, “Early” responders who showed a treatment response at both Week 2 and Week 24 had substantial improvements from baseline in OFF-time, UPDRS Part II and III scores, and PDQ-39 summary index scores through Week 24. The safinamide group had a higher proportion of early responders than the placebo group (39% vs 20%, p < 0.0001). At baseline, early responders in the safinamide group had significantly higher UPDRS Part II and III scores, shorter ON-time, and longer OFF-time than the other responder populations. In conclusion, the results of the present post hoc analysis suggest that patients with a short ON-time, severe motor symptoms, and highly compromised activities of daily living can benefit from safinamide early in treatment and over the long term.

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Long-term changes in short-interval intracortical facilitation modulate motor cortex plasticity and L-dopa-induced dyskinesia in Parkinson's disease

Cited by 16 publications

References 52 publications

Long-term effects of safinamide adjunct therapy on levodopa-induced dyskinesia in Parkinson’s disease: post-hoc analysis of a Japanese phase III study

Long-term effects of safinamide adjunct therapy on levodopa-induced dyskinesia in Parkinson’s disease: post-hoc analysis of a Japanese phase III study

Assessing the interaction between L‐dopa and γ‐transcranial alternating current stimulation effects on primary motor cortex plasticity in Parkinson's disease

Sustained response in early responders to safinamide in patients with Parkinson's disease and motor fluctuations: A post hoc analysis of the SETTLE study

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