Background. Parkinson's disease (PD) is a neurodegenerative disorder characterised clinically by predominantly motor symptoms (bradykinesia, rigidity, and rest tremor). The progressive depletion of midbrain dopaminergic neurons results in functional alterations in the basal ganglia. In particular, the presence of hypersynchronous oscillations in the beta frequency band (13-30 Hz) at the level of the Subthalamic Nucleus (STN) and the Globus Pallidus internus (GPi) is well documented. This abnormal activity, documented by recording Local Field Potentials (LFP) in advanced PD patients (aPD) treated with Deep Brain Stimulation (DBS), is effectively suppressed by L-Dopa therapy and DBS, correlating with symptom improvement. However, most of the neurophysiological studies have been conducted on the STN and in the intraoperative and immediate postoperative (acute phase) phases of DBS implantation, whereas evidence on GPi is limited. With the introduction of DBS systems capable of chronically acquiring LFPs, it is possible to perform neurophysiological recordings several months after surgery. Aim of the study. This thesis study aims to analyse and compare the neurophysiological characteristics of the STN and GPi in patients with aPD treated with DBS, assessed months after the intervention (chronic phase). A further aim is to evaluate the presence of a correlation between these neurophysiological measures and the motor symptoms of PD. Materials and methods. Fourteen patients with aPD treated by DBS implantation with Medtronic Percept PC system (8 STN-DBS, 6 GPi-DBS, 28 total nuclei) were recruited. Patients were evaluated > 6 months after implantation by recording LFPs using the BrainSense Streaming method. In each subject, LFPs were recorded under two conditions: clinical OFF phase (> 4 hours after the last L-Dopa dose, MED OFF) and one hour after L-Dopa intake (MED ON). Both recordings were performed at least 5 minutes after switching off the DBS (DBS OFF). In each condition, motor symptoms were clinically assessed using the MDS-UPDRS-III scale. Spectral characteristics of LFPs in the main frequency bands (alpha, beta, low-gamma), and peak activity in the beta band (13-30 Hz) were analysed. Finally, several characteristics of the bursts activity were evaluated. All neurophysiological measures and their variations with L-Dopa were correlated with the severity of motor symptoms. Results. The amplitude of the beta peak was greater in the STN than in the GPi, while the average beta-band power did not differ between the two groups. The mean burst duration was higher in the STN, while the total number and rate of bursts were greater in the GPi. L-Dopa caused a reduction in beta activity in both nuclei, inducing a reduction in the power of low-beta, an increase in the bursts rate, and their redistribution with an increase in short-duration bursts and a reduction in long-duration bursts. In addition, the severity of bradykinesia and rigidity in MED OFF correlated with beta peak amplitude and low-beta power in the STN and with the number of long bursts in the GPi. Conclusions. The present study confirms the role of beta activity and its modulation with L-Dopa in PD. It demonstrates the existence of different beta-band dynamics between STN and GPi, although both demonstrated a similar neurophysiological response to therapy. The different correlation of cardinal motor symptoms with neurophysiology in the two nuclei could suggest a different role of specific abnormalities in the pathophysiology of PD. These findings are relevant for the possible use of beta activity as a biomarker for adaptive DBS (aDBS) of the STN and the GPi.
La malattia di Parkinson (MP) è una patologia neurodegenerativa caratterizzata clinicamente da prevalenti sintomi motori (bradicinesia, rigidità e tremore a riposo). La progressiva deplezione di neuroni dopaminergici mesencefalici determina alterazioni funzionali a livello dei gangli della base. In particolare, è ben documentata la presenza di oscillazioni ipersincrone nella banda di frequenza beta (13-30 Hz) a livello del Nucleo Subtalamico (STN) e del Globo Pallido interno (GPi). Tale attività anomala, studiata grazie alla registrazione dei potenziali di campo locale (Local Field Potentials, LFP) in pazienti affetti da MP avanzata (aMP) trattati con stimolazione cerebrale profonda (Deep Brain Stimulation, DBS), risulta efficacemente soppressa dalla terapia con L-Dopa e dalla DBS, correlando con il miglioramento dei sintomi. Tuttavia, la maggioranza degli studi neurofisiologici è stata condotta sul STN e nelle fasi intraoperatorie e nell’immediato postoperatorio (fase acuta) dell’impianto della DBS, mentre le evidenze sul GPi sono scarse. Grazie all’introduzione di sistemi DBS in grado di acquisire cronicamente LFPs, è possibile eseguire registrazioni neurofisiologiche diversi mesi dopo l’intervento (fase cronica). Scopo. Il presente studio di tesi ha lo scopo di analizzare e confrontare le caratteristiche neurofisiologiche del STN e del GPi in pazienti con aMP trattati con DBS, valutate in fase cronica. Inoltre, vuole valutare la presenza di una correlazione tra tali misure neurofisiologiche e i sintomi motori della MP. Materiali e metodi. Sono stati reclutati 14 pazienti con aMP trattati con impianto di DBS con sistema Medtronic Percept PC (8 STN-DBS, 6 GPi-DBS, 28 nuclei totali). I pazienti sono stati valutati almeno 6 mesi dopo l’impianto mediante registrazione degli LFPs con il metodo BrainSense Streaming. In ciascun soggetto, gli LFP sono stati registrati in due condizioni: fase di OFF clinico (dopo almeno 4 ore dall’ultima dose di L-Dopa, MED OFF) e dopo un’ora dall’assunzione di L-Dopa (MED ON). Entrambe le registrazioni sono state eseguite dopo almeno 5 minuti dallo spegnimento della DBS (DBS OFF). In ciascuna condizione, i sintomi motori sono stati valutati clinicamente attraverso la scala MDS-UPDRS-III. Sono state analizzate le caratteristiche spettrali degli LFPs nelle principali bande di frequenza (alfa, beta, low-gamma), ed i picchi di attività in banda beta. Sono state infine valutate diverse caratteristiche dell’attività dei burst. Tutte le misure neurofisiologiche e le loro variazioni con la L-Dopa sono state correlate con la severità dei sintomi motori. Risultati. L’ampiezza del picco beta è risultata maggiore nel STN, mentre il potere medio in banda beta non è risultato differente tra i due gruppi. La durata media dei burst è risultata superiore nel STN, mentre il numero totale e la frequenza dei bursts sono risultate maggiori nel GPi. La L-Dopa ha ridotto l’attività beta in entrambi i nuclei, inducendo una riduzione del potere del low-beta, un aumento della frequenza dei bursts e una loro redistribuzione con incremento dei bursts di breve durata e riduzione dei bursts di lunga durata. Inoltre, la gravità della bradicinesia e della rigidità in MED OFF erano correlate con l’ampiezza del picco beta e il potere del low-beta nel STN e con il numero di bursts lunghi nel GPi. Conclusioni. Il presente studio conferma il ruolo dell'attività beta e della sua modulazione con L-Dopa nella MP. Dimostra l'esistenza di differenti dinamiche in banda beta tra STN e GPi, sebbene entrambi abbiano dimostrato una risposta neurofisiologica simile alla terapia. La differente correlazione dei sintomi motori cardine con la neurofisiologia nei due nuclei potrebbe suggerire un ruolo diverso di specifiche anomalie nella fisiopatologia della MP. Tali risultati sono rilevanti per il possibile utilizzo dell’attività in beta come biomarcatore nella DBS adattativa (aDBS) del STN e del GPi.
Neurophysiological characterization of oscillatory activity in the Subthalamic Nucleus and the Globus Pallidus internus in patients with Parkinson's disease and Deep Brain Stimulation
PAVAN, SOFIA
2023/2024
Abstract
Background. Parkinson's disease (PD) is a neurodegenerative disorder characterised clinically by predominantly motor symptoms (bradykinesia, rigidity, and rest tremor). The progressive depletion of midbrain dopaminergic neurons results in functional alterations in the basal ganglia. In particular, the presence of hypersynchronous oscillations in the beta frequency band (13-30 Hz) at the level of the Subthalamic Nucleus (STN) and the Globus Pallidus internus (GPi) is well documented. This abnormal activity, documented by recording Local Field Potentials (LFP) in advanced PD patients (aPD) treated with Deep Brain Stimulation (DBS), is effectively suppressed by L-Dopa therapy and DBS, correlating with symptom improvement. However, most of the neurophysiological studies have been conducted on the STN and in the intraoperative and immediate postoperative (acute phase) phases of DBS implantation, whereas evidence on GPi is limited. With the introduction of DBS systems capable of chronically acquiring LFPs, it is possible to perform neurophysiological recordings several months after surgery. Aim of the study. This thesis study aims to analyse and compare the neurophysiological characteristics of the STN and GPi in patients with aPD treated with DBS, assessed months after the intervention (chronic phase). A further aim is to evaluate the presence of a correlation between these neurophysiological measures and the motor symptoms of PD. Materials and methods. Fourteen patients with aPD treated by DBS implantation with Medtronic Percept PC system (8 STN-DBS, 6 GPi-DBS, 28 total nuclei) were recruited. Patients were evaluated > 6 months after implantation by recording LFPs using the BrainSense Streaming method. In each subject, LFPs were recorded under two conditions: clinical OFF phase (> 4 hours after the last L-Dopa dose, MED OFF) and one hour after L-Dopa intake (MED ON). Both recordings were performed at least 5 minutes after switching off the DBS (DBS OFF). In each condition, motor symptoms were clinically assessed using the MDS-UPDRS-III scale. Spectral characteristics of LFPs in the main frequency bands (alpha, beta, low-gamma), and peak activity in the beta band (13-30 Hz) were analysed. Finally, several characteristics of the bursts activity were evaluated. All neurophysiological measures and their variations with L-Dopa were correlated with the severity of motor symptoms. Results. The amplitude of the beta peak was greater in the STN than in the GPi, while the average beta-band power did not differ between the two groups. The mean burst duration was higher in the STN, while the total number and rate of bursts were greater in the GPi. L-Dopa caused a reduction in beta activity in both nuclei, inducing a reduction in the power of low-beta, an increase in the bursts rate, and their redistribution with an increase in short-duration bursts and a reduction in long-duration bursts. In addition, the severity of bradykinesia and rigidity in MED OFF correlated with beta peak amplitude and low-beta power in the STN and with the number of long bursts in the GPi. Conclusions. The present study confirms the role of beta activity and its modulation with L-Dopa in PD. It demonstrates the existence of different beta-band dynamics between STN and GPi, although both demonstrated a similar neurophysiological response to therapy. The different correlation of cardinal motor symptoms with neurophysiology in the two nuclei could suggest a different role of specific abnormalities in the pathophysiology of PD. These findings are relevant for the possible use of beta activity as a biomarker for adaptive DBS (aDBS) of the STN and the GPi.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/65723