Search

Post-traumatic Parkinsonism (PTP) is a complex neurological disorder that is often associated with the occurrence of a traumatic brain injury (TBI). PTP can occur either in the acute or chronic phase of TBI. There is still uncertainty about the mechanisms provoking PTP, which can be the result of the acute blast itself or secondary neurodegenerative process occurring months to years post the acute trauma. Currently there is an underestimation of the clinical importance of PTP and lack of specific and proven therapeutic interventions, both in the pharmacological and the neurorehabilitation field. This narrative review aims to summarize the actual knowledge about PTP in terms of its pathophysiology, clinical aspects, treatments and perspective of care in the neurorehabilitative setting., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Between August and 28 October 2024, 199 autochthonous cases of dengue virus serotype 2 were notified in the city of Fano, central Italy. We describe the ongoing epidemiological and microbiological investigation and public health measures implemented to contain the outbreak. The high transmissibility and the extension of the outbreak suggest that dengue should be expected in temperate regions during favourable seasons, highlighting the need for heightened awareness among healthcare providers and the public to ensure timely detection and response.

Objective: Persistent fatigue is a major symptom of the so-called 'long-COVID syndrome', but the pathophysiological processes that cause it remain unclear. We hypothesized that fatigue after COVID-19 would be associated with altered cortical activity in premotor and motor regions., Methods: We used transcranial magnetic stimulation combined with EEG (TMS-EEG) to explore the neural oscillatory activity of the left primary motor area (l-M1) and supplementary motor area (SMA) in a group of sixteen post-COVID patients complaining of lingering fatigue as compared to a sample of age-matched healthy controls. Perceived fatigue was assessed with the Fatigue Severity Scale (FSS) and Fatigue Rating Scale (FRS)., Results: Post-COVID patients showed a remarkable reduction of beta frequency in both areas. Correlation analysis exploring linear relation between neurophysiological and clinical measures revealed a significant inverse correlation between the individual level of beta oscillations evoked by TMS of SMA with the individual scores in the FRS (r(15) = -0.596; p = 0.012)., Conclusions: Post-COVID fatigue is associated with a reduction of TMS-evoked beta oscillatory activity in SMA., Significance: TMS-EEG could be used to identify early alterations of cortical oscillatory activity that could be related to the COVID impact in central fatigue., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) is a redox active molecule that is universally found in biology. Despite the importance and simplicity of this molecule, few reports exist that investigate which molecular features are important for the activity of this ribodinucleotide. By exploiting the nonenzymatic reduction and oxidation of NAD + by pyruvate and methylene blue, respectively, we were able to identify key molecular features necessary for the intrinsic activity of NAD + through kinetic analysis. Such features may explain how NAD + could have been selected early during the emergence of life. Simpler molecules, such as nicotinamide, that lack an anomeric carbon are incapable of accepting electrons from pyruvate. The phosphate moiety inhibits activity in the absence of metal ions but facilitates activity at physiological pH and model prebiotic conditions by recruiting catalytic Mg 2+ . Reduction proceeds through consecutive single electron transfer events. Of the derivatives tested, including nicotinamide mononucleotide, nicotinamide riboside, 3-(aminocarbonyl)-1-(2,3-dihydroxypropyl)pyridinium, 1-methylnicotinamide, and nicotinamide, only NAD + and nicotinamide mononucleotide would be capable of efficiently accepting and donating electrons within a nonenzymatic electron transport chain. The data are consistent with early metabolic chemistry exploiting NAD + or nicotinamide mononucleotide and not simpler molecules., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

HapX and SreA are transcription factors that regulate the response of the fungus Aspergillus fumigatus to the availability of iron. During iron starvation, HapX represses genes involved in iron consuming pathways and upon a shift to iron excess, HapX activates these same genes. SreA blocks the expression of genes needed for iron uptake during periods of iron availability. Both proteins possess cysteine-rich regions (CRR) that are hypothesized to be necessary for the sensing of iron levels. However, the contribution of each of these domains to the function of the protein has remained unclear. Here, the ability of peptide analogs of each CRR is determined to bind an iron-sulfur cluster in vitro. UV-vis and resonance Raman (RR) spectroscopies reveal that each CRR is capable of coordinating a [2Fe-2S] cluster with comparable affinities. The iron-sulfur cluster coordinated to the CRR-B domain of HapX displays particularly high stability. The data are consistent with HapX and SreA mediating responses to cellular iron levels through the direct coordination of [2Fe-2S] clusters. The high stability of the CRR-B peptide may also find use as a starting point for the development of new green catalysts., (© 2024 The Authors. Advanced Biology published by Wiley‐VCH GmbH.)

There is currently no plausible path for the emergence of a self-replicating protocell, because prevalent formulations of model protocells are built with fatty acid vesicles that cannot withstand the concentrations of Mg 2+ needed for the function and replication of nucleic acids. Although prebiotic chelates increase the survivability of fatty acid vesicles, the resulting model protocells are incapable of growth and division. Here, we show that protocells made of mixtures of cyclophospholipids and fatty acids can grow and divide in the presence of Mg 2+ -citrate. Importantly, these protocells retain encapsulated nucleic acids during growth and division, can acquire nucleotides from their surroundings, and are compatible with the nonenzymatic extension of an RNA oligonucleotide, chemistry needed for the replication of a primitive genome. Our work shows that prebiotically plausible mixtures of lipids form protocells that are active under the conditions necessary for the emergence of Darwinian evolution.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

In post-COVID-19 syndrome (PCS), neurocognitive symptoms and fatigue are often associated with alterations in electroencephalographic (EEG) activity. The present study investigates the brain source activity at rest in PCS patients (PCS-pts) perceiving cognitive deficits and fatigue. A total of 18 PCS-pts and 18 healthy controls (HCs) were enrolled. A Montreal Cognitive Assessment (MoCA), Perceived Cognitive Difficulties Scale (PDCS) and Fatigue Severity Scale (FSS) were administered for assessing the symptoms' severity. Brain activity at rest, both with open (OE) and closed eyes (CE), was recorded by high-density EEG (Hd-EEG) and localized by source estimation. Compared to HCs, PCS-pts exhibited worse performance in executive functions, language and memory, and reported higher levels of fatigue. At resting OE state, PCS-pts showed lower delta source activity over brain regions known to be associated with executive processes, and these changes were negatively associated with PDCS scores. Consistent with recent literature data, our findings could indicate a dysfunction in the neuronal networks involved in executive functions in PCS-pts complaining of fatigue and cognitive impairment.

Modulation of the blink reflex (BR) to supraorbital nerve (SON) stimulation by a weak somatosensory prepulse (sPP) consists of inhibition of R2 and facilitation of R1. Similar BR changes occur with self-stimulation. Our aim was to compare neurophysiological processes underlying both effects. We assessed BR parameters in 18 healthy participants following right SON stimulation either performed by an experimenter (experiment 1A) or following self-stimulation (experiments 1B, 1C). In experiments 1A and 1C, sPPs to digit 2 preceded SON stimuli by 40, 100, 200 and 500 ms. In experiment 1B: self-stimulation was delayed by 40, 100, 200, and 500 ms. In experiment 2, BRs were elicited by an experimenter randomly during a 2-s period before participants applied self-stimulation. In experiment 1, as expected, sPPs caused facilitation of R1 and inhibition of R2, which peaked at 100 ms ISI, similarly in experiments 1A and 1C. Self-stimulation caused a decrease of R2, which was evident in a broad range of time intervals. In experiment 2, R2 was already inhibited at the onset of the 2-s period, while R1 began to rise significantly 1.4 s before self-stimulation. Both effects progressively increased until self-triggering. The results concur with a time-locked gating mechanism of prepulses at brainstem level, whereas self-stimulation modulates BR in a tonic manner, reflecting a cognitive influence due to self-agency., (© 2022 Society for Psychophysiological Research.)

Objective: Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABA B- ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI., Methods: Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity., Results: Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected., Conclusions: Eight weeks of treatment with PEA-LUT restore GABA B activity and cortical plasticity in long Covid patients., Significance: This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Fatigue, attentional deficits and cognitive fluctuations are the most characterizing symptoms of neurological involvement in Post COVID-19 syndrome (PCS). As the intraindividual variability (IIV) in cognitive performances has been recognized as a hallmark of brain-related disorders associated with cognitive deficits, it could be an interesting measure to elucidate the mechanisms subtending both the attentive impairment and the cognitive fluctuations in these patients. By referring to IIV analysis of Reaction Times (RTs), the present study aims to define the attentive impairment and its relation to fluctuations and fatigue, in patients suffering from Post COVID-19 neurological symptoms. 74 patients were enrolled. They underwent an extensive clinical and neuropsychological assessments, as well as computerized Sustained Attention and Stroop tasks. For studying IIV, RTs distributions of performances in computerized tasks were fitted with ex-Gaussian distribution, for obtaining the τ values. Finally, the Resting Motor Threshold (RMT) was also collected to estimate cortical excitability. 29 healthy volunteers served as controls. Patients showed poorer scores in Montreal Cognitive Assessment and higher RMT, in comparison with controls. In Sustained Attention Task, Mean, µ, σ and τ values were significantly higher in PCS patients (p value =  < 0.0001; 0.001; 0.018 and < 0.0001, respectively). Repeated measures ANOVA comparing the RTs mean in Stroop task within-subject and between-subjects revealed significant condition and group effect (p < 0.0001 both) and significant interaction (p = 0.005), indicating worst performances in patients. The mean of the derived interference value was significantly higher in PCS patients than in controls (p = 0.036). Patients suffering from PCS show deficits in attention, both in the sustained and executive components. Both high RTs means and high IIV subtend these deficits and could explain the often-complained cognitive fluctuations in this population., (© 2022. The Author(s).)

Iron-sulfur clusters are thought to be ancient cofactors that could have played a role in early protometabolic systems. Thus far, redox active, prebiotically plausible iron-sulfur clusters have always contained cysteine ligands to the cluster. However, extant iron-sulfur proteins can be found to exploit other modes of binding, including ligation by histidine residues, as seen with [2Fe-2S] Rieske and MitoNEET proteins. Here, we investigated the ability of cysteine- and histidine-containing peptides to coordinate a mononuclear Fe 2+ center and a [2Fe-2S] cluster and compare their properties with purified iron-sulfur proteins. The iron-sulfur peptides were characterized by UV-vis, circular dichroism, and paramagnetic NMR spectroscopies and cyclic voltammetry. Small (≤6 amino acids) peptides can coordinate [2Fe-2S] clusters through a combination of cysteine and histidine residues with similar reduction potentials as their corresponding proteins. Such complexes may have been important for early cell-like systems., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

It is common to compare life with machines. Both consume fuel and release waste to run. In biology, the engine that drives the living system is referred to as metabolism. However, attempts at deciphering the origins of metabolism do not focus on this energetic relationship that sustains life but rather concentrate on nonenzymatic reactions that produce all the intermediates of an extant metabolic pathway. Such an approach is akin to studying the molecules produced from the burning of coal instead of deciphering how the released energy drives the movement of pistons and ultimately the train when investigating the mechanisms behind locomotion. Theories that do explicitly invoke geological chemical gradients to drive metabolism most frequently feature hydrothermal vent conditions, but hydrothermal vents are not the only regions of the early Earth that could have provided the fuel necessary to sustain the Earth's first (proto)cells. Here, we give examples of prior reports on protometabolism and highlight how more recent investigations of out-of-equilibrium systems may point to alternative scenarios more consistent with the majority of prebiotic chemistry data accumulated thus far. This article is part of the theme issue 'Emergent phenomena in complex physical and socio-technical systems: from cells to societies'.

Background and Purpose: Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions., Methods: Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and 'well-being' were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks., Results: Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABA B -ergic and cholinergic neurotransmission. Short-interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention., Conclusions: Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention., (© 2022 European Academy of Neurology.)

The assessment of cognitive deficits is pivotal for diagnosis and management in patients with parkinsonisms. Low levels of correspondence are observed between evaluations assessed with screening cognitive tests in comparison with those assessed with in-depth neuropsychological batteries. A new tool, we named CoMDA (Cognition in Movement Disorders Assessment), was composed by merging Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery (FAB). In total, 500 patients (400 with Parkinson's disease, 41 with vascular parkinsonism, 31 with progressive supranuclear palsy, and 28 with multiple system atrophy) underwent CoMDA (level 1-L1) and in-depth neuropsychological battery (level 2-L2). Machine learning was developed to classify the CoMDA score and obtain an accurate prediction of the cognitive profile along three different classes: normal cognition (NC), mild cognitive impairment (MCI), and impaired cognition (IC). The classification accuracy of CoMDA, assessed by ROC analysis, was compared with MMSE, MoCA, and FAB. The area under the curve (AUC) of CoMDA was significantly higher than that of MMSE, MoCA and FAB (p < 0.0001, p = 0.028 and p = 0.0007, respectively). Among 15 different algorithmic methods, the Quadratic Discriminant Analysis algorithm (CoMDA-ML) showed higher overall-metrics performance levels in predictive performance. Considering L2 as a 3-level continuous feature, CoMDA-ML produces accurate and generalizable classifications: micro-average ROC curve, AUC = 0.81; and AUC = 0.85 for NC, 0.67 for MCI, and 0.83 for IC. CoMDA and COMDA-ML are reliable and time-sparing tools, accurate in classifying cognitive profile in parkinsonisms.This study has been registered on ClinicalTrials.gov (NCT04858893)., (© 2022. The Author(s).)

The knowledge about the effects of cannabis on human cortical brain processes is increasing. In this regard, transcranial magnetic stimulation (TMS) enables the evaluation of central nervous system function, including drug effects. Moreover, repetitive TMS (rTMS) has been used therapeutically in several substance use disorders. In this scoping review, we summarize and discuss studies that have employed TMS and rTMS techniques in users of cannabis for recreational purposes. In subjects with a history of persistent cannabis use, TMS studies showed reduced short-interval cortical inhibition (SICI). This observation points more at neurobiological changes of chronic cannabis use than to a direct effect of cannabis on gamma-aminobutyric acid (GABA) A receptors. Moreover, individuals vulnerable to becoming long-term users of cannabis may also have underlying pre-existing abnormalities in SICI. Of note, the use of cannabis is associated with an increased risk of schizophrenia, and the down-regulation of GABAergic function may play a role. Less frequent cannabis use and spontaneous craving were observed following rTMS applied to the dorsolateral prefrontal cortex (DLPFC). There is emerging evidence that the posterior cingulate cortex and the precuneus are potential targets for rTMS intervention in cannabis use disorder. However, larger and randomized trials should corroborate these encouraging findings., (Copyright © 2022. Published by Elsevier B.V.)

Background and Purpose: Cortical visuomotor integration is altered in Alzheimer's disease (AD), even at an early stage of the disease. The aim of this study was to assess the connections between the primary visual (V1) and motor (M1) areas in patients with early AD using a paired-pulse, twin-coil transcranial magnetic stimulation (TMS) technique., Methods: Visuomotor connections (VMCs) were assessed in 13 subjects with probable AD and 16 healthy control subjects. A conditioning stimulus over the V1 phosphene hotspot was followed at interstimulus intervals (ISIs) of 18 and 40 ms by a test stimulus over M1, to elicit motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle., Results: Significant effects due to VMCs, consisting of enhanced MEP suppression at ISI of 18 and 40 ms, were observed in the AD patients. Patients with AD showed an excessive inhibitory response of the right M1 to inputs travelling from V1 at given ISIs., Conclusions: This study provides neurophysiological evidence of altered functional connectivity between visual and motor areas in AD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Encapsulation of RNA within model protocells promotes folding, promotes the binding of substrates, promotes catalysis, and protects against denaturation. A new study argues for an active role of lipid vesicles in the origins of life., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In patients with restless legs syndrome (RLS) a motor cortical disinhibition has been reported in transcranial magnetic stimulation (TMS) studies, but the neuronal excitability in other cortical areas has been poorly explored. The aim of this study was the functional evaluation of thalamo-cortical circuits and inhibitory cortical responses in the sensory cortex in RLS. We assessed the high-frequency somatosensory evoked potentials (HF-SEP) in sixteen subjects suffering from RLS of different degrees of severity. In patients with severe or very severe RLS we found a significant desynchronization with amplitude reduction of both pre- and post-synaptic HF-SEP bursts, which suggest an impairment in the thalamo-cortical projections and in the cortical inhibitory interneurons activity, respectively. The assessment of the central sensory pathways by means of HF-SEP may shed light on the pathophysiological mechanisms of RLS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Transcranial magnetic stimulation (TMS) can be a useful tool for the assessment of the brain functional reorganization in subjects with hemiplegic cerebral palsy (HCP). In this review, we performed a systematic search of all studies using TMS in order to explore the neuroplastic changes that occur in HCP patients. We aimed at investigating the usefulness of TMS to explore cortical excitability, plasticity and connectivity changes in HCP. Children with HCP due to unilateral lesions of the corticospinal system had ipsilateral motor evoked potentials (MEPs) similar to those recorded contralaterally. TMS studies demonstrated that occupational and constraint-induced movement therapy were associated with significant improvements in contralateral and ipsilateral corticomotor projection patterns. In addition, after intensive bimanual therapy, children with HCP showed increased activation and size of the motor areas controlling the affected hand. A TMS mapping study revealed a mediolateral location of the upper and lower extremity map motor cortical representations. Deficits in intracortical and interhemispheric inhibitory mechanisms were observed in HCP. Early hand function impairment correlated with the extension of brain damage, number of involved areas, and radiological signs of corticospinal tract (CST) degeneration. Clinical mirror movements (MMs) correlated with disability and CST organization in subjects with HCP and a positive relationship was found between MMs and MEPs strength. Therefore, TMS studies have shed light on important pathophysiological aspects of motor cortex and CST reorganization in HCP patients. Furthermore, repetitive TMS (rTMS) might have therapeutic effects on CST activities, functional connectivity and clinical status in children with HCP., Competing Interests: Declaration of Competing Interest None of the authors has potential conflicts of interest to be disclosed., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Implicit and explicit motor learning processes work interactively in everyday life to promote the creation of highly automatized motor behaviors. The cerebellum is crucial for motor sequence learning and adaptation, as it contributes to the error correction and to sensorimotor integration of on-going actions. A non-invasive cerebellar stimulation has been demonstrated to modulate implicit motor learning and adaptation. The present study aimed to explore the potential role of cerebellar theta burst stimulation (TBS) in modulating explicit motor learning and adaptation, in healthy subjects. Cerebellar TBS will be applied immediately before the learning phase of a computerized task based on a modified Serial Reaction Time Task (SRTT) paradigm. Here, we present a study protocol aimed at evaluating the behavioral effects of continuous (cTBS), intermittent TBS (iTBS), or sham Theta Burst Stimulation (TBS) on four different conditions: learning, adaptation, delayed recall and re-adaptation of SRTT. We are confident to find modulation of SRTT performance induced by cerebellar TBS, in particular, processing acceleration and reduction of error in all the conditions induced by cerebellar iTBS, as already known for implicit processes. On the other hand, we expect that cerebellar cTBS could induce opposite effects. Results from this protocol are supposed to advance the knowledge about the role of non-invasive cerebellar modulation in neurorehabilitation, providing clinicians with useful data for further exploiting this technique in different clinical conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ortelli, Ferrazzoli, Maestri, Saltuari, Kofler, Alibardi, Koch, Spampinato, Castagna, Sebastianelli and Versace.)

Introduction: Many researchers took advantage of the well-established rubber hand illusion (RHI) paradigm to explore the link between the sense of body ownership and the different brain structures and networks. Here, we aimed to review the studies that have investigated this phenomenon by means of neurophysiological techniques., Methods: The MEDLINE, accessed by Pubmed and EMBASE electronic databases, was searched using the medical subject headings: "Rubber hand illusion" AND "Transcranial magnetic stimulation (TMS)" OR "Evoked potentials (EP)" OR "Event related potentials (ERP)" OR "Electroencephalography (EEG)"., Results: Transcranial magnetic stimulation studies revealed a significant excitability drop in primary motor cortex hand circuits accompanying the disembodiment of the real hand during the RHI experience and that the perceived ownership over the rubber hand is associated with normal parietal-motor communication. Moreover, TMS provided causal evidence that the extrastriate body area is involved in the RHI and subsequently in body representation, while neuromodulation of ventral premotor area and the inferior parietal lobe did not result in an enhancement of embodiment. EP and ERP studies suggest that pre-existing body representations may affect larger stages of tactile processing and support predictive coding models of the functional architecture of multisensory integration in bodily perceptual experience. High-frequency oscillations on EEG play a role in the integrative processing of stimuli across modalities, and EEG activity in γ band activity in the parietal area reflects the visuotactile integration process. EEG studies also revealed that RHI is associated with the neural circuits underlying motor control and that premotor areas play a crucial role in mediating illusory body ownership., Conclusion: Neurophysiological studies shed new light on our understanding of the different aspects that contribute to the formation of a coherent self-awareness in humans., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The clock drawing test (CDT) is widely used in clinical neuropsychological practice. However, its neuroanatomical correlates have not been well established. This study investigated the effects of theta burst stimulation (TBS) applied over different brain regions on CDT scores in patients with Alzheimer's disease (AD). The 10-20 positions F3, F4, T3, T4, TP3, TP4, P3, P4, as determined by a 10-20 positioning cap, were targeted. Excitatory intermittent TBS (iTBS) was given over the above-mentioned eight regions to ten AD patients and ten control subjects on separate days. CDT was administered at baseline (T0), during the 5 min following the TBS (T1) and 60 min after TBS (T2), with an inter-session interval of at least 4 days. iTBS over TP4 and P4 transiently increased Rouleau CDT score in AD patients. When targeting TP4 and P4, mainly the area of the supramarginal/angular gyrus and the inferior parietal lobe, corresponding respectively to the Brodmann areas 40/39 and 7/40, are reached. iTBS thus seems able to modulate activity of the right posterior parietal cortex in AD patients performing the CDT. Our results provide physiological evidence that those parietal regions are functionally important for the execution of the Rouleau CDT. This finding suggests that CDT has reliable neuroanatomical correlates, and support the notion that this test can be used as a good marker of right parietal brain dysfunction. The present study also highlights the therapeutic potential of the induction of neuromodulatory effects using non-invasive brain stimulation techniques.

We focus attention on problems that are affecting the informal caregivers of patients with neurodegenerative disorders in the time of COVID-19. The pandemic is increasing difficulties in the management of the frailest people and their isolation is actually even more tangible than it was in the past. The social restrictions and the lockdown of many activities are putting the system of care provided by informal caregivers on the edge of collapse. We incite the scientific community to face these concerns and provide clinicians clear indications for assisting and supporting caregivers in the care of their relatives during this period. We suggest that e-health programs could become the ideal "environment" to favor the continuity of care for patients with neurodegenerative conditions and guarantee the required support to their caregivers, both directly in terms of psychological management and indirectly for helping them in disease management., Competing Interests: There are no disclosures or conflicts of interests to declare., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Objective: A high proportion of patients experience fatigue and impairment of cognitive functions after coronavirus disease 2019 (COVID-19). Here we applied transcranial magnetic stimulation (TMS) to explore the activity of the main inhibitory intracortical circuits within the primary motor cortex (M1) in a sample of patients complaining of fatigue and presenting executive dysfunction after resolution of COVID-19 with neurological manifestations., Methods: Twelve patients who recovered from typical COVID-19 pneumonia with neurological complications and complained of profound physical and mental fatigue underwent, 9 to 13 weeks from disease onset, a psychometric evaluation including a self-reported fatigue numeric-rating scale (FRS, Fatigue Rating Scale) and the Frontal Assessment Battery (FAB). Intracortical activity was evaluated by means of well-established TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABA A -mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABA B receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission. TMS data were compared to those obtained in a control group of ten healthy subjects (HS) matched by age, sex and education level., Results: Post-COVID-19 patients reported marked fatigue according to FRS score (8.1 ± 1.7) and presented pathological scores at the FAB based on Italian normative data (12.2 ± 0.7). TMS revealed marked reduction of SICI, and disruption of LICI as compared to HS. SAI was also slightly diminished., Conclusions: The present study documents for the first time reduced GABAergic inhibition in the M1 in patients who recovered from COVID-19 with neurological complications and manifested fatigue and dysexecutive syndrome., Significance: TMS may serve as diagnostic tool in cognitive disturbances and fatigue in post-COVID-19 patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Movement disorders encompass various conditions affecting the nervous system. The pathological processes underlying movement disorders lead to aberrant synaptic plastic changes, which in turn alter the functioning of large-scale brain networks. Therefore, clinical phenomenology does not only entail motor symptoms but also cognitive and motivational disturbances. The result is the disruption of motor learning and motor behavior. Due to this complexity, the responsiveness to standard therapies could be disappointing. Specific forms of rehabilitation entailing goal-based practice, aerobic training, and the use of noninvasive brain stimulation techniques could "restore" neuroplasticity at motor-cognitive circuitries, leading to clinical gains. This is probably associated with modulations occurring at both molecular (synaptic) and circuitry levels (networks). Several gaps remain in our understanding of the relationships among plasticity and neural networks and how neurorehabilitation could promote clinical gains is still unclear. Purposes: In this review, we outline first the networks involved in motor learning and behavior and analyze which mechanisms link the pathological synaptic plastic changes with these networks' disruption in movement disorders. Therefore, we provide theoretical and practical bases to be applied for treatment in rehabilitation.

Introduction: Trauma injuries and oncologic resection are common aetiologies of complex abdominal wall defect. Reconstruction of abdominal wall is an everlasting question for general, paediatric and reconstructive surgeons. The plethora of techniques, bioprosthetic and engineered tissues offer countless possibilities., Presentation of Case: The patient was a 28 years old woman, with past history of untreated giant liver omphalocele, admitted for a suspicious hepatic tumefaction without specific clinical signs. The thoraco abdominopelvic CT scan revealed lung metastasis and a bilobed left hepatic tumour. Pre-operative cytologic findings of mild differentiated hepatocellular carcinoma differed from the post-operative findings of hepatoblastoma. The full-thickness abdominal wall defect after a radical resection was reconstructed with a combined acellular dermal matrix, NPWT and skin graft solution. A total epithelization was obtained after 8 weeks follow-up., Discussion: Hepatoblastoma in adult is rare, with no consensus. A radical resection in context of giant untreated omphalocele is an unusual challenge for the surgical team. The pre-operative evaluation, the defect classification and the general conditions of the patient are paramount steps for an appropriate reconstruction. Primary or delayed reconstruction with myocutaneous flap as gold standard, depends on the oncologic management and anticipated post-operative complications. Acellular dermal matrix used for a bridged fascial repair directly on viscera and covered by NPWT, favourited a healthy granulation tissue. The full-thickness defect was then reconstructed with an ADM, NPWT and skin graft instead of an association with the myocutaneous flap. The patient follow-up was emphasized in the hepatoblastoma, but the complications of this reconstruction strategy are unknown. A total epithelization was obtained, the abdominal bulge or hernia is the first complication under surveillance., Conclusion: Delayed reconstruction after an oncologic large abdominal wall resection has the advantage to manage post-operative complications and prepare alternative solutions. Acellular dermal matrix was not first designed for skin tissue regeneration, some authors as us experimented the conclusion that this matrix could be used for permanent abdominal wall reconstruction., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

An established method to assess effective brain connectivity is the combined use of transcranial magnetic stimulation with simultaneous electroencephalography (TMS-EEG) because TMS-induced cortical responses propagate to distant anatomically connected brain areas. Alzheimer's disease (AD) and other dementias are associated with changes in brain networks and connectivity, but the underlying pathophysiology of these processes is poorly defined. We performed here a systematic review of the studies employing TMS-EEG co-registration in patients with dementias. TMS-EEG studies targeting the motor cortex have revealed a significantly reduced TMS-evoked P30 in AD patients in the temporo-parietal cortex ipsilateral to stimulation side as well as in the contralateral fronto-central area, and we have demonstrated a deep rearrangement of the sensorimotor system even in mild AD patients. TMS-EEG studies targeting other cortical areas showed alterations of effective dorsolateral prefrontal cortex connectivity as well as an inverse correlation between prefrontal-to-parietal connectivity and cognitive impairment. Moreover, TMS-EEG analysis showed a selective increase in precuneus neural activity. TMS-EEG co-registrations can also been used to investigate whether different drugs may affect cognitive functions in patients with dementias.

The excitability of brainstem circuitries mediating defensive blinking in response to abrupt sensory inputs is continuously modulated by cortical areas, e.g., the hand-blink reflex (HBR), elicited by intense electrical median nerve stimulation, is enhanced when the stimulated hand is close to the face, with the behavioural purpose to optimize self-protection from increased threat. Here we investigated whether such cortically mediated HBR facilitation can be influenced by prepulse inhibition (PPI), which is known to occur entirely at the subcortical level. Twenty healthy volunteers underwent HBR recordings in five experimental conditions. In conditions 1 and 2, the stimulated hand was held either near (1) or far (2) from the face, respectively. In conditions 3 and 4, stimulation of the hand near the face was preceded by a peri-liminal prepulse to the index finger of the contralateral hand held either near (3) or far from the face (4). In condition 5, participants self-triggered the stimulus eliciting the HBR. We observed a reproducible HBR in 14 out of 20 participants and measured onset latency and area of the HBR in orbicularis oculi muscles bilaterally. HBR area decreased and latency increased in condition 2 relative to condition 1; HBR area decreased and latency increased markedly in condition 3, and somewhat less in condition 4, relative to conditions 1 and 2; self-stimulation (condition 5) also suppressed HBRs, but less than prepulses. These findings indicate that PPI of the HBR is more robust than the cognitive modulation exerted by top-down cortical projections. Possibly, an attentional shift to a prepulse may serve to reduce blinking in response to perturbation when it is convenient, in a given situation, not to interrupt ongoing visual processing.

The Roux-en-Y gastric bypass (RYGB) is a worldwide-performed procedure as primary surgery, and as conversional procedure after complications and/or failure of other bariatric procedures. RYGB can be performed as revisional surgery after adjustable gastric banding, vertical banded gastroplasty, sleeve gastrectomy and one anastomosis gastric bypass. Each of these revisional procedures may be technically challenging, and accurate preoperative work-up and operative planning is required. If correctly performed, RYGB as revisional procedure is associated with satisfying outcomes and is indicated in the treatment of insufficient weight loss and postoperative complications of a primary bariatric procedure - such as chronic leak or gastroesophageal reflux after sleeve gastrectomy. The present article analyzes the most important indications, technical points and tips and tricks to safely perform RYGB as a secondary procedure.

Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult. Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients. Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Versace, Sebastianelli, Ferrazzoli, Saltuari, Kofler, Löscher and Uncini.)

More than half of patients who recover from COVID-19 experience fatigue. We studied fatigue using neuropsychological and neurophysiological investigations in post-COVID-19 patients and healthy subjects. Neuropsychological assessment included: Fatigue Severity Scale (FSS), Fatigue Rating Scale, Beck Depression Inventory, Apathy Evaluation Scale, cognitive tests, and computerized tasks. Neurophysiological examination was assessed before (PRE) and 2 min after (POST) a 1-min fatiguing isometric pinching task and included: maximum compound muscle action potential (CMAP) amplitude in first dorsal interosseous muscle (FDI) following ulnar nerve stimulation, resting motor threshold, motor evoked potential (MEP) amplitude and silent period (SP) duration in right FDI following transcranial magnetic stimulation of the left motor cortex. Maximum pinch strength was measured. Perceived exertion was assessed with the Borg-Category-Ratio scale. Patients manifested fatigue, apathy, executive deficits, impaired cognitive control, and reduction in global cognition. Perceived exertion was higher in patients. CMAP and MEP were smaller in patients both PRE and POST. CMAP did not change in either group from PRE to POST, while MEP amplitudes declined in controls POST. SP duration did not differ between groups PRE, increased in controls but decreased in patients POST. Patients' change of SP duration from PRE to POST was negatively correlated to FSS. Abnormal SP shortening and lack of MEP depression concur with a reduction in post-exhaustion corticomotor inhibition, suggesting a possible GABA B -ergic dysfunction. This impairment might be related to the neuropsychological alterations. COVID-19-associated inflammation might lead to GABAergic impairment, possibly representing the basis of fatigue and explaining apathy and executive deficits., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: Lewy body (LB)-related α-synucleinopathy (LBAS) is the neuropathological hallmark of several neurodegenerative diseases such as Parkinson disease (PD), but it is also found in neurologically asymptomatic subjects. An abnormal accumulation of α-synuclein has been reported also in the spinal cord, but extent and significance of the spinal cord involvement are still poorly defined. Objective: We aimed to review the studies addressing the spinal cord involvement of LBAS in healthy subjects and in patients with PD or other neurodegenerative diseases. Methods: A MEDLINE search was performed using following terms: "spinal cord", " α-synucleinopathy", "α-synuclein", "Lewy body", "Parkinson's disease", "multiple system atrophy", "neurodegenerative disorder". Results: LBAS in the spinal cord is associated with that of the medullary reticular formation and locus ceruleus in the brainstem but not with that in the olfactory bulb and amygdala. The intermediolateral columns of the thoracic and sacral cord are the most frequently and severely affected region of the spinal cord. LBAS occurs in centrally projecting spinal cord neurons integrating pain, in particular from lower body periphery. It also involves the sacral parasympathetic nucleus innervating the smooth muscles of the bladder and distal colon and the Onuf's nucleus innervating the striated sphincters. The spinal cord lesions may thus play a crucial role in the genesis of frequent non-motor symptoms such as pain, urinary symptoms, bowel dysfunction, autonomic failure including orthostatic hypotension and sexual disturbances. Moreover, these may also contribute to the motor symptoms, since α-synuclein inclusions have been observed in the pyramidal tracts of patients with PD and multiple system atrophy. Conclusion: Recognition of this peculiar spinal cord pathology may help in the management of the related symptoms in subjects affected by α-synucleinopathies.

The magnitude of the defensive blink reflex is modulated by continuous assessment of its protective value. Here, we studied whether the trigeminal blink reflex (TBR) is modulated by a potentially offensive object close to the face, and, if so, whether self-stimulation or observation of the act of stimulus triggering counteracts such modulation. In all, 26 healthy volunteers participated in various experimental conditions. At baseline, an experimenter triggered supraorbital nerve stimuli remotely, unseen by the participants; in experimental conditions, the experimenter held a stimulation probe close to the participant's face but triggered the stimuli either remotely, "surprising" participants (S 1 ), or directly on the probe, observed by participants (S 2 ). In other conditions, participants triggered stimuli themselves on the probe held next to their body (S 3 ) or held in front of their face (S 4 ). The latter condition was repeated similarly, but pressing the button only randomly generated electrical stimuli (S5, "Russian roulette"). The size of the R2 component of the TBR (TBR-R2) was the main outcome measure. Compared to baseline, TBR-R2 area was significantly larger in S 1 when the "threatening" probe was close to the face and the participant had no control over stimulation. Conversely, TBR-R2 was suppressed when participants either saw the action of triggering, thus being aware (S 2 ), or had full initiative over stimulation (S 3 , S 4 ). Random self-generated stimuli (S 5 ) inhibited TBR-R2, but to a lesser extent than S 3 and S 4. Perceived threat close to the face facilitates TBR-R2, but knowledge about impending stimulation or self-agency overrules this effect., (© 2020 Society for Psychophysiological Research.)