Lactate levels affect motor performance in MD 1

Myotonic Dystrophy type 1 (DM1) is a dominantly inherited disease comprehending multiple features. Fatigue and exhaustion during exercise often represent significant factors able to negatively influence their compliance to rehabilitation programs. Mitochondrial abnormalities and a significant increase in oxidative markers, previously reported, suggest the hypothesis of a mitochondrial functional impairment. The study aims at evaluating oxidative metabolism efficiency in 18 DM1 patients and in 15 healthy subjects, through analysis of lactate levels at rest and after an incremental exercise test. The exercise protocol consisted of a submaximal incremental exercise performed on an electronically calibrated treadmill, maintained in predominantly aerobic condition. Lactate levels were assessed at rest and at 5, 10 and 30 minutes after the end of the exercise. The results showed early exercise-related fatigue in DM1 patients, as they performed a mean number of 9 steps, while controls completed the whole exercise. Moreover, while resting values of lactate were comparable between the patients and the control group (p=0.69), after the exercise protocol, dystrophic subjects reached higher values of lactate, at any recovery time (p<0,05). These observations suggest an early activation of anaerobic metabolism, thus evidencing an alteration in oxidative metabolism of such dystrophic patients. As far as intense aerobic training could be performed in DM1 patients, in order to improve maximal muscle oxidative capacity and blood lactate removal ability, then, this safe and validate method could be used to evaluate muscle oxidative metabolism and provide an efficient help on rehabilitation programs to be prescribed in such patients

Muscle function impairment in cancer patients in pre-cachexia stage

Cancer cachexia has been reported to be directly responsible for at least 20% of cancer deaths. Management of muscle wasting in cancer-associated cachexia appears to be of pivotal importance for survival of patients. In this regard, it would be interesting to identify before its patent appearance eventual functional markers of muscle damage, to plan specific exercise protocols to counteract cachexia. The muscle function of 13 oncologic patients and 15 controls was analyzed through: i) analysis of the oxidative metabolism, indirectly evaluated trough dosage of blood lactate levels before and after a submaximal incremental exercise on a treadmill; ii) analysis of strength and, iii) endurance, in both lower and upper limbs muscles, employing an isokinetic dynamometer. Statistical analyses were carried out to compare the muscle activities between groups. Analysis of oxidative metabolism during the incremental exercise on a treadmill showed that patients performed a shorter exercise than controls. Lactate levels were significantly higher in patients both at baseline and after the task. Muscle strength analysis in patients group showed a reduction of Maximum Voluntary Contraction during the isometric contraction and, a tendency to fatigue during endurance task. Data emerging from this study highlight an impairment of muscle oxidative metabolism in subjects affected by a pre-cachexia stage of cancer. A trend of precocious fatigability and an impairment of muscle strength production were also observed. This evidence underlines the relevance of assessing muscle function in order to develop novel rehabilitative approaches able to counteract motor impairment and eventually to prevent cachexia in these patients

Neurophysiological underpinnings of an intensive protocol for upper limb motor recovery in subacute and chronic stroke patients

Background: Upper limb (UL) motor impairment following stroke is a leading cause of functional limitations in activities of daily living. Robot-assisted therapy supports rehabilitation, but how its efficacy and the underlying neural mechanisms depend on the time after stroke is yet to be assessed. Aim: We investigated the response to an intensive protocol of robot-assisted rehabilitation in sub-acute and chronic stroke patients, by analyzing the underlying changes in clinical scores, electroencephalography (EEG) and end-effector kinematics. We aimed at identifying neural correlates of the participants' upper limb motor function recovery, following an intensive 2-week rehabilitation protocol. Design: Prospective cohort study. Setting: Inpatients and outpatients from the Neurorehabilitation Unit of Pisa University Hospital, Italy. Population: Sub-acute and chronic stroke survivors. Methods: Thirty-one stroke survivors (14 sub-acute, 17 chronic) with mild-to-moderate UL paresis were enrolled. All participants underwent ten rehabilitative sessions of task-oriented exercises with a planar end-effector robotic device. All patients were evaluated with the Fugl-Meyer Assessment Scale and the Wolf Motor Function Test, at recruitment (T0), end-of-treatment (T1), and one-month follow-up (T2). Along with clinical scales, kinematic parameters and quantitative EEG were collected for each patient. Kinematics metrics were related to velocity, acceleration and smoothness of the movement. Relative power in four frequency bands was extracted from the EEG signals. The evolution over time of kinematic and EEG features was analyzed, in correlation with motor recovery. Results: Both groups displayed significant gains in motility after treatment. Sub-acute patients displayed more pronounced clinical improvements, significant changes in kinematic parameters, and a larger increase in Beta-band in the motor area of the affected hemisphere. In both groups these improvements were associated to a decrease in the Delta-band of both hemispheres. Improvements were retained at T2. Conclusions: The intensive two-week rehabilitation protocol was effective in both chronic and sub-acute patients, and improvements in the two groups shared similar dynamics. However, stronger cortical and behavioral changes were observed in sub-acute patients suggesting different reorganizational patterns. Clinical rehabilitation impact: This study paves the way to personalized approaches to UL motor rehabilitation after stroke, as highlighted by different neurophysiological modifications following recovery in subacute and chronic stroke patients

Clinical efficacy of botulinum toxin type A in patients with traumatic brain injury, spinal cord injury, or multiple sclerosis: An observational longitudinal study

Botulinum toxin type A (BoNT-A) is the treatment of choice for focal spasticity, with a concomitant effect on pain reduction and improvement of quality of life (QoL). Current evidence of its efficacy is based mainly on post stroke spasticity. This study aims to clarify the role of BoNT-A in the context of non-stroke spasticity (NSS). We enrolled 86 patients affected by multiple sclerosis, spinal cord injury, and traumatic brain injury with clinical indication to perform BoNT-A treatment. Subjects were evaluated before injection and after 1, 3, and 6 months. At every visit, spasticity severity using the modified Ashworth scale, pain using the numeric rating scale, QoL using the Euro Qol Group EQ-5D-5L, and the perceived treatment effect using the Global Assessment of Efficacy scale were recorded. In our population BoNT-A demonstrated to have a significant effect in improving all the outcome variables, with different effect persistence over time in relation to the diagnosis and the number of treated sites. Our results support BoNT-A as a modifier of the disability condition and suggest its implementation in the treatment of NSS, delivering a possible starting point to generate diagnosis-specific follow-up programs.Clinical trial identifierNCT04673240

Studio della rigenerazione del Sistema Nervoso Centrale dopo ictus ischemico: strategie riabilitative a confronto in modelli sperimentali.

Nei pazienti con lesioni del Sistema Nervoso Centrale (SNC) i fenomeni di neuroplasticità rappresentano i meccanismi alla base del recupero spontaneo. La sfida delle neuroscienze consiste nel comprendere pienamente questi processi di riorganizzazione funzionale con lo scopo di individuare modi e mezzi per ”evocarla, guidarla e ottimizzarla”, in maniera da promuovere approcci riabilitativi sempre più personalizzati e specifici. Il lavoro presentato in questa tesi è la prima parte di un progetto di ricerca che ha come scopo principale quello di valutare gli effetti di un intervento riabilitativo combinato con l’impianto di cellule staminali, in un modello sperimentale di ictus cerebrale. L’ipotesi chiave che sta dietro questa ricerca è che, il trattamento riabilitativo motorio sia in grado di modificare alcuni parametri biochimici che possono avere un ruolo nella proliferazione e differenziamento di neuroblasti impiantati, e che sia in grado quindi di modificare positivamente l’outcome funzionale in un modello sperimentale di ictus. In particolare abbiamo voluto identificare il tipo di trattamento riabilitativo più appropriato da somministrare, in modo da definire le variabili implicate, e ottimizzare al meglio gli eventuali effetti della riabilitazione sull’impianto di cellule staminali. La prima fase di questo studio è stata svolta su una popolazione di ratti sani sottoposti a due differenti protocolli riabilitativi, ovvero Treadmill ed Elettrostimolazione muscolare localizzata (E-stim), al fine di valutare gli effetti dei due diversi approcci su parametri biochimici e funzionali. Entrambi i trattamenti sono stati somministrati ad intensità diverse su popolazioni diverse di animali. Nella seconda fase dello studio sono stati utilizzati ratti sottoposti ad intervento di Occlusione dell’Arteria Cerebrale Media (MCAO). Questa popolazione è stata poi successivamente divisa in maniera random in due gruppi, di cui uno è stato sottoposto ad intervento riabilitativo e l’altro ha rappresentato la popolazione di controllo. I risultati hanno evidenziato delle differenze statisticamente significative per quel che riguarda la popolazione sottoposta al trattamento su treadmill, per tutte le intensità selezionate, confrontate con la popolazione di controllo. In particolare le due popolazioni sottoposte a trattamento su treadmill a media ed alta intensità hanno mostrato valori di velocità significativamente maggiori anche rispetto al trattamento su treadmill a bassa intensità, risultando pertanto i due trattamenti in cui la funzione muscolare raggiungeva le performances migliori. Nessuna differenza è risultata dal confronto tra il trattamento su treadmill a media e ad alta intensità. Inoltre, è stato osservato un trend in aumento della forza muscolare al termine delle 4 settimane di trattamento nel gruppo sottoposto ad E-Stim a varie intensità, popolazione in cui il suddetto arto veniva stimolato. Tali differenze non sono però risultate statisticamente significative, per cui abbiamo considerato questi trattamenti non impattanti per quel che riguarda la forza muscolare distrettuale. È stato inoltre ipotizzato che questo parametro non sia affidabile per una corretta valutazione del follow-up funzionale. Un significativo aumento dei livelli sierici di BDNF è stato riscontrato solamente negli animali sottoposti a training su treadmill. Per quanto riguarda la seconda parte dello studio, eseguita sul modello di stroke, nessuna differenza è risultata statisticamente significativa nel confronto tra il gruppo trattato su treadmill (approccio riabilitativo risultato più impattante) e quello di controllo. Questo ha suggerito che il trattamento riabilitativo somministrato non ha avuto, almeno nella fase in cui sono state effettuate le valutazioni, nessun impatto nel miglioramento dell’outcome funzionale, rispetto al recupero spontaneo osservato nella popolazione di controllo. In conclusione, i risultati della prima fase di questo studio estensivo sull’efficacia del trattamento cellulare combinato con la riabilitazione, hanno permesso di identificare meglio una strategia riabilitativa specifica, adeguata in termini di modalità, timing, intensità e durata, potenzialmente capace di modulare in senso positivo la plasticità cerebrale. Questi risultati incoraggiano l’approccio scientifico verso i meccanismi molecolari di plasticità cerebrale, che necessitano un approfondimento nell’ambito della ricerca di base e della ricerca clinica al fine di sviluppare tecniche e strategie capaci di potenziare i fenomeni plastici nell’organismo adulto

Brain and Muscle: How Central Nervous System Disorders Can Modify the Skeletal Muscle

It is widely known that nervous and muscular systems work together and that they are strictly dependent in their structure and functions. Consequently, muscles undergo macro and microscopic changes with subsequent alterations after a central nervous system (CNS) disease. Despite this, only a few researchers have addressed the problem of skeletal muscle abnormalities following CNS diseases. The purpose of this review is to summarize the current knowledge on the potential mechanisms responsible for changes in skeletal muscle of patients suffering from some of the most common CSN disorders (Stroke, Multiple Sclerosis, Parkinson’s disease). With this purpose, we analyzed the studies published in the last decade. The published studies show an extreme heterogeneity of the assessment modality and examined population. Furthermore, it is evident that thanks to different evaluation methodologies, it is now possible to implement knowledge on muscle morphology, for a long time limited by the requirement of muscle biopsies. This could be the first step to amplify studies aimed to analyze muscle characteristics in CNS disease and developing rehabilitation protocols to prevent and treat the muscle, often neglected in CNS disease

Le modificazioni del trofismo muscolare in un modello animale knockout per l'aptoglobina

In questo studio sono state valutate le modificazioni del trofismo muscolare in un modello animale knockout (KO) per l’aptoglobina in condizioni di dieta libera (CF) e di dieta ipercalorica (HFD). Il mantenimento del trofismo muscolare dipende dal bilancio di processi anabolici e catabolici che determinano il livello delle proteine muscolari. Tutte le condizioni di atrofia condividono uno stato di disequilibrio di questo sistema, nel senso di una diminuita sintesi e di una aumentata ripartizione proteica o proteolisi. In queste condizioni la perdita di massa muscolare comporta uno schema comune di modifiche trascrizionali, con l'induzione di alcuni geni per la degradazione proteica e una downregolazione di altri geni per i processi correlati alla crescita e al rendimento energetico. Recentemente è stato stabilito il marcato e rapido aumento d'espressione di un set comune di geni, definiti come "atrogeni", in condizioni predisponenti all’atrofia muscolare. Due in particolare, atrogin-1/MAFbx e MuRF1, sono risultati drasticamente upregolati ancora prima della comparsa dei sintomi della perdita muscolare in più modelli sperimentali. Diversi sono i fattori che modulano l’espressione di questi atrogeni, e tra questi anche diverse citochine e molecole infiammatorie. Nell’obesità viene descritta una condizione di ipotrofia muscolare in larga parte dovuta allo stato di insulino-resistenza che frequentemente si instaura in questa condizione. D’altra parte l’obesità si accompagna ad uno stato infiammatorio cronico con conseguente aumento di citochine e molecole infiammatorie sia a livello tissutale che sistemico. Questo potrebbe contribuire al grado di ipotrofia descritto in questa condizione. Recentemente è stata descritta negli stati di obesità una aumentata concentrazione sierica di aptoglobina, che è una proteina di fase acuta con capacità chemiotattiche e pro-infiammatorie. Abbiamo quindi indagato le modificazioni del trofismo muscolare nell'animale obeso, e le eventuali modificazioni prodotte dalla mancata espressione di aptoglobina. I risultati ottenuti hanno mostrato ipotrofia muscolare negli animali HFD sia Wild Type che KO. Inoltre in questi ultimi l'ipotrofia risultava significativamente maggiore. I dati evidenziati in questo lavoro escludono la capacità protettiva della mancanza di aptoglobina sull'ipotrofia muscolare in condizioni di obesità. Inoltre sembra esistere un meccanismo di sinergia tra obesità e deficit di aptoglobina nell'attivazione di programmi di induzione degli atrogeni

Brain and Muscle: How Central Nervous System Disorders Can Modify the Skeletal Muscle

It is widely known that nervous and muscular systems work together and that they are strictly dependent in their structure and functions. Consequently, muscles undergo macro and microscopic changes with subsequent alterations after a central nervous system (CNS) disease. Despite this, only a few researchers have addressed the problem of skeletal muscle abnormalities following CNS diseases. The purpose of this review is to summarize the current knowledge on the potential mechanisms responsible for changes in skeletal muscle of patients suffering from some of the most common CSN disorders (Stroke, Multiple Sclerosis, Parkinson's disease). With this purpose, we analyzed the studies published in the last decade. The published studies show an extreme heterogeneity of the assessment modality and examined population. Furthermore, it is evident that thanks to different evaluation methodologies, it is now possible to implement knowledge on muscle morphology, for a long time limited by the requirement of muscle biopsies. This could be the first step to amplify studies aimed to analyze muscle characteristics in CNS disease and developing rehabilitation protocols to prevent and treat the muscle, often neglected in CNS disease

Chronic muscle stimulation improves muscle function and reverts the abnormal surface EMG pattern in Myotonic Dystrophy: a pilot study

To date, in Myotonic Dystrophy type 1 (DM1) the rehabilitative interventions have always been aimed at muscle strengthening, increasing of fatigue resistance and improving of aerobic metabolism efficiency whereas the electrical membrane fault has always been addressed pharmacologically. Neuromuscular electrical stimulation (NMES) is a useful therapeutic tool in sport medicine and in the rehabilitation of many clinical conditions characterized by motor impairment such as stroke, cerebral palsy and spinal cord injury. METHODS: Five DM1 patients and one patient with Congenital Myotonia (CM) performed a home electrical stimulation of the tibialis anterior muscle lasting 15 days with a frequency of two daily sessions of 60 minutes each. Muscle strength was assessed according to the MRC scale (Medical Research Council) and functional tests (10 Meter Walking Test, 6 Minutes Walking Test and Timed Up and Go Test) were performed. We analyzed the average rectified value of sEMG signal amplitude (ARV) to characterize the sarcolemmal excitability. RESULTS: After the treatment an increase of muscle strength in those DM1 patients with a mild strength deficit was observed. In all subjects an improvement of 10MWT was recorded. Five patients improved their performance in the 6MWT. In TUG test 4 out of 6 patients showed a slight reduction in execution time. All patients reported a subjective improvement when walking. A complete recovery of the normal increasing ARV curve was observed in 4 out of 5 DM1 patients; the CM patient didn't show modification of the ARV pattern. CONCLUSIONS: NMES determined a clear-cut improvement of both the muscular weakness and the sarcolemmal excitability alteration in our small group of DM1 patients. Therefore this rehabilitative approach, if confirmed by further extensive studies, could be considered early in the management of muscular impairment in these patients. An attractive hypothesis to explain our encouraging result could be represented by a functional inhibition of SK3 channels expressed in muscle of DM1 subjects