A Few-Shot Transfer Learning Approach for Motion Intention Decoding from Electroencephalographic Signals.

In this study, a few-shot transfer learning approach was introduced to decode movement intention from electroencephalographic (EEG) signals, allowing to recognize new tasks with minimal adaptation. To this end, a dataset of EEG signals recorded during the preparation of complex sub-movements was created from a publicly available data collection. The dataset was divided into two parts: the source domain dataset (including 5 classes) and the support (target domain) dataset, (including 2 classes) with no overlap between the two datasets in terms of classes. The proposed methodology consists in projecting EEG signals into the space-frequency-time domain, in processing such projections (rearranged in channels × frequency frames) by means of a custom EEG-based deep neural network (denoted as EEGframeNET5), and then adapting the system to recognize new tasks through a few-shot transfer learning approach. The proposed method achieved an average accuracy of 72.45 ± 4.19% in the 5-way classification of samples from the source domain dataset, outperforming comparable studies in the literature. In the second phase of the study, a few-shot transfer learning approach was proposed to adapt the neural system and make it able to recognize new tasks in the support dataset. The results demonstrated the system's ability to adapt and recognize new tasks with an average accuracy of 80 ± 0.12% in discriminating hand opening/closing preparation and outperforming reported results in the literature. This study suggests the effectiveness of EEG in capturing information related to the motor preparation of complex movements, potentially paving the way for BCI systems based on motion planning decoding. The proposed methodology could be straightforwardly extended to advanced EEG signal processing in other scenarios, such as motor imagery or neural disorder classification.

Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients.

AIMS: Neuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity. SUBJECTS AND METHODS: Blood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score). RESULTS: Age at onset was 65y (58-71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48-78) in PLS and 56y (44-68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158-360] vs. Controls = 174[113-240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels. CONCLUSIONS: We show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis.

The HFE p.H63D (p.His63Asp) Polymorphism Is a Modifier of ALS Outcome in Italian and French Patients with SOD1 Mutations.

Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

How brain-computer interface technology may improve the diagnosis of the disorders of consciousness: A comparative study.

Objective: Clinical assessment of consciousness relies on behavioural assessments, which have several limitations. Hence, disorder of consciousness (DOC) patients are often misdiagnosed. In this work, we aimed to compare the repetitive assessment of consciousness performed with a clinical behavioural and a Brain-Computer Interface (BCI) approach. Materials and methods: For 7 weeks, sixteen DOC patients participated in weekly evaluations using both the Coma Recovery Scale-Revised (CRS-R) and a vibrotactile P300 BCI paradigm. To use the BCI, patients had to perform an active mental task that required detecting specific stimuli while ignoring other stimuli. We analysed the reliability and the efficacy in the detection of command following resulting from the two methodologies. Results: Over repetitive administrations, the BCI paradigm detected command following before the CRS-R in seven patients. Four clinically unresponsive patients consistently showed command following during the BCI assessments. Conclusion: Brain-Computer Interface active paradigms might contribute to the evaluation of the level of consciousness, increasing the diagnostic precision of the clinical bedside approach. Significance: The integration of different diagnostic methods leads to a better knowledge and care for the DOC.

Reversible radiculomyelitis after ChAdOx1 nCoV-19 vaccination.

Adverse events occurring after SARS-CoV-2 vaccination have been reported and are the subject of ongoing research. We present the case of a young woman with fully reversible radiculomyelitis, which happened after the first dose of the ChAdOx1 nCOVID-19 vaccine. A previously healthy woman in her 20s presented with a subacute onset of legs' weakness and sensory disturbances, urinary dysfunction and cramping pain after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. A diagnostic workup led to the diagnosis of inflammatory radiculomyelitis. Her clinical status improved, with complete recovery after a few months. The case described a reversible radiculomyelitis associated with the ChAdOx1 nCOVID-19 vaccine. The clinical picture and evolution supported the diagnosis. No other identifiable causes of myelopathy were found. Our patient showed clinically moderate symptoms and signs, showing good recovery. The post-vaccine inflammatory radiculomyelitis is a rare side effect of the anti-COVID-19 vaccination, and it should not discourage the SARS-CoV-2 vaccination programme.

A novel compound heterozygous mutation in GALC associated with adult-onset Krabbe disease: case report and literature review.

Krabbe disease (KD) is a rare autosomal recessive lipid storage leukodystrophy. It is caused by deficient enzyme activity resulting from mutations of the ß-galactocerebrosidase (GALC) gene. KD is distinguished into subtypes based on the age of onset; these are early infantile, late infantile, juvenile, and adult-onset. We report a case of a 47-year-old Caucasian man with a 2-year history of muscle atrophy and weakness in both hands associated with pyramidal signs and mild spasticity in the lower limbs. An extensive work-up led this motor neuron disease-like disorder to be diagnosed as adult-onset KD. The patient was found to be compound heterozygous for two GALC mutations (p.G286D and p.Y490N). These two rare missense mutations have previously been reported with other heterozygous mutations. However, their co-occurrence in a KD patient is novel. From the perspective of this case, we review the current literature on compound heterozygous mutations in adult-onset KD and their phenotypic variability.

Brain-Computer Interfaces in Acute and Subacute Disorders of Consciousness.

SUMMARY: Disorders of consciousness include coma, unresponsive wakefulness syndrome (also known as vegetative state), and minimally conscious state. Neurobehavioral scales such as coma recovery scale-revised are the gold standard for disorder of consciousness assessment. Brain-computer interfaces have been emerging as an alternative tool for these patients. The application of brain-computer interfaces in disorders of consciousness can be divided into four fields: assessment, communication, prediction, and rehabilitation. The operational theoretical model of consciousness that brain-computer interfaces explore was reviewed in this article, with a focus on studies with acute and subacute patients. We then proposed a clinically friendly guideline, which could contribute to the implementation of brain-computer interfaces in neurorehabilitation settings. Finally, we discussed limitations and future directions, including major challenges and possible solutions.

The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial.

Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.

Prognostic Role of CSF ß-amyloid 1-42/1-40 Ratio in Patients Affected by Amyotrophic Lateral Sclerosis.

The involvement of ß-amyloid (Aß) in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been widely discussed and its role in the disease is still a matter of debate. Aß accumulates in the cortex and the anterior horn neurons of ALS patients and seems to affect their survival. To clarify the role of cerebrospinal fluid (CSF) Aß 1-42 and Aß 42/40 ratios as a potential prognostic biomarker for ALS, we performed a retrospective observational study on a cohort of ALS patients who underwent a lumbar puncture at the time of the diagnosis. CSF Aß 1-40 and Aß 1-42 ratios were detected by chemiluminescence immunoassay and their values were correlated with clinical features. We found a significant correlation of the Aß 42/40 ratio with age at onset and Mini Mental State Examination (MMSE) scores. No significant correlation of Aß 1-42 or Aß 42/40 ratios to the rate of progression of the disease were found. Furthermore, when we stratified patients according to Aß 1-42 concentration and the Aß 42/40 ratio, we found that patients with a lower Aß 42/40 ratio showed a shorter survival. Our results support the hypothesis that Aß 1-42 could be involved in some pathogenic mechanism of ALS and we suggest the Aß 42/40 ratio as a potential prognostic biomarker.

Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To test the hypothesis that total tau (tTau), tau phosphorylated at threonine 181 (pTau) and pTau/tTau ratio in the cerebrospinal fluid (CSF) are diagnostic and prognostic biomarkers of amyotrophic lateral sclerosis (ALS), we performed a retrospective observational study in a large cohort of ALS patients and controls. METHODS: We enrolled 196 ALS patients and 91 controls, who included patients with ALS-mimicking diseases and those with non-neurodegenerative diseases. All patients underwent lumbar puncture for CSF analysis at the time of the diagnostic evaluation or to first referral. We measured tTau and pTau levels in the CSF by chemiluminescence enzyme immunoassay. RESULTS: Patients with ALS showed significantly higher levels of CSF tTau and a lower pTau/tTau ratio than controls (tTau: 245 vs. 146 pg/ml; p < 0.001; pTau/tTau ratio: 0.12 vs. 0.18; p < 0.001, respectively). No differences in pTau levels were detected. Receiver-operating characteristic curve analysis showed a good diagnostic accuracy of tTau and pTau/tTau ratio (tTau: area under the curve [AUC] 0.685, 95% confidence interval [CI] 0.616-0.754, p = 0.039; pTau/tTau ratio: AUC 0.777, 95% CI 0.707-0.848, p < 0.001). Among ALS patients, increased tTau levels were associated with advanced age of onset, increased revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (ΔFS) rate of progression, and spinal onset. Multivariate analysis showed that in ALS patients, this biomarker was an independent negative predictor of overall survival. CONCLUSIONS: Our findings suggest that tTau and pTau/tTau ratio can be diagnostic biomarkers of ALS. In addition, CSF tTau level at diagnosis might play a relevant prognostic role in the disease.

Genetic investigation of amyotrophic lateral sclerosis patients in south Italy: a two-decade analysis.

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease characterized by the interplay of genetic and environmental factors. In the majority of cases, ALS is sporadic, whereas familial forms occur in less than 10% of patients. Herein, we present the results of molecular analyses performed in a large cohort of Italian ALS patients, focusing on novel and already described variations in ALS-linked genes. Our analysis revealed that more than 10% of tested patients carried a mutation in one of the major ALS genes, with C9orf72 hexanucleotide expansion being the most common mutation. In addition, our study confirmed a significant association between ALS patients carrying the ATNX-1 intermediate repeat and the pathological C9orf72 expansion, supporting the involvement of this risk factor in neuronal degeneration. Overall, our study broadens the known mutational spectrum in ALS and provides new insights for a more accurate view of the genetic pattern of the disease.

The capacity to consent to treatment in amyotrophic lateral sclerosis: a preliminary report.

BACKGROUND: Facing the relentless worsening of their condition, ALS patients are required to make decisions on treatments and end-of-life care. A cognitive impairment showed to be a negative prognostic factor in ALS patients, perhaps affecting the ability to make informed decisions. Notwithstanding its crucial role, the capacity to consent to treatment (CCT) has never been evaluated in these patients. OBJECTIVES: To assess the CCT in an ALS cohort in comparison to a control group, and to study the effects of demographic and clinical variables on this high-level cognitive function. METHODS: 102 ALS patients and 106 healthy controls (HC) were enrolled. CCT was assessed using the MacArthur Competence Assessment Tool for Treatment (MAC-CAT-T) and the performance was classified into the three CCT outcomes (full credit, partial credit, no credit). Cognitive and psychological variables were assessed by MMSE, phonemic fluencies, Frontal System Behavioural Scale (FrSBe), and ALS Depression Inventory (ADI). Clinical and demographic variables were analyzed as possible predictors of the MAC-CAT-T outcomes. After a 1-year follow-up, CCT and neuropsychological assessments were repeated. RESULTS: Most ALS patients (i.e., from 75 to 83% according to the different sub-items) retain full CCT. However, a subpopulation of the ALS patients showed a reduced CCT with respect to the HC. Age, education, phonemic fluency, and depression appeared related to the CCT outcomes. After 1 year, only the reasoning items worsened. CONCLUSIONS: This is a preliminary report suggesting that the large majority of ALS patients can retain full ability to choose between treatment options. However, demographic and neuropsychological variables may affect CCT, pointing to the need for special attention to the consent disclosure in this disease.

Diabetic thoracic radiculopathy: a case of a young woman with clinical improvement following immunotherapy.

Thoracic radiculopathy is a rare cause of thoracic-abdominal or abdominal pain in subjects with poorly controlled diabetes. We present a case of a young woman with type I diabetes and a severe abdominal pain in both lower quadrants. An extensive diagnostic gastroenterological and gynaecological workup did not disclose abnormalities. Electromyography revealed an initial polyneuropathy and significant neurogenic abnormalities in the T10-T12 paravertebral muscles. Following the hypothesis that the radiculopathy-related abdominal pain might have an immuno-mediated pathogenesis, the patient underwent a complex trial of immunotherapy, which was accompanied by a sustained improvement over months to full recovery. This report would support the hypothesis that immune-mediated mechanisms are still active even months after onset of symptoms.

Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family.

BACKGROUND: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. METHODS: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. RESULTS: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. CONCLUSIONS: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

Effects of a Vibro-Tactile P300 Based Brain-Computer Interface on the Coma Recovery Scale-Revised in Patients With Disorders of Consciousness.

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor and cognitive disabilities. Recent research has shown that non-invasive brain-computer interface (BCI) technology could help assess these patients' cognitive functions and command following abilities. 20 DOC patients participated in the study and performed 10 vibro-tactile P300 BCI sessions over 10 days with 8-12 runs each day. Vibrotactile tactors were placed on the each patient's left and right wrists and one foot. Patients were instructed, via earbuds, to concentrate and silently count vibrotactile pulses on either their left or right wrist that presented a target stimulus and to ignore the others. Changes of the BCI classification accuracy were investigated over the 10 days. In addition, the Coma Recovery Scale-Revised (CRS-R) score was measured before and after the 10 vibro-tactile P300 sessions. In the first run, 10 patients had a classification accuracy above chance level (>12.5%). In the best run, every patient reached an accuracy ≥60%. The grand average accuracy in the first session for all patients was 40%. In the best session, the grand average accuracy was 88% and the median accuracy across all sessions was 21%. The CRS-R scores compared before and after 10 VT3 sessions for all 20 patients, are showing significant improvement (p = 0.024). Twelve of the twenty patients showed an improvement of 1 to 7 points in the CRS-R score after the VT3 BCI sessions (mean: 2.6). Six patients did not show a change of the CRS-R and two patients showed a decline in the score by 1 point. Every patient achieved at least 60% accuracy at least once, which indicates successful command following. This shows the importance of repeated measures when DOC patients are assessed. The improvement of the CRS-R score after the 10 VT3 sessions is an important issue for future experiments to test the possible therapeutic applications of vibro-tactile and related BCIs with a larger patient group.

Corrigendum: Performance Differences Using a Vibro-Tactile P300 BCI in LIS-Patients Diagnosed With Stroke and ALS.

[This corrects the article DOI: 10.3389/fnins.2018.00514.].

A novel S379A TARDBP mutation associated to late-onset sporadic ALS.

Since 2008, several groups have reported a lot of dominant mutations in TARDBP gene as a primary cause of Amyotrophic lateral sclerosis (ALS). Mutations in TARDBP gene are responsible for 4-5% of familial ALS (fALS) and nearly 1% of sporadic ALS (sALS). To date, over 50 dominant mutations were found in TDP-43 in both familial and sporadic ALS patients, most of which were missense mutations in the C-terminal glycine-rich region. Herein, we describe the clinical and genetic analysis of an Italian non-familial ALS patient with a late onset and a rapid disease progression, which led to the discovery of a novel TARDBP mutation. After neurological evaluation, molecular investigation highlighted the heterozygous substitution in exon 6 of TARDBP gene (S379A), which has previously neither been described nor reported in the ALS database. Several evidences supported the S379A mutation as causative in our patient: (a) it was neither found in ExAC nor 1000G and it was absent in our database of control subjects; (b) the position of the mutation involves an evolutionarily highly conserved residue; (c) two different amino acid substitutions in the same 379 codon were already reported in Swedish and Italian fALS cases, supporting the critical role of this codon for the protein function. The identification of this novel mutation enlarges the number of TARDBP mutations in ALS patients.