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Innovative research techniques applied to sleep: an insight into sleep patophysiology
No full textI sostanziali progressi tecnologici occorsi nell’arco dell’ultimo secolo, a partire dalla osservazione dell’attività elettrica cerebrale (EEG) da parte di Berger negli anni ‘20 del secolo scorso ai recenti studi di optogentica (Adamantidis et al., 2013), hanno fatto luce su parte della fisiologia del sonno, in maniera impensabile fino alla introduzione di queste metodiche. Il sonno quindi è passato dall’essere considerato uno stato di assoluta inerzia, paragonabile alla morte, ad uno stato di attività cerebrale proteiforme, passando da stadi di ipersincronizzazione a stadi di attività cerebrale simili alla veglia, mantenendo sempre un certo grado di reattività a stimoli esterni perturbanti (Terzano and Parrino, 2000). Il sonno, o la sua mancanza, sono inoltre a loro volta in grado di modulare funzioni cerebrale: è partica clinica comune la privazione di sonno come tecnica di facilitazione per la comparsa di anomalie epilettiche. Questi fenomeni sono stati studiati dal punto di vista patofisiologico con l’osservazione di un abbassamento della soglia di eccitabilità neuronale nell’animale deprivato di sonno (Cohen and Dement, 1965) ed una facilitazione al kindling (Shouse, 1988) possibilmente dovuto ad uno sbilanciamento tra neurotrasmettitori eccitatori ed inibitori (Naitoh and Dement, 1974).
Il limite di questo tipo di studi è però la loro invasività, così come lo era stato per gli studi pionieristici sulla fisiologia del sonno di Bremer (1935, 1936) e Moruzzi e Magoun (1949): la crescente consapevolezza delle problematiche etiche legate a questo tipo di esperimenti, unito alla loro non applicabilità sull’uomo, ha spinto verso la ricerca di nuove metodiche non invasive ed applicabili in vivo.
All’inizio degli anni ’80 è stata introdotta la risonanza magnetica cerebrale (RMN) che ha permesso, oltre alla più dettagliata definizione anatomica, lo studio di attivazione di aree cerebrali implicate in task specifici (risonanza magnetica cerebrale funzionale) grazie alla implementazione di specifiche sequenze che identificano la variazione di segnale determinata dalla quantità di desossiemoglobina che si forma in quella area cerebrale e che presenta proprietà paramagnetiche, rispetto ad una condizione di riposo. Si ottiene così il cosiddetto segnale BOLD (blood oxygenation level dependent), che permette di identificare le aree cerebrale a maggior consumo metabolico all’interno della finestra di tempo studiata, e che quindi sono correlabili al task eseguito. L’osservazione casuale di una attivazione BOLD task-indipendente ha portato alla formulazione del concetto di default mode network (DMN), una serie di aree cerebrali costanti inter-individuo che sembrano attivarsi una condizione di veglia rilassata (Raichle et al., 2001), e che, sorprendentemente, persistono sia pur modulate anche durante il sonno. I diversi network che sono presenti in questa condizione di riposo sono stati successivamente classificati grazie alla implementazione di modelli matematici di calcolo in grado di scomporre il segnale nelle sue costituenti: si è così arrivati alla definizione dei resting state networks (RSNs) (Rosazza and Minati, 2011), ognuno dei quali pare relato ad una specifica funzione fisiologica.
Un ulteriore sviluppo tecnologico, introdotto circa 15 anni fa, è stata l’entrata in commercio di sistemi EEG compatibili con campi magnetici, siano questi in RMN, permettendo così la registrazione della attività cerebrale all’interno dello scanner, che durante stimolazioni magnetiche. La stimolazione magnetica transcranica (TMS), sfruttando il principio della induzione elettromagnetica, è in grado di applicare uno stimolo elettrico agli strati superficiali della corteccia, ed elettrodi EEG compatibili (sistemi di co-registrazione EEG-TMS) permettono di studiare gli effetti diretti di uno stimolo TMS sulla attività cerebrale (Ilmoniemi et al., 1997) senza le possibili interferenze delle vie discendenti, che contribuiscono a costituire il potenziale evocato motorio (Groppa et al., 2012). La modulazione che la TMS induce a livello della corteccia cerebrale può essere anche valutata in base alla modificazione dei ritmi cerebrali (Thut and Miniussi, 2009), che reagiscono in maniera differente a seconda del paradigma somministrato (Manganotti and Del Felice, 2012) o delle frequenze cerebrali intrinseche o della frequenza di stimolo (Thut et al., 2012).
Infine, nell’ultimo decennio sono state realizzati e commercializzati sistemi EEG ad alta densità di elettrodi (256). Questa elevata risoluzione spaziale ha riportato in auge un modello di analisi matematica, la cosiddetta ricostruzione inversa della sorgente, tramite la quale si cerca di ricostruire il generatore profondo dell’attività elettrica registrata sullo scalpo (Fender, 1987; Brunet et al., 2011). Questa metodica, denominata electrical source imaging (ESI), sfruttando l’elevata risoluzione della cuffia a 256 canali e la possibilità di proiettare il dato sulla RMN del paziente, è quindi stata applicata all’identificazione della sorgente di grafoelementi epilettici (Scherg and Von Cramon, 1985, Liu et al., 1998, Babiloni et al., 2003, Michel et al., 2004), mentre sono ancora scarsi in letteratura dati sul sonno (Siniatchkin et al., 2010).
Lo scopo di questa tesi è la discussione delle possibili applicazioni di queste tecnologie allo studio di quesiti ancora aperti nella fisiologia e patofisiologia del sonno. Un primo approccio è stato lo studio della modulazione della reattività corticale in soggetti sani e pazienti epilettici in sonno e privazione di sonno con co-registrazioni EEG-TMS, valutando sia le componenti evocate lente che le variazione dei ritmi indotte dallo stimolo. Un secondo set di esperimenti ha indagato tramite risonanza magnetica funzionale le attivazioni cerebrali in sonno durante una stimolazione elettrica. Infine le potenzialità dell’electrical source imaging sono state applicate per chiarire quale sia il numero e la localizzazione dei generatori corticali dei fusi del sonno in volontari sani ed in pazienti epilettici, e la correlazione delle sorgenti delle figure del sonno con il focus epilettogeno in questa ultima popolazione.
I diversi aspetti neurofisiologici che queste tecniche indagano offrono una prospettiva sfaccettata dei fenomeni del sonno. La traslazione di questi paradigmi di studio a stati di ridotta coscienza dovrebbe essere una delle future prospettive di ricerca.As has been stated, we have gained more knowledge on sleep physiology in the last 60 years than in the previous 6000 (Hobson, 1989). This holds true thanks to the massive advances technologies have provided in the past century, ranging from the introduction of electroencephalogram (EEG) in the twenties of the last century by Berger to the latest optogenetic approaches (Adamantidis et al., 2013). The major change put forward by this more detailed understanding of sleep function and functioning has been the transition of sleep as a state of absolute inertia, paralleled to death by almost all the ancient literature, to a reactive state of the brain: during sleep, cerebral activity presents its most diverse expressions, from the bold slow waves sleep of the deep stages to the wake like activity of REM associated with muscular atonia, and is able to differently react to external perturbations with rapid frequency shifts (Terzano and Parrino, 2000). Moreover, the modulations that sleep and sleep deprivation exert have been postulated deriving both from plain clinical observations, i.e. in epilepsy, and from animal studies. Sleep deprivation is the best method for provoking EEG epileptiform abnormalities and seizures (Bennett, 1963; Pratt et al., 1968; Jovanovic, 1991; King et al., 1998) in most types of epilepsy (Dinner, 2002), and many epileptic syndromes, such as the generalized idiopathic epilepsies (IGE), are prone to circadian fluctuations related to the sleep-wake cycle - with seizures gathering mostly early in the morning or at awakening (Niedermeyer et al., 1985). The mechanisms underlying the activation of paroxysmal activity remain to be elucidated. The activation of epileptic patterns has been attributed to drowsiness and sleep (Pratt et al., 1968), while sleep deprivation has been shown to have a specific activating effect on patients who remain awake during recording (Naitoh and Dement, 1974). In animals, sleep deprivation results in a lowering of the threshold for electroshock convulsions (Cohen and Dement, 1965) and kindling (Shouse, 1988) due to a shift in the balance between excitatory and inhibitory neurotransmitters (Naitoh and Dement, 1974). But while animal studies deploy invasive techniques, as did the pioneer physiology studies by (Bremer 1935 and 1936; Moruzzi and Magoun, 1949) that allowed the definition of cerebral and truncal structures involved in sleep building-up and maintenance and their neurotransmitters, growing concerns about in vivo animal studies have pushed towards other research methods, that moreover could be applied to the human being too. Indeed, one of the major limitations in the field of sleep research up to the last decades was determined by the only available technique applicable in humans - electroencephalogram.
Since the eighties of the last century, a series of technological advances introduced in clinical practice Magnetic Resonance Imaging (MRI). MRI permits not only a more detailed visualization of brain structures than those of previous neuroimaging, such as computed tomography (CT) scanning, but also, due to the implementation of new acquisition sequences and analysis procedures, the identification of blood oxygenation level dependent (BOLD) activations. The latter consists of a cerebral area in which any sort of metabolic process is going on, in a frame time of a few seconds, and is generally related to areas active due to a given task. The serendipitous observation that persistent BOLD activated areas are present also in the idling brain led to the proposal of the concept of a default mode network (DMN), that is, a series of possibly interconnected cerebral regions that switch on in the very moment any brain engagement is supposed to switch off (Raichle et al., 2001). The persistence of an analogous pattern also during sleep led to the hypothesis of this network to be the neural substrate of mentation and perhaps consciousness. Further improvements in the mathematical models that support BOLD signal analysis were subsequently able to disentangle the various components of the this “resting brain activity”, generating an array of so called resting state networks (RSNs) (Rosazza and Minati, 2011) that encompass diverse physiological functions.
A step further was possible with the introduction, almost 15 years ago, of MRI compatible EEG equipment that prevents the generation of oddy currents inside the electrode: the concomitant EEG registration with an MRI scan permits to relate a particular EEG activity with the underlying BOLD signal. The same magnetic field shielded electrodes were later on exploited in the contest of electro-magnetic fields generated through wires rolled into a coil, that were presented by Baker in 1985 as transcranial magnetic stimulation (TMS). TMS final effect is that of electrically stimulating the superficial layers of the cortex, and EEG-TMS co-registration offered the chance to investigate the direct effect of a pulse on the cortex (Ilmoniemi et al., 1997) by removing possible interferences from the descending motor pathways, that were intermixed in the standard parameter by which TMS alone is evaluated - the motor evoked potential (MEP) recorded from a muscle corresponded to the cortical activated area (Groppa et al., 2012). The perturbation TMS induces on the cerebral activity can also be studied as the modulation of EEG rhythms (Thut and Miniussi, 2009), that react differently depending on the stimulating paradigm (Manganotti and Del Felice, 2012) or on the intrinsic brain rhythm or stimulus frequency (Thut et al., 2012).
The last technological innovation I am going to describe has been developed over the last decade: the introduction of high-density scalp EEGs (hdEEG), with up to 256 electrodes spread out over the scalp, the occiput and the cheeks of the subject, that offers a much higher spatial resolution than standard EEG caps. This high spatial resolution sampling has revived an older analysis method aimed at identifying via a mathematical approach called the inverse solution method the number, location and orientation of deep generators of scalp activity, the so called electrical source imaging (ESI) (Fender, 1987; Brunet et al., 2011). ESI involves numerous scalp electrodes, HdEEG , and realistic head models derived from structural MRI, and has so far mainly been applied to epileptic discharges (Scherg and Von Cramon, 1985, Liu et al., 1998, Babiloni et al., 2003, Michel et al., 2004), with only few reports in sleep (Siniatchkin et al., 2010).
The aim of this dissertation thesis is to discuss the application of these technologies to the clarification of open issues in sleep physiology and pathophysiology. A first approach was to study the effects of sleep deprivation on cortical excitability through EEG-TMS co-registration experiments, both in healthy controls and in the frame of pathologically abnormal cortical excitability (i.e. epilepsy). A second set of experiments focused on fMRI data of subjects sleeping in the bore of the scanner during a concomitant external perturbation – an electrical stimulation at the wrist in the specific case. Finally, the potentiality of ESI has been applied to physiological sleep figures, in order to contribute to the open issue of their generators’ nature. A similar study design was also used in a population of focal epileptic patients, given the still actual debate over the relation of sleep figures and epileptic spikes.
These techniques encompass different neurophysiological aspects providing a multiprospective view of sleep phenomena. The translation of such an approach to other states of reduced consciousness (i.e. vegetative or minimally conscious states) should be one of the future directions of research
Sleep homeostatic and ultradian adjustments in SAS patients after prolonged CPAP treatment
No full textOBJECTIVE: To evaluate the immediate and long-term recovery processes of sleep and daytime vigilance in patients with sleep apnea syndrome (OSAS) after continuous CPAP treatment. METHODS: Five consecutive polysomnographic (PSG) studies were carried out on 10 male patients with severe OSAS. The first recording (baseline) was accomplished without ventilatory support (N0). The other 4 recordings were carried out during the CPAP titration night (N1), during the second night of treatment (N2), during the third night of treatment (N3), and after 30 days of regular CPAP use (N30). Ten age-balanced healthy male subjects were selected from the Parma Sleep Center database as controls. Respiratory variables, conventional PSG variables, arousals, CAP (cyclic alternating pattern) variables, and daytime function (including MSLT) were quantified. ANOVA followed by post-hoc tests explored the differences between controls and OSAS patients in the different recording conditions (N0, N1, N2, N3, N30). The PSG measures that showed significant ANOVA values were correlated with the MSLT scores. RESULTS: Values of control subjects were recovered by REM sleep, REM latency, subtypes A3 and arousal index during N1, by CAP rate and total arousals during N2, by deep sleep (stages 3 + 4) during N3, by light sleep (stages 1 + 2) during N30. The only measures which remained below control values even after 1 month of sustained treatment were the amount of CAP cycles and A1 subtypes. MSLT scores correlated significantly with CAP rate, deep sleep and arousals. CONCLUSIONS: The changes induced by CPAP treatment do not restore immediately a normal sleep structure, which is re-established with different time scales SIGNIFICANCE: The modifications of sleep patterns and the different adjustments of phase A subtypes allow us to monitor the reorganization of sleep in OSAS patients treated with CPAP and the hierarchy of the mechanisms involved in sleep regulatio
Disentangling Cerebellar and Parietal Contributions to Gait and Body Schema: A Repetitive Transcranial Magnetic Stimulation Study
Full text linkThe overlap between motor and cognitive signs resulting from posterior parietal cortex (PPC) and cerebellar lesions can mask their relative contribution in the sensorimotor integration process. This study aimed to identify distinguishing motor and cognitive features to disentangle PPC and cerebellar involvement in two sensorimotor-related functions: gait and body schema representation. Thirty healthy volunteers were enrolled and randomly assigned to PPC or cerebellar stimulation. Sham stimulation and 1 Hz-repetitive-Transcranial-Magnetic-Stimulation were delivered over P3 or cerebellum before a balance and a walking distance estimation task. Each trial was repeated with eyes open (EO) and closed (EC). Eight inertial measurement units recorded spatiotemporal and kinematic variables of gait. Instability increased in both groups after real stimulation: PPC inhibition resulted in increased instability in EC conditions, as evidenced by increased ellipse area and range of movement in medio-lateral and anterior–posterior (ROMap) directions. Cerebellar inhibition affected both EC (increased ROMap) and EO stability (greater displacement of the center of mass). Inhibitory stimulation (EC vs. EO) affected also gait spatiotemporal variability, with a high variability of ankle and knee angles plus different patterns in the two groups (cerebellar vs parietal). Lastly, PPC group overestimates distances after real stimulation (EC condition) compared to the cerebellar group. Stability, gait variability, and distance estimation parameters may be useful clinical parameters to disentangle cerebellar and PPC sensorimotor integration deficits. Clinical differential diagnosis efficiency can benefit from this methodological approach
Ultrasound follow-up study in two cases of inflammatory demyelinating sensory-motor neuropathy
No full textBackground: Ultrasound imaging is an emerging method for visualizing peripheral nerve pathology, since it is painless, non invasive and inexpensive (Martinoli et al, 2004; Padua et al, 2007). First focused on nerve entrapment pathology (Beekman and Vissler, 2003), its applications have widened to chronic inflammatory demyelinating neuropathies (CIDP), Charcot-Marie-Tooth and multifocal neuropathies, demonstrating focal enlargements. To our knowledge, only a few ultrasound studies focused on immune mediated neuropathies with repeated measures (Zaidman et al., 2009). Here, we report two cases of demyelinating sensory-motor neuropathy and their follow up at 6 months with electroneurographic and ultrasound studies.
Methods and results: The first patient (female, age 77) (see Figure 1 and 2) presented to the outpatients EMG clinic due to lower limbs tingling and marked hypostenia that prevented her from autonomous walking, that spread also to the upper arms, and began 10 days before the neurophysiological examination. ENG showed clear-cut conduction blocks (Hadden et al., 1998) at multiple sites, with distal latencies (DLs) lengthening, and proximal nerve (F waves) and nerve conduction velocities (NCVs) involvement. Marked amplitude reductions were also observed. No sensory potential was detected either at upper and lower limbs. Ultrasound at the site of a block showed only a minor nerve enlargement (peroneal nerve) in comparison to normative values as measured by nerve cross-sectional area (NCSA) (see Table 1). She was treated with a course of IvIG and tapered on steroid. At follow up, 6 months later, she was able to stand and walk alone; amplitude and NVCs reductions persisted although with slight improvements towards the lower limit values. Late responses and SAPs reappeared. Ultrasound reveled persistence of nerve hypoechoic enlargements at the site of previous blocks, with a tendency toward NCSA reduction.
The second patient (female, age 77) (see Figure 3 and 4) was admitted for progressive distal lower limbs hypostenia and tingling. ENG showed clear-cut conduction blocks at the lower segments and right median nerve, with amplitude reductions, VdCs slowing and distal latency increase in the other sites. SAPs were unobtainable. Ultrasound visualized increased NCSAs at the site of the block and at the site were temporal dispersion was identified by ENG. She was treated with IvIG. At follow up, she had clinically improved. At ENG, potentials amplitudes increased, although they remained under the lower normal value, with only a slight recovery of DLs and VdCs (see Figure 3), and SAP reappeared. Ultrasound study visualized multiple areas of enlargement at the site of previous block and temporal dispersions; comparison with previous examination available values pointed to a trend toward further enlargement (tibial) and only minor reductions of NCSA otherwise (p= 0.82) (Table 2).
Conclusion: We demonstrated the presence at ultrasound imaging in the early phases of demyelinating sensory-motor neuropathy of focal nerve enlargements at the site of block. At follow up, although the number of sites compared was limited, we were not able to determine a clear NCSAs reduction at such site in one patient despite the slight clinical improvement, posing further questions on the pathophysiology of this neuropathy and the correlation of ultrasounds parameters with ENG ones
Intra-articular botulinum toxin injection in complex regional pain syndrome: Case report and review of the literature
No full textComplex regional pain syndrome (CRPS) is characterized by hyperalgesia, autonomic and trophic alterations of bones, muscles and skin. It is supported by neurogenic inflammation and impairment of sympathetic nervous system. Botulinum Toxin (BTX) is an option for the management of pain, with level B evidence of efficacy in neuropathic, joint and myofascial pain syndrome. We report a case of CRPS treated with intra articular injection of BTX-A (IaBI). BTX-A 100 U in 2 cc Na Cl 0,9% was injected into the gleno-humeral joint. Visual analogue scale (VAS) pain score and McGill Pain Questionnaire (MPQ) were administered at T0 (baseline), T1 (one month after IaBI) and T2 (four months after IaBI). Autonomic and trophic skin disorders were clinically monitored. Pain decreased at T1, with a lasting effect at T2, associated with improvement of range of motion (ROM). No improvement in terms of autonomic and trophic skin disorders were reported neither at T1 nor T2. These findings support a possible antinociceptive role of BTX-A in the management of CRPS pain related to inhibition of pain neurotransmitters release. A literature revision of IaBI is provided
TMS-evoked N100 responses as a prognostic factor in acute stroke
Full text linkRehabilitation programs, to be efficiently tailored, need clear prognostic markers. In acute stroke, neurophysiological measures, such as motor evoked potentials (MEPs), have been proposed, although with discordant results. The aim of this study was to identify a reliable neurophysiological measure of recovery in acute poststroke individuals by combining MEPs and the N100 component of transcranial magnetic stimulationevoked potentials (TEPs). Nine acute post-stroke subjects were included. Clinical evaluation performed in the first week after the event included administration of the European Stroke Scale and Barthel Index and recording of MEPs and TEPs; administration of the clinical scales was repeated after one and three months. The presence/absence of MEPs and TEPs showed correlations with motor outcome. Individuals with a poorer outcome showed absence of both MEPs and TEPs; absence of MEPs alone was related to a partial recovery. Given the results of this exploratory study, further investigation is needed to define the accuracy of combined use of MEPs and TEPs as an approach for predicting motor recovery after acute stroke
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