Sleep quality is usually characterized by a set of sleep indeces including total sleep and awake time and sleep efficiency. Sleep affects the physical and mental wellness of a person by influencing the processes of memorization, learning and concentration. In recent years, literature focused on the assessment of sleep quality parameters by investigating physiological variables. The traditional analysis approach requires the recording of several signals (polysomnography, PSG), including the electroencephalogram (EEG) that observes brain activity with electrodes placed on the scalp, the electroacoulogy (EOG) that measures the eyes movement and the electromyogram (EMG) that describes the physiological properties of muscles. The purpose of this thesis is to compute relevant features for waking, REM and non-REM sleep stages in order to investigate the effects induced by two different drugs. The two administrated drugs considered in the study are dexmedetomidine, an alpha-2a adrenergic agonist, and zolpidem, a GABA receptor agonist. The work was inspired by Akeju at al. research study, that analyzed the effects of dex and zolpidem at electroencephalographic level. The signals used in the analysis were collected at Massachusetts General Hospital in Boston, on 10 subjects (5 males) aged between 21-29 years. Sleep quality was assessed by means of traditional sleep indices including total sleep time (TST), sleep onset latency (SOL), total wake time, sleep efficiency, and sleep maintenance. Moreover, HRV, RSA and respiratory features were examined in time and frequency domains to provide further insights in sympatho-vagal tone dynamic changes occurring during the night. In particular, the variations of time and spectral components are investigated to identify those that best identify the transition between waking, REM and non-REM stages when drugs were administrated. This goal was pursued by applying a point process analysis to R-R interval series and RSA, and by an univariate analysis of respirogram. The point process algorithm was used to extract relevant features from HRV and RSA during the drugs administration, this algorithm was selected for its ability to detect significant fast dynamics changes; furthermore, it enhances sleep characterization at higher time resolution than traditional method. The approach is based on the heart probability model by defining a precise probabilistic prescription for conversion of the point-process R-R intervals to the continuous-valued function for heart rate parameters in continuous time. The dynamic HRV and RSA features extracted by the point process algorithm and respiratory features computed by univariate AR analysis provide the basis for the statistical analysis. Analyses were performed by following two methods: the first one focused on a single night and analyzed the features variation across different sleep stages, and the second one evaluated a single sleep stage across different nights. Moreover, the statistical analysis was performed with reference to the overall duration of the night and by splitting each night in two halves. Results on sleep stages indices confirm that dex and zolpidem induced an increase in the time spent in NR3 and NR2 stages and a decrease in the time spent in REM stage, moreover, the decrease in REM time during dex infusion is higher with respect to the REM time in zolpidem night. Moreover, dex drug reduces sleep latency but also sleep efficiency. Dex signatures are characterized by a marked sympathetic deactivation and by a sustained vagal activation evident in physiological dynamics, e.g, a lower heart and respiratory rate. Zolpidem tends to have an opposite effect compared to dex, indeed it tends to increase heart rate and sympathetic influence. Moreover, zolpidem increases breath variability and respiratory frequency, especially in NR2 - NR1 e REM stages. These effects are more marked in the second half of the night because of the slow oral release of the drug. Results emphasizes zolpidem ability to increase sleep efficiency, however from an autonomic point of view subjects appeared to be more stressed. However, most hypnotics inhibit neuronal activity throughout the brain by activating GABAA receptors (zolpidem), which is not a physiologically relevant mechanism of sleep promotion. Indeed, such an overpowering mechanism of sleep induction would be maladaptive.
La qualità del sonno di solito è caratterizzata da una serie di indici come il sonno totale, il tempo di veglia durante il sonno e l'efficienza del sonno. Il sonno influisce sul benessere fisico e mentale di una persona influenzando i processi di memorizzazione, apprendimento e concentrazione. Negli ultimi anni, la letteratura si è concentrata sulla valutazione dei parametri qualitativi del sonno tramite lo studio delle variabili fisiologiche. L'approccio tradizionale all'analisi richiede la registrazione di diversi segnali (polisonnografia, PSG), incluso l'elettroencefalogramma (EEG) che osserva l'attività cerebrale con elettrodi posti sul cuoio capelluto, l'elettrooculogramma (EOG) che misura il movimento oculare e l'elettromiogramma (EMG) che descrive le proprietà fisiologiche dei muscoli. Lo scopo di questa tesi è quello di calcolare le caratteristiche rilevanti per le fasi del sonno, REM e non-REM al fine di indagare gli effetti indotti da due diversi farmaci. I due farmaci considerati in questo studio sono: dexmedetomidina, un agonista alpha-2a adrenergico e zolpidem, un agonista del recettore GABA. Il lavoro è stato ispirato dalla ricerca condotta da Akeju at al. in cui gli effetti di dex e zolpidem sono stati investigati a livello elettroencefalografico. I segnali utilizzati nell'analisi sono stati raccolti presso il Massachusetts General Hospital di Boston, su 10 soggetti (5 maschi) di età compresa tra 21-29 anni. La qualità del sonno è stata valutata per mezzo di indici di sonno tradizionali, tra cui il tempo totale di sonno (TST), la latenza di inizio del sonno (SOL), il tempo di veglia totale durante il sonno, l'efficienza e il mantenimento del sonno. Inoltre, gli indici riguardanti variabilità cardiaca, respiro e aritmia sinusale respiratoria sono stati esaminati nel dominio del tempo e delle frequenze al fine di fornire informazioni sui cambiamenti dinamici del tono simpatico-vagale che si verificano durante la notte. In particolare, le variazioni delle componenti temporali e spettrali sono state investigate per identificare quelle che meglio identificano la transizione tra fasi di veglia, REM e non-REM quando vengono somministrati i farmaci. Questo obiettivo è stato perseguito applicando il modello del point process alla serie di intervalli R-R e all'RSA ed effettuando un'analisi univariata del respirogramma. L'algoritmo del point process è stato utilizzato per estrarre le caratteristiche rilevanti dalla variabilità cardiaca e dell'aritmia sinusale respiratoria durante la somministrazione dei farmaci. Tale algoritmo è stato selezionato per la sua capacità di rilevare significative variazioni delle dinamiche veloci; inoltre, esso consente la caratterizzazione del sonno con una maggiore risoluzione temporale rispetto al metodo tradizionale. Le caratteristiche dinamiche dell'HRV e RSA estratte dall'algoritmo del point process e le caratteristiche respiratorie calcolate mediante analisi AR univariata forniscono la base per l'analisi statistica. Le analisi sono state effettuate seguendo due metodi: il primo si è concentrato su una singola notte e ha analizzato la variazione delle caratteristiche tra i diversi stadi del sonno, e il secondo ha valutato un singolo stadio del sonno in diverse notti. Inoltre, l'analisi statistica è stata eseguita con riferimento alla durata complessiva della notte e dividendo ogni notte in due metà. I risultati sugli indici delle fasi del sonno confermano che dex e zolpidem hanno indotto un aumento del tempo trascorso negli stadi NR3 e NR2 e una diminuzione del tempo trascorso nella fase REM; inoltre, la diminuzione del tempo REM durante l'infusione di dex è più alta rispetto al tempo REM nella notte zolpidem. Infine il farmaco dex riduce la latenza del sonno ma anche l'efficienza del sonno. L'influenza di dex è evidenziata da una marcata disattivazione simpatica e da un'attivazione vagale sostenuta evidente nelle dinamiche fisiologiche, ad esempio una frequenza cardiaca e respiratoria inferiore. Zolpidem tende ad avere un effetto opposto rispetto a dex, tende infatti ad aumentare la frequenza cardiaca e l'influenza del sistema simpatico. Inoltre, lo zolpidem aumenta la variabilità del respiro e la frequenza respiratoria, specialmente negli stadi NR2 - NR1 e REM. Questi effetti sono più marcati nella seconda metà della notte a causa del lento rilascio orale del farmaco.
Multivariate analysis of physiological variables for the assessment of drug administration during sleep
d'AMICO, ESTER
2016/2017
Abstract
Sleep quality is usually characterized by a set of sleep indeces including total sleep and awake time and sleep efficiency. Sleep affects the physical and mental wellness of a person by influencing the processes of memorization, learning and concentration. In recent years, literature focused on the assessment of sleep quality parameters by investigating physiological variables. The traditional analysis approach requires the recording of several signals (polysomnography, PSG), including the electroencephalogram (EEG) that observes brain activity with electrodes placed on the scalp, the electroacoulogy (EOG) that measures the eyes movement and the electromyogram (EMG) that describes the physiological properties of muscles. The purpose of this thesis is to compute relevant features for waking, REM and non-REM sleep stages in order to investigate the effects induced by two different drugs. The two administrated drugs considered in the study are dexmedetomidine, an alpha-2a adrenergic agonist, and zolpidem, a GABA receptor agonist. The work was inspired by Akeju at al. research study, that analyzed the effects of dex and zolpidem at electroencephalographic level. The signals used in the analysis were collected at Massachusetts General Hospital in Boston, on 10 subjects (5 males) aged between 21-29 years. Sleep quality was assessed by means of traditional sleep indices including total sleep time (TST), sleep onset latency (SOL), total wake time, sleep efficiency, and sleep maintenance. Moreover, HRV, RSA and respiratory features were examined in time and frequency domains to provide further insights in sympatho-vagal tone dynamic changes occurring during the night. In particular, the variations of time and spectral components are investigated to identify those that best identify the transition between waking, REM and non-REM stages when drugs were administrated. This goal was pursued by applying a point process analysis to R-R interval series and RSA, and by an univariate analysis of respirogram. The point process algorithm was used to extract relevant features from HRV and RSA during the drugs administration, this algorithm was selected for its ability to detect significant fast dynamics changes; furthermore, it enhances sleep characterization at higher time resolution than traditional method. The approach is based on the heart probability model by defining a precise probabilistic prescription for conversion of the point-process R-R intervals to the continuous-valued function for heart rate parameters in continuous time. The dynamic HRV and RSA features extracted by the point process algorithm and respiratory features computed by univariate AR analysis provide the basis for the statistical analysis. Analyses were performed by following two methods: the first one focused on a single night and analyzed the features variation across different sleep stages, and the second one evaluated a single sleep stage across different nights. Moreover, the statistical analysis was performed with reference to the overall duration of the night and by splitting each night in two halves. Results on sleep stages indices confirm that dex and zolpidem induced an increase in the time spent in NR3 and NR2 stages and a decrease in the time spent in REM stage, moreover, the decrease in REM time during dex infusion is higher with respect to the REM time in zolpidem night. Moreover, dex drug reduces sleep latency but also sleep efficiency. Dex signatures are characterized by a marked sympathetic deactivation and by a sustained vagal activation evident in physiological dynamics, e.g, a lower heart and respiratory rate. Zolpidem tends to have an opposite effect compared to dex, indeed it tends to increase heart rate and sympathetic influence. Moreover, zolpidem increases breath variability and respiratory frequency, especially in NR2 - NR1 e REM stages. These effects are more marked in the second half of the night because of the slow oral release of the drug. Results emphasizes zolpidem ability to increase sleep efficiency, however from an autonomic point of view subjects appeared to be more stressed. However, most hypnotics inhibit neuronal activity throughout the brain by activating GABAA receptors (zolpidem), which is not a physiologically relevant mechanism of sleep promotion. Indeed, such an overpowering mechanism of sleep induction would be maladaptive.| File | Dimensione | Formato | |
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https://hdl.handle.net/10589/137881