Relating Alpha Power and Phase to Population Firing and Hemodynamic Activity Using a Thalamo-cortical Neural Mass Model

Oscillations are ubiquitous phenomena in the animal and human brain. Among them, the alpha rhythm in human EEG is one of the most prominent examples. However, its precise mechanisms of generation are still poorly understood. It was mainly this lack of knowledge that motivated a number of simultaneous electroencephalography (EEG) – functional magnetic resonance imaging (fMRI) studies. This approach revealed how oscillatory neuronal signatures such as the alpha rhythm are paralleled by changes of the blood oxygenation level dependent (BOLD) signal. Several such studies revealed a negative correlation between the alpha rhythm and the hemodynamic BOLD signal in visual cortex and a positive correlation in the thalamus. In this study we explore the potential generative mechanisms that lead to those observations. We use a bursting capable Stefanescu-Jirsa 3D (SJ3D) neural-mass model that reproduces a wide repertoire of prominent features of local neuronal-population dynamics. We construct a thalamo-cortical network of coupled SJ3D nodes considering excitatory and inhibitory directed connections. The model suggests that an inverse correlation between cortical multi-unit activity, i.e. the firing of neuronal populations, and narrow band local field potential oscillations in the alpha band underlies the empirically observed negative correlation between alpha-rhythm power and fMRI signal in visual cortex. Furthermore the model suggests that the interplay between tonic and bursting mode in thalamus and cortex is critical for this relation. This demonstrates how biophysically meaningful modelling can generate precise and testable hypotheses about the underpinnings of large-scale neuroimaging signals

Stochastic epidemic models for emerging diseases incorporating household structure and contact tracing

In this thesis, three stochastic epidemic models for intervention for emerging diseases are considered. The models are variants of real-time, responsive intervention, based upon observing diagnosed cases and targeting intervention towards individuals they have infected or are likely to have infected, be they housemates or named contacts. These models are: (i) a local tracing model for a disease spreading amongst a community of households, wherein intervention (vaccination and/or isolation) is directed towards housemates of diagnosed individuals, (ii) a contact tracing model for a disease spreading amongst a homogeneously-mixing population, with isolation of traced contacts of a diagnosed individual, (iii) a local tracing and contact tracing model for a disease spreading amongst a community of households, with intervention directed towards housemates of both diagnosed and traced individuals. These are quantified by deriving threshold parameters that determine whether the disease will infect a few individuals or a sizeable proportion of the population, as well as probabilities for such events occurring

Relating Alpha Power and Phase to Population Firing and Hemodynamic Activity Using a Thalamo-cortical Neural Mass Model

International audienceOscillations are ubiquitous phenomena in the animal and human brain. Among them, the alpha rhythm in human EEG is one of the most prominent examples. However, its precise mechanisms of generation are still poorly understood. It was mainly this lack of knowledge that motivated a number of simultaneous electroencephalography (EEG) – functional magnetic resonance imaging (fMRI) studies. This approach revealed how oscillatory neuronal signatures such as the alpha rhythm are paralleled by changes of the blood oxygenation level dependent (BOLD) signal. Several such studies revealed a negative correlation between the alpha rhythm and the hemodynamic BOLD signal in visual cortex and a positive correlation in the thalamus. In this study we explore the potential generative mechanisms that lead to those observations. We use a bursting capable Stefanescu-Jirsa 3D (SJ3D) neural-mass model that reproduces a wide repertoire of prominent features of local neuronal-population dynamics. We construct a thalamo-cortical network of coupled SJ3D nodes considering excitatory and inhibitory directed connections. The model suggests that an inverse correlation between cortical multi-unit activity, i.e. the firing of neuronal populations , and narrow band local field potential oscillations in the alpha band underlies the empirically observed negative correlation between alpha-rhythm power and fMRI signal in visual cortex. Furthermore the model suggests that the interplay between tonic and bursting mode in thalamus and cortex is critical for this relation. This demonstrates how biophysically meaningful modelling can generate precise and testable hypotheses about the underpinnings of large-scale neuroimaging signals

Stochastic epidemic models for emerging diseases incorporating household structure and contact tracing

In this thesis, three stochastic epidemic models for intervention for emerging diseases are considered. The models are variants of real-time, responsive intervention, based upon observing diagnosed cases and targeting intervention towards individuals they have infected or are likely to have infected, be they housemates or named contacts. These models are: (i) a local tracing model for a disease spreading amongst a community of households, wherein intervention (vaccination and/or isolation) is directed towards housemates of diagnosed individuals, (ii) a contact tracing model for a disease spreading amongst a homogeneously-mixing population, with isolation of traced contacts of a diagnosed individual, (iii) a local tracing and contact tracing model for a disease spreading amongst a community of households, with intervention directed towards housemates of both diagnosed and traced individuals. These are quantified by deriving threshold parameters that determine whether the disease will infect a few individuals or a sizeable proportion of the population, as well as probabilities for such events occurring

Late-onset Tay-Sachs disease

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of β-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease

Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (χ2, p 2, p = 0.75) correlated with mislocalisation of TDP-43, which is the hallmark of ALS neurodegeneration. This has implications for translational approaches to C9ORF72 disease, and furthermore interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets

Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions

GGGGCC repeat expansions of C9orf72 represent the most common genetic variant of amyotrophic lateral sclerosis and frontotemporal degeneration, but the mechanism of pathogenesis is unclear. Recent reports have suggested that the transcribed repeat might form toxic RNA foci that sequester various RNA processing proteins. Consensus as to the identity of the binding partners is missing and whole neuronal proteome investigation is needed. Using RNA fluorescence in situ hybridization we first identified nuclear and cytoplasmic RNA foci in peripheral and central nervous system biosamples from patients with amyotrophic lateral sclerosis with a repeat expansion of C9orf72 (C9orf72 + ), but not from those patients without a repeat expansion of C9orf72 (C9orf72) or control subjects. Moreover, in the cases examined, the distribution of foci-positive neurons correlated with the clinical phenotype (t-test P5 0.05). As expected, RNA foci are ablated by RNase treatment. Interestingly, we identified foci in fibroblasts from an asymptomatic C9orf72 + carrier. We next performed pulldown assays, with GGGGCC5, in conjunction with mass spectrometry analysis, to identify candidate binding partners of the GGGGCC repeat expansion. Proteins containing RNA recognition motifs and involved in splicing, messenger RNA nuclear export and/or translation were significantly enriched. Immunohistochemistry in central nervous system tissue from C9orf72 + patients with amyotrophic lateral sclerosis demonstrated co-localization of RNA foci with SRSF2, hnRNP H1/F, ALYREF and hnRNP A1 in cerebellar granule cells and with SRSF2, hnRNP H1/F and ALYREF in motor neurons, the primary target of pathology in amyotrophic lateral sclerosis. Direct binding of proteins to GGGGCC repeat RNA was confirmed in vitro by ultraviolet-crosslinking assays. Co-localization was only detected in a small proportion of RNA foci, suggesting dynamic sequestration rather than irreversible binding. Additional immunohistochemistry demonstrated that neurons with and without RNA foci were equally likely to show nuclear depletion of TDP-43 (2 P = 0.75) or poly-GA dipeptide repeat protein inclusions (2 P = 0.46). Our findings suggest two non-exclusive pathogenic mechanisms: (i) functional depletion of RNA-processing proteins resulting in disruption of messenger RNA splicing; and (ii) licensing of expanded C9orf72 pre-messenger RNA for nuclear export by inappropriate association with messenger RNA export adaptor protein(s) leading to cytoplasmic repeat associated non-ATG translation and formation of potentially toxic dipeptide repeat protein.

Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe