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Introduction: The Coma Recovery Scale-Revised (CRS-R) is the recommended tool to assess consciousness in patients with prolonged Disorders of Consciousness (pDoC). However, the time needed to administer it may limit its use. A shorter tool has been validated: the Simplified Evaluation of CONsciousness Disorders (SECONDs). This multicentre study aimed to develop and validate a cross-cultural adaptation of the SECONDs into Italian. Methods: An interdisciplinary expert team, from both Fondazione Don Carlo Gnocchi and Istituto Neurologico Carlo Besta, led the translation processes. Independent certified translators were also involved in a blinded modality. Patients diagnosed with Unresponsive Wakefulness Syndrome (UWS) or Minimally Conscious State (MCS) admitted to 3 Italian rehabilitation units were enrolled. The CRS-R and SECONDs were administered in 5 sessions over two weeks by 3 blinded examiners at each center (3 times, with 2 sessions conducted by the same examiner). Weighted Fleiss' kappa and Spearman correlation coefficients were used to assess intrarater and interrater reliability and concurrent validity. Results: Sixty adults with pDoC were assessed: 23 women; median age: 64 years; 14 trauma, median post-onset time: 2 months. Intrarater and interrater reliability showed almost perfect agreement (kappa coefficients 0.968 and 0.935, respectively; p<0.001). The comparison of CRS-R vs. SECONDs on the same day or the best out of 5 SECONDs/CRS-R led to a substantial to almost perfect agreement both for the total score of the CRS-R and the SECONDs' Additional Index (ρ = 0.772–1.000; p<0.001) and for the consciousness diagnosis (k = 0.784–0.935; p<0.001). The disagreement rate between the overall best diagnosis of the SECONDs and the best CRS-R diagnosis was 6.7%. Conclusion: The Italian version of the SECONDs has been cross-culturally adapted to serve as a shorter assessment tool for the diagnosis of pDoC. Our study shows its excellent reliability and concurrent validity when compared to the CRS-R. [ABSTRACT FROM AUTHOR]

Summary: Postural balance requires the interplay between several physiological signals. Indirect evidence suggests that the perception of signals arising from the autonomic nervous system might play a role (e.g. cardiac awareness). Here, we tested this hypothesis by investigating the relationship between postural control and cardiac awareness (i.e. interoception) in a sample of N = 70 healthy individuals. Postural control was measured using a medical robotic device, while cardiac awareness was evaluated using the heartbeat counting task. A within-subject design included two platform configurations (static, unstable) and two visual feedback conditions (eyes open, eyes closed). For each condition, we measured the sway area and the range of oscillation of the platform, as well as the range of oscillation and the quantity of movement of participants' trunk. In the "platform unstable, eyes closed" condition, participants with higher cardiac awareness demonstrated a significantly smaller sway area and reduced oscillations of both the platform and their trunk. These findings hint at a potential link between interoception and postural control, suggesting that the perception of internal body signals might sustain balance. [ABSTRACT FROM AUTHOR]

Summary: Postural balance requires the interplay between several physiological signals. Indirect evidence suggests that the perception of signals arising from the autonomic nervous system might play a role (e.g. cardiac awareness). Here, we tested this hypothesis by investigating the relationship between postural control and cardiac awareness (i.e. interoception) in a sample of N = 70 healthy individuals. Postural control was measured using a medical robotic device, while cardiac awareness was evaluated using the heartbeat counting task. A within-subject design included two platform configurations (static, unstable) and two visual feedback conditions (eyes open, eyes closed). For each condition, we measured the sway area and the range of oscillation of the platform, as well as the range of oscillation and the quantity of movement of participants' trunk. In the "platform unstable, eyes closed" condition, participants with higher cardiac awareness demonstrated a significantly smaller sway area and reduced oscillations of both the platform and their trunk. These findings hint at a potential link between interoception and postural control, suggesting that the perception of internal body signals might sustain balance. [ABSTRACT FROM AUTHOR]

The Coma Recovery Scale-revised (CRS-r) is the gold standard for the behavioral assessment of patients with Disorders of Consciousness (DoCs). However, the misdiagnosis rate is around 40%. For this reason, recent guidelines suggested enhancing the assessment with neurophysiological measures: among these, surface electromyography (sEMG) represents a convenient bedside solution. This work presents the use of the STRIVEfc system, a wearable device that allows CRS-r administration while recording four sEMG signals. STRIVEfc was employed in 40 sessions on 33 DoCs patients and the sEMG was analyzed to look for voluntary and consistent over threshold (OT) muscular activities. Their duration, amplitude, and number were retained and compared between patients in Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS), revealing more numerous and significantly longer OTs in the latter group. Lastly, the EMG information was exploited to enrich the behavioral assessment by building the instrumented CRS-r score (ICRS-r). In 9/16 UWS sessions, the ICRS-r score suggested a higher-level functioning, not translated into a behavioral response, compatible with MCS diagnosis. Overall, the use of STRIVEfc allows to reveal hidden muscular patterns not detectable by the clinician, thus improving the characterization of DoCs patient's functional capabilities and supporting the diagnostic process. [ABSTRACT FROM AUTHOR]

Purpose: Regorafenib is a multikinase inhibitor, approved as a preferred regimen for recurrent glioblastoma (rGB). Although its effects on prolonging survival could seem modest, it is still unclear whether a subset of patients, potentially identifiable by imaging biomarkers, might experience a more substantial positive effect. Our aim was to evaluate the potential value of magnetic resonance imaging-derived parameters as non-invasive biomarkers to predict response to regorafenib in patients with rGB. Methods: 20 patients with rGB underwent conventional and advanced MRI at diagnosis (before surgery), at recurrence and at first follow-up (3 months) during regorafenib. Maximum relative cerebral blood volume (rCBVmax) value, intra-tumoral susceptibility signals (ITSS), apparent diffusion coefficient (ADC) values, and contrast-enhancing tumor volumes were tested for correlation with response to treatment, progression-free survival (PFS), and overall survival (OS). Response at first follow-up was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. Results: 8/20 patients showed stable disease at first follow-up. rCBVmax values of the primary glioblastoma (before surgery) significantly correlated to treatment response; specifically, patients with stable disease displayed higher rCBVmax compared to progressive disease (p = 0.04, 2-group t test). Moreover, patients with stable disease showed longer PFS (p = 0.02, 2-group t test) and OS (p = 0.04, 2-group t test). ITSS, ADC values, and contrast-enhancing tumor volumes showed no correlation with treatment response, PFS nor OS. Conclusion: Our results suggest that rCBVmax of the glioblastoma at diagnosis could serve as a non-invasive biomarker of treatment response to regorafenib in patients with rGB. [ABSTRACT FROM AUTHOR]

Precise synapse formation is essential for normal functioning of the nervous system. Retinal photoreceptors establish selective contacts with bipolar cells, aligning the neurotransmitter release apparatus with postsynaptic signaling cascades. This involves transsynaptic assembly between the dystroglycan-dystrophin complex on the photoreceptor and the orphan receptor GPR179 on the bipolar cell, which is mediated by the extracellular matrix protein pikachurin (also known as EGFLAM). This complex plays a critical role in the synaptic organization of photoreceptors and signal transmission, and mutations affecting its components cause blinding disorders in humans. Here, we investigated the structural organization and molecular mechanisms by which pikachurin orchestrates transsynaptic assembly and solved structures of the human pikachurin domains by x-ray crystallography and of the GPR179-pikachurin complex by single-particle, cryo–electron microscopy. The structures reveal molecular recognition principles of pikachurin by the Cache domains of GPR179 and show how the interaction is involved in the transsynaptic alignment of the signaling machinery. Together, these data provide a structural basis for understanding the synaptic organization of photoreceptors and ocular pathology. Editor's summary: In the retina, photoreceptors form synaptic contacts with ON-type bipolar cells to ensure efficient synaptic transmission. The extracellular matrix protein pikachurin connects a presynaptic complex on the photoreceptor with the postsynaptic orphan receptor GPR179. Patil et al. used a combination of x-ray crystallography and cryo–electron microscopy to determine the structures of regions of pikachurin alone and in combination with GPR179. Together, these findings provide insights into how pikachurin precisely positions GPR179 at synapses to ensure neurotransmission. —John F. Foley [ABSTRACT FROM AUTHOR]

The presence of involuntary, non-functional jaw muscle activity (NFJMA) has not yet been assessed in patients with disorders of consciousness (DOC), although the presence of bruxism and other forms of movement disorders involving facial muscles is probably more frequent than believed. In this work, we evaluated twenty-two prolonged or chronic DOC patients with a long-lasting polygraphic recording to verify NFJMA occurrence and assess its neurophysiological patterns in this group of patients. A total of 5 out of 22 patients showed the presence of significant NFJMA with electromyographic patterns similar to what can be observed in non-DOC patients with bruxism, thus suggesting a disinhibition of masticatory motor nuclei from the cortical control. On the other hand, in two DOC patients, electromyographic patterns advised for the presence of myorhythmia, thus suggesting a brainstem/diencephalic involvement. Functional, non-invasive tools such as long-lasting polygraphic recordings should be extended to a larger sample of patients, since they are increasingly important in revealing disorders potentially severe and impacting the quality of life of DOC patients. [ABSTRACT FROM AUTHOR]

Background and Hypothesis A primary disruption of the bodily self is considered a core feature of schizophrenia (SCZ). The "disembodied" self might be underpinned by inefficient body-related multisensory integration processes, normally occurring in the peripersonal space (PPS), a plastic sector of space surrounding the body whose extent is altered in SCZ. Although PPS is a malleable interface marking the perceptual border between self and others, no study has addressed the potential alteration of its plasticity in SCZ. We investigated the plasticity of PPS in SCZ patients after a motor training with a tool in the far space. Study Design Twenty-seven SCZ patients and 32 healthy controls (HC) underwent an audio-tactile task to estimate PPS boundary before (Session 1) and after (Session 3) the tool-use. Parameters of PPS, including the size and the slope of the psychometric function describing audio-tactile RTs as a function of the audio-tactile distances, were estimated. Study Results Results confirm a narrow PPS extent in SCZ. Surprisingly, we found PPS expansion in both groups, thus showing for the first time a preserved PPS plasticity in SCZ. Patients experienced a weaker differentiation from others, as indicated by a shallower PPS slope at Session 1 that correlated positively with negative symptoms. However, at Session 3, patients marked their bodily boundary in a steeper way, suggesting a sharper demarcation of PPS boundaries after the action with the tool. Conclusions These findings highlight the importance of investigating the multisensory and motor roots of self-disorders, paving the way for future body-centred rehabilitation interventions that could improve patients' altered body boundary. [ABSTRACT FROM AUTHOR]

Background: Neurological conditions are highly prevalent and disabling, in particular in the elderly. The Italian population has witnessed sharp ageing and we can thus expect a rising trend in the incidence, prevalence and disability of these conditions. Methods: We relied on the Global Burden of Disease 2019 study to extract Italian data on incidence, prevalence and years lived with a disability (YLDs) referred to a broad set of neurological disorders including, brain and nervous system cancers, stroke, encephalitis, meningitis, tetanus, traumatic brain injury, and spinal cord injury. We assessed changes between 1990 and 2019 in counts and age-standardized rates. Results: The most prevalent conditions were tension-type headache, migraine, and dementias, whereas the most disabling were migraine, dementias and traumatic brain injury. YLDs associated with neurological conditions increased by 22.5%, but decreased by 2.3% in age-standardized rates. The overall increase in prevalence and YLDs counts was stronger for non-communicable diseases with onset in old age compared to young to adult-age onset ones. The same trends were in the opposite direction when age-standardized rates were taken into account. Conclusions: The increase in YLDs associated with neurological conditions is mostly due to population ageing and growth: nevertheless, lived disability and, as a consequence, impact on health systems has increased. Actions are needed to improve outcome and mitigate disability associated with neurological conditions, spanning among diagnosis, treatment, care pathways and workplace interventions. [ABSTRACT FROM AUTHOR]

Background: Several people affected by COVID-19 experienced neurological manifestations, altered sleep quality, mood disorders, and disability following hospitalization for a long time. Objective: To explore the impact of different neurological symptoms on sleep quality, mood, and disability in a consecutive series of patients previously hospitalized for COVID-19 disease. Methods: We evaluated 83 patients with COVID-19 around 3 months after hospital discharge. They were divided into 3 groups according to their neurological involvement (i.e., mild, unspecific, or no neurological involvement). Socio-demographic, clinical data, disability level, emotional distress, and sleep quality were collected and compared between the three groups. Results: We found that higher disability, depressive symptoms, and lower sleep quality in patients with mild neurological involvement compared to patients with unspecific and no neurological involvement. Differences between groups were also found for clinical variables related to COVID-19 severity. Conclusion: After 3 months from hospital discharge, patients with more severe COVID-19 and mild neurological involvement experienced more psychosocial alterations than patients with unspecific or no neurological involvement. Both COVID-19 and neurological manifestations' severity should be considered in the clinical settings to plain tailored interventions for patients recovering from COVID-19. [ABSTRACT FROM AUTHOR]

Monitoring the level of responsiveness of patients with Disorders of Consciousness (DoCs) represents an issue in all the settings where there is not the daily presence of clinicians, such as long-term and domestic settings. The involvement of patients' informal caregivers (i.e., patients' family) in such a monitoring process is thus fundamental. However, to date, no standardized tailored-made instruments exist that informal caregivers can use without the presence of clinicians, despite evidence illustrating the good accuracy of caregivers when expressing their opinions about the level of responsiveness of DoC patients. The present work aims to set the foundational knowledge, to create a standardized instrument that is able to assess the level of responsiveness of patients with DoCs by their informal caregivers. After selecting and modifying the items to be included in the new scale from the gold standard to diagnose DoCs (i.e., the Coma Recovery Scale-revised), and following a consensus process, we created the Social and Family Evaluation (SAFE) scale for caregivers of patients with DoCs. Although the SAFE needs a validation process, with the present work we provided its preliminary description along with insights into its clinical utility. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic outbreak has dramatically disrupted healthcare systems. Two rapid WHO pulse surveys studied disruptions in mental health services, but did not particularly focus on neurology. Here, a global survey was conducted and addresses the impact of the pandemic on neurology services. Methods: A cross-sectional study was carried out in which 34 international neurological associations were asked to distribute the survey to national associations. The responses represented the national situation, in November–December 2020, with regard to the main disrupted neurological services, reasons and the mitigation strategies implemented as well as the disruption on training of residents and on neurological research. A comparison with the situation in February–April 2020, first pandemic wave, was also requested. Findings: 54 completed surveys came from 43 countries covering all the 6 WHO regions. Overall, neurological services disruption was reported as mild by 26%, moderate by 30%, complete by 13% of associations. The most affected services were cross-sectoral neurological services (57%) and neurorehabilitation (56%). The second wave of the pandemic, however, was associated with the improvement of service provision for diagnostics services (44%) and for neurorehabilitation (41%). Governmental directives were the major cause of services' disruption (56%). Mitigation strategies were mostly established through telemedicine (48%). Almost half of respondents reported a significant impact on neurological research (48%) and educational activities (60%). Most associations (67%) were not involved in decision making for neurological patients' issues by their national government. Interpretation: The COVID-19 pandemic affects neurological services and raises the universal need for the development of neurological health care at the policy, systems and services levels. A global national plan on mitigation strategies for disruption of neurological services during pandemic situations should be established and neurological scientific and patients associations should get involved in decision making. [ABSTRACT FROM AUTHOR]

During COVID-19 pandemic, older adults are the segment of the population at higher health risk. Given the important role the risk perception has in influencing both the behaviors and psychological well-being, it appears useful exploring this factor in this segment of the population. Despite different studies already described the factors influencing the risk perception, few focused on older adults. For this reason, we investigated risk perception in 514 people over 60 years during the lockdown. We administered a structured interview collecting socio-demographic information, sources of information used, actions undertaken to avoid contagion, and risk perception. Risk perception related to COVID-19 was significantly lower than the perceived risk associated with other threats, and it was correlated to the number of sources of information used but not to the actions undertaken. Furthermore, we found higher risk perception in who knew infected persons, and a negative correlation between the risk perception and age, with the over 75 perceiving a lower risk of getting infected compared to the younger participants. Our results should be taken as informative for future studies. Indeed, further studies on the older adults and the risk perception during emergencies are needed to better orient both communication and supporting strategies. [ABSTRACT FROM AUTHOR]

The analysis of the central and the autonomic nervous systems (CNS, ANS) activities during general anesthesia (GA) provides fundamental information for the study of neural processes that support alterations of the consciousness level. In the present pilot study, we analyzed EEG signals and the heart rate (HR) variability (HRV) in a sample of 11 patients undergoing spinal surgery to investigate their CNS and ANS activities during GA obtained with propofol administration. Data were analyzed during different stages of GA: baseline, the first period of anesthetic induction, the period before the loss of consciousness, the first period after propofol discontinuation, and the period before the recovery of consciousness (ROC). In EEG spectral analysis, we found a decrease in posterior alpha and beta power in all cortical areas observed, except the occipital ones, and an increase in delta power, mainly during the induction phase. In EEG connectivity analysis, we found a significant increase of local efficiency index in alpha and delta bands between baseline and loss of consciousness as well as between baseline and ROC in delta band only and a significant reduction of the characteristic path length in alpha band between the baseline and ROC. Moreover, connectivity results showed that in the alpha band there was mainly a progressive increase in the number and in the strength of incoming connections in the frontal region, while in the beta band the parietal region showed mainly a significant increase in the number and in the strength of outcoming connections values. The HRV analysis showed that the induction of anesthesia with propofol was associated with a progressive decrease in complexity and a consequent increase in the regularity indexes and that the anesthetic procedure determined bradycardia which was accompanied by an increase in cardiac sympathetic modulation and a decrease in cardiac parasympathetic modulation during the induction. Overall, the results of this pilot study showed as propofol-induced anesthesia caused modifications on EEG signal, leading to a "rebalance" between long and short-range cortical connections, and had a direct effect on the cardiac system. Our data suggest interesting perspectives for the interactions between the central and autonomic nervous systems for the modulation of the consciousness level. [ABSTRACT FROM AUTHOR]

Body representation (BR) refers to the mental representation of motor, sensory, emotional and semantic information about the physical body. This cognitive representation is used in our everyday life, continuously, even though most of the time we do not appreciate it consciously. In some cases, BR is vital to be able to communicate. A crucial feature of signed languages (SLs), for instance, is that body parts such as hands are used to communicate. Nevertheless, little is known about BR in SL: is the communicative function of the body overwriting the physical constraints? Here, we explored this question by comparing twelve British Sign Language (BSL) learners to seventeen tango dancers (body expertise but not for communication) and fourteen control subjects (no special body expertise). We administered the Body Esteem Scale (BES), the Hand Laterality Task (HLT) and the Mental Motor Chronometry (MMC). To control for visual imagery, we administered ad hoc control tasks. We did not identify parameters able to differentiate between SL users and the other groups, whereas the more implicit parameters distinguished clearly tango dancers from controls. Importantly, neither tasks on visual imagery nor the BES revealed differences. Our findings offer initial evidence that linguistic use of the body not necessarily influences the cognitive components we explored of body representation. [ABSTRACT FROM AUTHOR]

One of the major challenges for clinicians who treat patients with Disorders of Consciousness (DoCs) concerns the detection of signs of consciousness that distinguish patients in Vegetative State from those in Minimally Conscious State. Recent studies showed how visual responses to tailored stimuli are one of the first evidence revealing that one patient is changing from one state to another. This study aimed to explore the integrity of the neural structures being part of the visual system in patients with DoCs manifesting a reflexive behavior (visual blink) and in those manifesting a cognitively and cortically mediated behavior (visual pursuit). We collected instrumental data using specialized equipment (EEG following the rules of the International 10–20 system, 3T Magnetic Resonance, and Positron Emission Tomography) in 54 DoC patients. Our results indicated that visual pursuit group showed a better fVEPs response than the visual blink group, because of a greater area under the N2/P2 component of fVEPs (AUC could be seen as an indicator of the residual activity of visual areas). Considering neuroimaging data, the main structural differences between groups were found in the retrochiasmatic areas, specifically in the right optic radiation and visual cortex (V1), areas statistically less impaired in patients able to perform a visual pursuit. FDG‐PET analysis confirmed difference between groups at the level of the right calcarine cortex and neighboring right lingual gyrus. In conclusion, although there are methodological and theoretical limitations that should be considered, our study suggests a new perspective to consider for a future diagnostic protocol. [ABSTRACT FROM AUTHOR]

Objectives: Caregivers of patients diagnosed with disorders of consciousness (DoCs) play a pivotal role in the care pathway of these patients. Due to the high costs of care, among other symptoms and disorders previously described in the literature, they can manifest also mood and stress-related disorders which greatly impact their life and increase their burden. It is noteworthy to identify which factors are better related to the manifestation of mood and stress-related disorders to care for the caregivers in time. However, no studies have explored which factors are related to the manifestation of these disorders within this population yet. Materials and methods: We explored with different questionnaires whether patient-, caregiver-, and caregiving environment-related factors are associated with mood and stress-related disorders on 114 caregivers of patients with DoCs. Results: Our results showed that female caregivers manifested higher levels of both depression and prolonged grief disorder; furthermore, the presence of economic problems increased the levels of depression. Moreover, different levels of caregivers' depression, anxiety, anger expression, and prolonged grief disorder were closely linked to the degree of behavioural responsiveness of the patients. Conclusions: Our results highlighted the need to consider also caregivers' mood and stress-related disorders when defining the care pathway of patients with DoCs; indeed, caregivers constitute the main environment of DoC patients and they need tailored interventions aimed at reducing their burden due to caregiving. [ABSTRACT FROM AUTHOR]

Mutating the side‐chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half‐life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]6‐Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4‐disubstituted 1,2,3‐triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT2R/AT1R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross‐peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21. [ABSTRACT FROM AUTHOR]

It is now accepted that reactive oxygen species (ROS) are not only dangerous oxidative agents but also chemical mediators of the redox cell signaling and innate immune response. A central role in ROS‐controlled production is played by the NADPH oxidases (NOXs), a group of seven membrane‐bound enzymes (NOX1‐5 and DUOX1‐2) whose unique function is to produce ROS. Here, we describe the regulation of NOX5, a widespread family member present in cyanobacteria, protists, plants, fungi, and the animal kingdom. We show that the calmodulin‐like regulatory EF‐domain of NOX5 is partially unfolded and detached from the rest of the protein in the absence of calcium. In the presence of calcium, the C‐terminal lobe of the EF‐domain acquires an ordered and more compact structure that enables its binding to the enzyme dehydrogenase (DH) domain. Our spectroscopic and mutagenesis studies further identified a set of conserved aspartate residues in the DH domain that are essential for NOX5 activation. Altogether, our work shows that calcium induces an unfolded‐to‐folded transition of the EF‐domain that promotes direct interaction with a conserved regulatory region, resulting in NOX5 activation. [ABSTRACT FROM AUTHOR]

Background and Purpose: The number of people suffering from stroke is strongly increasing, giving rise to multiple cognitive deficits which frequently prevent a full recovery. The identification of both spared and impaired cognitive domains has a key role to plan adequate interventions. However, the existing standard tests are either too expensive in terms of time and efforts for patients in acute stage or they derived from instruments addressing different pathologies such as dementia.Methods: We developed a brief neuropsychological battery (mental performance in acute stroke, MEPS) to assess different cognitive domains (language, memory, praxis, visual perception) in acute stroke patients. MEPS was validated by enrolling a sample of 204 patients suffering from stroke in acute stage, and 263 healthy controls participants.Results: The results indicated an adequate construct validity and a high ability in discriminating patients from healthy controls.Conclusions: MEPS can be considered a simple and highly valuable bedside battery, easy to administer, with values of sensitivity and specificity suitable to be proposed as a screening tool for patients with acute stroke. [ABSTRACT FROM AUTHOR]

Mixed findings characterize studies in Parkinson's disease (PD): some studies indicate a relationship between physical impairments and the ability to mentally represent the body, while others suggest spared abilities for this cognitive function. To clarify the matter, in the present study we explored the mental representations of the body in action in the same PD patients, taking also into account lateralization of symptoms and visual imagery skills. 10 PD patients with left- (lPD), 10 with right (rPD) lateralized symptoms (lPD), and 20 matched healthy controls have been recruited for the study. All patients were screened for neuropsychological impairments. To explore a more implicit component we used the hand laterality task (HLT), while the mental motor chronometry (MMC) was used to explore a more explicit one. Two control tasks, with objects instead of body parts, were administered to control for visual imagery skills. In the HLT, we detected the effects of biomechanical constraints effects in both controls and PD patients. In the latter group, importantly, this was true independently from lateralization of symptoms. In the MMC, we found the expected positive correlation between executed and imagined movements for both hands in controls only, while all PD patients, again independently form lateralization, only showed this effect for the left hand. In terms of visual imagery, only rPD patients differed from controls when asked to implicitly rotate letters, and in terms of accuracy only. However, this difference is explained by executive functions measured through the neuropsychological assessment rather than by a "pure" visual imagery impairment. In summary, our findings suggest that two different aspects of the mental representations of the body in action, one more implicit and the other more explicit, can be differently affected by PD. These impairments are unlikely explained by a basic visual imagery deficit. When present, impairments concern a higher dimension, related to motor functions and awareness, and not driven by sensory impairments, as shown by the independence of effects from physical laterality of symptoms. [ABSTRACT FROM AUTHOR]

The first crystal structure of mammalian monoamine oxidases (MAOs) was solved in 2002; almost 65 years after, these FAD-dependent enzymes were discovered and classified as responsible for the oxidation of aromatic neurotransmitters. Both MAO A and MAO B feature a two-domain topology characterized by the Rossmann fold, interacting with dinucleotide cofactors, which is intimately associated to a substrate-binding domain. This globular body is endowed with a C-terminal α-helix that anchors the protein to the outer mitochondrial phospholipid bilayer. As monotopic membrane proteins, the structural elucidation of MAOs was a challenging task that required the screening of different detergent conditions for their purification and crystallization. MAO A and MAO B structures differ both in their oligomerization architecture and in details of their active sites. Purified human MAO B and rat MAO A are dimeric, whereas human MAO A was found to be monomeric, which is believed to result from the detergent treatments used to extract the protein from the membrane. The active site of MAOs consists of a hydrophobic cavity located in front of the flavin cofactor and extending to the protein surface. Some structural features are highly conserved in the two isozymes, such as a Tyr-Tyr aromatic sandwich in front of the flavin ring and a Lys residue hydrogen-bonded to the cofactor N5 atom, whereas a pair of gating residues (Phe208/Ile335 in MAO A; Ile199/Tyr326 in MAO B) specifically determines the different substrate and inhibitor properties of the two enzymes. [ABSTRACT FROM AUTHOR]

NADPH oxidases (NOXs) are the only enzymes exclusively dedicated to reactive oxygen species (ROS) generation. Dysregulation of these polytopic membrane proteins impacts the redox signaling cascades that control cell proliferation and death. We describe the atomic crystal structures of the catalytic flavin adenine dinucleotide (FAD)- and heme-binding domains of Cylindrospermum stagnale NOX5. The two domains form the core subunit that is common to all seven members of the NOX family. The domain structures were then docked in silico to provide a generic model for the NOX family. A linear arrangement of cofactors (NADPH, FAD, and two membraneembedded heme moieties) injects electrons from the intracellular side across the membrane to a specific oxygen-binding cavity on the extracytoplasmic side. The overall spatial organization of critical interactions is revealed between the intracellular loops on the transmembrane domain and the NADPH-oxidizing dehydrogenase domain. In particular, the C terminus functions as a toggle switch, which affects access of the NADPH substrate to the enzyme. The essence of this mechanistic model is that the regulatory cues conformationally gate NADPH-binding, implicitly providing a handle for activating/deactivating the very first step in the redox chain. Such insight provides a framework to the discovery of much needed drugs that selectively target the distinct members of the NOX family and interfere with ROS signaling. [ABSTRACT FROM AUTHOR]

NADPH oxidases (NOXs) are membrane enzymes whose sole function is the generation of reactive oxygen species. Humans have seven NOX isoenzymes that feature distinct functions in immune response and cell signaling but share the same catalytic core comprising a FAD-binding dehydrogenase domain and a heme-binding transmembrane domain. We previously described a mutation that stabilizes the dehydrogenase domain of a prokaryotic homolog of human NOX5. The thermostable mutant exhibited a large 19 °C increase in the apparent melting temperature (app Tm) and a much tighter binding of the FAD cofactor, which allowed the crystallization and structure determination of the domain holo-form. Here, we analyze the transferability of this mutation onto prokaryotic and eukaryotic full-length NOX enzymes. We found that the mutation exerts a significative stabilizing effect on the full-length NOX5 from both Cylindrospermum stagnale (app Tm increase of 8 °C) and Homo sapiens (app ΔTm of 2 °C). Enhanced thermal stability resulted in more homogeneous preparations of the bacterial NOX5 with less aggregation problems. Moreover, we also found that the mutation increases the overall expression of recombinant human NOX4 and NOX5 in mammalian cells. Such a 2-5-fold increase is mainly due to the lowered cell toxicity, which leads to higher biomasses. Because of the high sequence identity of the catalytic core within this family of enzymes, this strategy can be a general tool to boost the production of all NOXs. [ABSTRACT FROM AUTHOR]

Introduction: Visual-motor skills are the basis for a great number of daily activities. To define a correct rehabilitation program for neurological patients who have impairment in these skills, there is a need for simple and cost-effective tools to determine which of the visual-motor system levels of organization are compromised by neurological lesions. In their 1995 book, The Visual Brain in Action (Oxford: Oxford University Press), AD Milner and MA Goodale proposed the existence of two pathways for the processing of visual information, the "ventral stream" and "dorsal stream," that interact in movement planning and programming. Beginning with this model, our study aimed to validate a method to quantify the role of the ventral and dorsal streams in perceptual and visual-motor skills. Subjects and methods: Nineteen right-handed healthy subjects (mean age 22.8 years ± 3.18) with normal or corrected-to-normal vision were recruited. We proposed that a delayed pointing task, a distance reproduction task, and a delayed anti-pointing task could be used to assess the ventral stream, while the dorsal stream could be evaluated with a grasping task and an immediate pointing task. Performance was recorded and processed with the video-analysis software Dartfish ProSuite. Results: Results showed the expected pattern of predominance of attention for the superior left visual field, predominance of the flexor tone in proximal peri-personal space arm movements, tendency toward overestimation of short distances, and underestimation of long distances. Conclusion: We believe that our method is advantageous as it is simple and easily transported, but needs further testing in neurologically compromised patients. [ABSTRACT FROM AUTHOR]

Structural studies on mammalian integral membrane proteins have long been hampered by their instability in detergent. This is particularly true for the agonist conformation of G protein-coupled receptors (GPCRs), where it is thought that the movement of helices that occurs upon agonist binding results in a looser and less stable packing in the protein. Here, we show that mutagenesis coupled to a specific selection strategy can be used to stabilize the agonist and antagonist conformations of the adenosine A2a receptor. Of the 27 mutations identified that improve the thermostability of the agonist conformation, only three are also present in the 17 mutations identified that improve the thermostability of the antagonist conformation, suggesting that the selection strategies used were specific for each conformation. Combination of the stabilizing mutations for the antagonist- or agonist-binding conformations resulted in mutants that are more stable at higher temperatures than the wild-type receptor by 17°C and 9°C, respectively. The mutant receptors both showed markedly improved stability in short-chain alkyl-glucoside detergents compared with the wild-type receptor, which will facilitate their. structural analysis. [ABSTRACT FROM AUTHOR]

There are ≈350 non-odorant G protein-coupled receptors (GPCRs) encoded by the human genome, many of which are predicted to be potential therapeutic targets, but there are only two structures available to represent the whole of the family. We hypothesized that improving the detergent stability of these receptors and simultaneously locking them into one preferred conformation will greatly improve the chances of crystallization. We developed a generic strategy for the isolation of detergent-solubilized thermo-stable mutants of a GPCR, the β1-adrenergic receptor. The most stable mutant receptor, βAR-m23, contained six point mutations that led to an apparent Tm 21°C higher than the native protein, and, in the presence of bound antagonist, βAR-m23 was as stable as bovine rhodopsin. In addition. βAR-m23 was significantly more stable in a wide range of detergents ideal for crystallization and was preferentially in an antagonist conformation in the absence of ligand. [ABSTRACT FROM AUTHOR]

Background: The multi-disciplinary tumor board (MTB) is essential to quality cancer care and currently recommended to offer the best personalized clinical approach, but little has been published regarding MTBs in neuro-oncology (nMTBs). The aim of the present paper is to describe our nMTB, to evaluate its impact on clinical management decisions, and to assess the role of neuroradiologists. Methods: The retrospective evaluation of the cases discussed at our nMTB from March 2017 to March 2020. From the electronic records, we extracted epidemiological, clinical and other specific data of nMTB. From the radiological records, we calculated data relating to the number, time for revision, and other specifications of MRI re-evaluation. Statistical analysis was performed. Results: a total of 447 discussions were analyzed, representing 342 patients. The requests for case evaluations came from radiation oncologists (58.8%) and neurosurgeons (40.5%), and were mainly addressed to the neuroradiologist (73.8%). The most frequent questions were about the treatment's changes (64.4%). The change in patient treatment was reported in 40.5% of cases, 76.8% of these were based on the neuroradiologic assessment. A total of 1514 MRI examinations were re-evaluated, employing approximately 67 h overall. The median of the MRI exams reviewed per patient was 3 (min–max 1–12). Conclusions: Our study supported that the multidisciplinary approach to patient care can be particularly effective in managing brain tumors. A review by an expert neuroradiologist impacts patient management in the context of nMTBs, but has costs in terms of the time and effort spent preparing for it. [ABSTRACT FROM AUTHOR]

Sleep disorders are among the main comorbidities in patients with a Disorder of Consciousness (DOC). Given the key role of sleep in neural and cognitive functioning, detecting and treating sleep disorders in DOCs might be an effective therapeutic strategy to boost consciousness recovery and levels of awareness. To date, no systematic reviews have been conducted that explore the effect of sleep treatments in DOCs; thus, we systematically reviewed the existing studies on both pharmacological and non-pharmacological treatments for sleep disorders in DOCs. Among 2267 assessed articles, only 7 were included in the systematic review. The studies focused on two sleep disorder categories (sleep-related breathing disorders and circadian rhythm dysregulation) treated with both pharmacological (Modafinil and Intrathecal Baclofen) and non-pharmacological (positive airway pressure, bright light stimulation, and central thalamic deep brain stimulation) interventions. Although the limited number of studies and their heterogeneity do not allow generalized conclusions, all the studies highlighted the effectiveness of treatments on both sleep disorders and levels of awareness. For this reason, clinical and diagnostic evaluations able to detect sleep disorders in DOC patients should be adopted in the clinical routine for the purpose of intervening promptly with the most appropriate treatment. [ABSTRACT FROM AUTHOR]

The amount of knowledge on human consciousness has created a multitude of viewpoints and it is difficult to compare and synthesize all the recent scientific perspectives. Indeed, there are many definitions of consciousness and multiple approaches to study the neural correlates of consciousness (NCC). Therefore, the main aim of this article is to collect data on the various theories of consciousness published between 2007–2017 and to synthesize them to provide a general overview of this topic. To describe each theory, we developed a thematic grid called the dimensional model, which qualitatively and quantitatively analyzes how each article, related to one specific theory, debates/analyzes a specific issue. Among the 1130 articles assessed, 85 full texts were included in the prefinal step. Finally, this scoping review analyzed 68 articles that described 29 theories of consciousness. We found heterogeneous perspectives in the theories analyzed. Those with the highest grade of variability are as follows: subjectivity, NCC, and the consciousness/cognitive function. Among sub-cortical structures, thalamus, basal ganglia, and the hippocampus were the most indicated, whereas the cingulate, prefrontal, and temporal areas were the most reported for cortical ones also including the thalamo-cortical system. Moreover, we found several definitions of consciousness and 21 new sub-classifications. [ABSTRACT FROM AUTHOR]

Neuroimaging tools could open a window on residual neurofunctional activity in the absence of detectable behavioural responses in patients with disorders of consciousness (DOC). Nevertheless, the literature on this topic is characterised by a large heterogeneity of paradigms and methodological approaches that can undermine the reproducibility of the results. To explicitly test whether task-related functional magnetic resonance imaging (fMRI) can be used to systematically detect neurofunctional differences between different classes of DOC, and whether these differences are related with a specific category of cognitive tasks (either active or passive), we meta-analyzed 22 neuroimaging studies published between 2005 and 2017 using the Activation Likelihood Estimate method. The results showed that: (1) active and passive tasks rely on well-segregated patterns of activations; (2) both unresponsive wakeful syndrome and patients in minimally conscious state activated a large portion of the dorsal-attentional network; (3) shared activations between patients fell mainly in the passive activation map (7492 voxels), while only 48 voxels fell in a subcortical region of the active-map. Our results suggest that DOCs can be described along a continuum—rather than as separated clinical categories—and characterised by a widespread dysfunction of brain networks rather than by the impairment of a well functionally anatomically defined one. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the "Multifrequency bioelectrical impedance analysis in women with a normal and hypertensive pregnancy" by Herbert Valensise, Stefano Lello, and Francesca Magnani in the September, 2000 issue.