Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA.

Predicting the functional recovery of patients with severe neurological condition due to coronavirus disease 2019 (COVID-19) is a challenging task. Only limited outcome data are available, the pathophysiology is poorly understood, and the time-course of recovery is still largely unknown. Here, we report the case of a patient with COVID-19 associated encephalitis presenting as a prolonged state of unresponsiveness for two months, who finally fully recovered consciousness, functional communication, and autonomy after immunotherapy. In a multimodal approach, a high-density resting state EEG revealed a rich brain activity in spite of a severe clinical presentation. Using our previously validated algorithms, we could predict a possible improvement of consciousness in this patient. This case report illustrates the value of a multimodal approach capitalizing on advanced brain-imaging and bedside electrophysiology techniques to improve prognosis accuracy in this complex and new aetiology.

Key points• The present study provides evidence that the cardiomyopathy observed in spinal muscular atrophy (SMA) model mice is mainly due to intrinsic cardiac alteration but not to autonomic impairment.• We demonstrated a non-pathological sympathetic activity on the heart of type 2 SMA-like mice, which likely counteracts the dramatic alteration of the cardiac function, such as arrhythmia and reduced heart rate.• We demonstrated for the first time that physical exercise partially restores cardiac conduction efficiency, prevents fibrosis, attenuates defects in protein expression, bradycardia and arrhythmias leading to the partial recovery of heart and respiratory rates in exercised SMA-like mice.• This study indicates a profound involvement of cellular, structural and vascular cardiac dysfunction in the pathogenesis of SMA, widely opening alternative pharmacological and non-pharmacological therapeutic strategies that would most certainly include physical exercise.Abstract Spinal muscular atrophy (SMA), the leading genetic cause of death in infants worldwide, is due to the misexpression of the survival of motor neuron protein, causing death of motor neurons. Several clinical symptoms suggested that, in addition to motor neurons, the autonomic nervous systems could be implicated in the cardiac function alterations observed in patienst with SMA. These alterations were also found in a severe SMA mouse model, including bradycardia and a reduction of sympathetic innervation, both associated with autonomic imbalance. In the present study, we investigate the extent of autonomic dysfunction and the effects of a running-based exercise on the altered cardiorespiratory function in type 2 SMA-like mice. We observed that the SMA induced: (1) a dramatic alteration of intrinsic cardiac conduction associated with bradycardia; (2) a severe cardiomyopathy associated with extensive ventricular fibrosis; and (3) a delay in cardiac muscle maturation associated with contractile protein expression defects. Furthermore, our data indicate that the sympathetic system is not only functioning, but also likely contributes to alleviate the bradycardia and the arrhythmia in SMA-like mice. Moreover, physical exercise provides many benefits, including the reduction of cardiac protein expression defect, the reduction of fibrosis, the increase in cardiac electrical conduction velocity, and the drastic reduction in bradycardia and arrhythmias resulting in the partial restoration of the cardiac function in these mice. Thus, modulating the cardiorespiratory function in SMA could O. Biondi and P. Lopes are joint first authors.

Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)—also coined unresponsive wakefulness syndrome (UWS)—and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15–20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

The clinical and fundamental exploration of patients suffering from disorders of consciousness (DoC) is commonly used by researchers both to test some of their key theoretical predictions and to serve as a unique source of empirical knowledge about possible dissociations between consciousness and cognitive and/or neural processes. For instance, the existence of states of vigilance free of any self-reportable subjective experience [e.g. “vegetative state (VS)” and “complex partial epileptic seizure”] originated from DoC and acted as a cornerstone for all theories by dissociating two concepts that were commonly equated and confused: vigilance and conscious state. In the present article, we first expose briefly the major achievements in the exploration and understanding of DoC. We then propose a synthetic taxonomy of DoC, and we finally highlight some current limits, caveats and questions that have to be addressed when using DoC to theorize consciousness. In particular, we show (i) that a purely behavioral approach of DoC is insufficient to characterize the conscious state of patients; (ii) that the comparison between patients in a minimally conscious state (MCS) and patients in a VS [also coined as unresponsive wakefulness syndrome (UWS)] does not correspond to a pure and minimal contrast between unconscious and conscious states and (iii) we emphasize, in the light of original resting-state positron emission tomography data, that behavioral MCS captures an important but misnamed clinical condition that rather corresponds to a cortically mediated state and that MCS does not necessarily imply the preservation of a conscious state.

This study aimed at probing covert language processing in patients with disorders of consciousness. An auditory paradigm contrasting words to pronounceable pseudowords was designed, while recording bedside electroencephalogram and computing the two main correlates of lexicality: N400 and late positive component (LPC). Healthy volunteers and 19 patients, 10 in a minimally conscious state and 9 in a vegetative state (also coined unresponsive wakefulness syndrome), were recorded. N400 was present in all groups, whereas LPC was only present in the healthy volunteers and minimally conscious state groups. At the individual level, an unprecedented detection rate of N400 and LPC was reached, and LPC predicted overt cognitive improvement at 6 months.

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