Impaired interhemispheric inhibition in isolated REM sleep Behavior Disorder: first exploratory Transcranial Magnetic Stimulation-based evidence

Lanza, Giuseppe;Quercia, Angelica;Antelmi, Elena;Bella, Rita;Cantone, Mariagiovanna;Congiu, Patrizia;Cosentino, Filomena I I;Deriu, Franca;Figorilli, Michela;Galeano, Annalisa;Garifoli, Angelo;Ginatempo, Francesca;Lanuzza, Bartolo;Liguori, Claudio;Marano, Pietro;Mogavero, Maria P;Morreale, Manuela;Palmigiano, Aurora;Pastorello, Giovanni;Paulus, Walter;Puligheddu, Monica F;Sarritzu, Francesco;Toscano, Giuseppe;Toscano, Rossella;Tripodi, Mariangela;Ferri, Raffaele;Pennisi, Manuela

2026-01-01

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Abstract

Study objectives: Isolated REM sleep Behavior Disorder (iRBD) is viewed as a prodromal stage of alpha-synuclein-related neurodegeneration. Transcranial Magnetic Stimulation (TMS) revealed early cortical excitability abnormalities in this condition. However, interhemispheric inhibitory mechanisms, measured through transcallosal inhibition, have not been previously investigated. Methods: In this pilot study, we explored both intracortical and interhemispheric inhibition in 20 de novo right-handed iRBD patients compared with 20 right-handed healthy controls. Participants underwent cognitive testing, mood and sleepiness assessments, and extrapyramidal motor and non-motor evaluations. TMS was used to measure contralateral and ipsilateral silent periods (cSP, iSP) during stimulation of the left primary motor cortex. Although groups were age-matched, patients had lower educational levels and were predominantly male. Results: iRBD patients displayed reduced cognitive performance but similar mood and sleepiness profiles. Motor symptoms were minimal, while non-motor symptoms showed a mild-to-moderate burden. Most TMS indices, i.e., resting motor threshold, cSP latency, cSP duration, and iSP latency, were comparable between groups. Conversely, iSP duration was significantly shorter in iRBD patients, indicating pronounced interhemispheric disinhibition. After correction for multiple comparisons, only the positive correlation between non-motor symptoms scale scores and cSP latency remained significant. This suggests that delayed onset of intracortical inhibition may accompany a greater non-motor symptom load. Conclusions: Prolonged iSP duration and the finding on cSP latency in iRBD strengthen the notion of GABAergic dysfunction extending to transcallosal pathways. Such alterations might contribute to dream-enactment behaviors and subtle cognitive deficits observed. These exploratory findings open new avenues for understanding RBD pathophysiology and may support the development of targeted "pharmaco-TMS" strategies in prodromal synucleinopathies.