Frontal Cortex Research Articles

TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.

TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS. The coding regions of TBK1, SOD1, TARDBP, and FUS were genetically analyzed using Sanger sequencing. Repeat-primed PCR was used to survey the GGGGCC repeat in C9ORF72. The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies. We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization. The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.

HIV transcription persists in the brain of virally suppressed people with HIV.

HIV persistence in the brain is a barrier to cure, and potentially contributes to HIV-associated neurocognitive disorders. Whether HIV transcription persists in the brain despite viral suppression with antiretroviral therapy (ART) and is subject to the same blocks to transcription seen in other tissues and blood, is unclear. Here, we quantified the level of HIV transcripts in frontal cortex tissue from virally suppressed or non-virally suppressed people with HIV (PWH). HIV transcriptional profiling of frontal cortex brain tissue (and PBMCs where available) from virally suppressed (n = 11) and non-virally suppressed PWH (n = 13) was performed using digital polymerase chain reaction assays (dPCR). CD68+ myeloid cells or CD3+ T cells expressing HIV p24 protein present in frontal cortex tissue was detected using multiplex immunofluorescence imaging. Frontal cortex brain tissue from PWH had HIV TAR (n = 23/24) and Long-LTR (n = 20/24) transcripts. Completion of HIV transcription was evident in brain tissue from 12/13 non-virally suppressed PWH and from 5/11 virally suppressed PWH, with HIV p24+CD68+ cells detected in these individuals. While a block to proximal elongation was present in frontal cortex tissue from both PWH groups, this block was more extensive in virally suppressed PWH. These findings suggest that the brain is a transcriptionally active HIV reservoir in a subset of virally suppressed PWH.

Functional network characteristics in anxiety- and mania-based subgroups of bipolar I disorder

BackgroundBipolar disorder I (BD-I) is a heterogeneous disorder with a high prevalence of comorbid anxiety. The aim of this study was to investigate whether anxiety and mania symptoms define distinct subgroups within BD-I and to explore potential differences in functional network characteristics between these subgroups. MethodsSubgroups were identified using scores from clinical anxiety and mania scales. After dimension reduction of these scores, data-driven clustering analysis with cross-validation was employed to reveal the existence of subgroups. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were pre-processed using fMRIPrep. After parcellation and network construction, global and regional graph theoretical measures were calculated per subgroup. ResultsClustering results revealed that, based on anxiety symptomatology, subjects fell into two distinct subgroups, whereas mania symptoms divided subjects into four unique subgroups. These subgroups varied notably on several symptom scales. Network assortativity was significantly associated with anxiety subgroups. Post-hoc pairwise comparisons did not reveal significant global functional network differences between the anxiety subgroups or between mania subgroups. Regional network differences between clinical subgroups were especially apparent for strength and degree in the temporal and frontal lobes. LimitationsSmall sample size of some subgroups is a limitation of this study as is the categorical rather than continuous representation of anxiety and mania symptoms. ConclusionsBD-I populations may be stratified into robust subgroups based on anxiety and mania symptoms, showing differences in functional network connectivity. Our findings highlight new avenues of research for investigating heterogeneity in psychiatric populations.

Real-world analysis of brain atrophy in multiple sclerosis patients with an artificial intelligence based software tool

BackgroundAtrophy of white and grey matter volumes occurs early in the brains of people with multiple sclerosis (pwMS) and has great clinical relevance. In clinical trials, brain atrophy can be quantified by magnetic resonance imaging (MRI) with automated software tools.MethodsIn this study, we analyze volumes of various brain regions with the software “md brain” based on routine MRI scans of 53 pwMS in a real-world setting. We compare brain volumes of pwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years to the brain volumes of pwMS with an EDSS < 3.5 and a disease duration < 10 years as well as with or without immunotherapy.ResultspwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years had significantly lower volumes of the total brain, the grey matter and of the frontal, temporal, parietal and occipital lobe regions as compared to pwMS with an EDSS < 3.5 and a disease duration < 10 years. Regional brain volumes were significantly lower in pwMS without immunotherapy.ConclusionsThe study showed that higher EDSS, longer disease duration and absence of immunotherapy was associated with lower volumes in a number of brain regions. Further real-world studies may include larger patient cohorts in longitudinal analyses.

Caffeine and modafinil modulate the effects of sleep deprivation on thalamic resting-state functional connectivity: A double-blind pilot study

BackgroundStudies have found that the use of clinically approved caffeine and modafinil can alleviate cognitive impairment due to sleep deprivation (SD) to some extent. However, the neural mechanisms by which these two cognitive enhancers work to counteract the effects of SD on cognitive impairment remain unclear. MethodsA double-blind within-subjects experiment using resting-state functional magnetic resonance imaging (rs-fMRI) was designed. Participants underwent three 36-h SD trials, each of which involved taking 200 mg of caffeine, modafinil, or placebo at the 28th and 32 nd h of SD. Sixteen subregions of the thalamus were selected as the regions of interest and changes in functional connectivity (FC) between the thalamus and the other brain regions were explored after the participants took caffeine or modafinil. ResultsThe subjective sleepiness of the participants increased with the duration of SD. compared with placebo, modafinil and caffeine had insignificant effects on wakefulness or sleepiness. However, in terms of neural FC, we found varying degrees of attenuation or enhancement of the FC between the thalamus and other regions. Taking caffeine during SD weakened the FC between the right rostral temporal thalamus (rTtha) subregion and the left lingual gyrus compared with placebo. Caffeine enhanced the FC between three subregions of the thalamus, namely the left sensory thalamus, the left rTtha, and the right lateral pre-frontal thalamus, and the right inferior temporal, left orbitofrontal, and right superior occipital gyris. Modafinil weakened the FC between the right posterior parietal thalamus and left middle temporal gyrus, and enhanced the FC between the left medial pre-frontal thalamus, left rTtha, and right occipital thalamus and left middle frontal gyrus. ConclusionsAfter 36 h of total SD, modafinil and caffeine administration enhanced or attenuated the time-domain correlations between various subregions of the thalamus and brain regions of the frontal and temporal lobes in healthy adults, compared with placebo. These results provide valuable evidence for further unraveling the neuropharmacological mechanisms of caffeine and modafinil, as well as important insights for exploring effective pharmacological intervention strategies against SD.

Age-related alterations in human cortical microstructure across the lifespan: Insights from high-gradient diffusion MRI.

The human brain undergoes age-related microstructural alterations across the lifespan. Soma and Neurite Density Imaging (SANDI), a novel biophysical model of diffusion MRI, provides estimates of cell body (soma) radius and density, and neurite density in gray matter. The goal of this cross-sectional study was to assess the sensitivity of high-gradient diffusion MRI toward age-related alterations in cortical microstructure across the adult lifespan using SANDI. Seventy-two cognitively unimpaired healthy subjects (ages 19-85 years; 40 females) were scanned on the 3T Connectome MRI scanner with a maximum gradient strength of 300mT/m using a multi-shell diffusion MRI protocol incorporating 8 b-values and diffusion time of 19 ms. Intra-soma signal fraction obtained from SANDI model-fitting to the data was strongly correlated with age in all major cortical lobes (r = -0.69 to -0.60, FDR-p < 0.001). Intra-soma signal fraction (r = 0.48-0.63, FDR-p < 0.001) and soma radius (r = 0.28-0.40, FDR-p < 0.04) were significantly correlated with cortical volume in the prefrontal cortex, frontal, parietal, and temporal lobes. The strength of the relationship between SANDI metrics and age was greater than or comparable to the relationship between cortical volume and age across the cortical regions, particularly in the occipital lobe and anterior cingulate gyrus. In contrast to the SANDI metrics, all associations between diffusion tensor imaging (DTI) and diffusion kurtosis imaging metrics and age were low to moderate. These results suggest that high-gradient diffusion MRI may be more sensitive to underlying substrates of neurodegeneration in the aging brain than DTI and traditional macroscopic measures of neurodegeneration such as cortical volume and thickness.

Selective attention function impairment in HIV-negative patients with early forms of neurosyphilis

BackgroundThe attentional network test (ANT) is widely used to evaluate the performance of three attentional networks: alerting, orienting and executive attention networks. This study aimed to investigate the characteristics of attention functions in HIV-negative patients with early forms of neurosyphilis (NS) and their correlation with abnormalities in brain magnetic resonance imaging (MRI).MethodsThirty patients with early forms of NS, 31 patients with syphilis but without NS (Non-NS) and 35 healthy controls were recruited from an HIV-negative cohort between September 2020 and November 2022. The participants were evaluated with the ANT and the Mini-Mental State Examination (MMSE). Brain MRI was performed in NS and Non-NS patients.ResultsNo significant differences were observed in the MMSE scores among the three groups. However, patients with early forms of NS showed poorer performance in orienting and alerting functions than Non-NS group (F = 6.952, P = 0.011 and F = 8.794, P = 0.004, respectively); No significant difference was observed in executive function between the two groups (F = 0.001, P = 0.980). Multivariate analysis of variance using the Bonferroni post hoc test indicated that patients with NS exhibited less efficient orienting function (P = 0.023), and alerting function (P = 0.003) but not executive function (P = 0.99), compared to Non-NS patients. Additionally, a significant difference was found in orienting function between patients with NS and healthy controls (P < 0.001) compared to healthy controls. MRI scans revealed that the NS group had a higher prevalence of abnormalities in the frontal lobes and/or the temporoparietal junction compared to the Non-NS group (24/25 vs. 13/19, P = 0.032).ConclusionsThe orienting and alerting functions but not executive function were significantly less efficient in early forms of NS group than in the Non-NS group (P < 0.01). This indicates deficits in selective attention in patients with early forms of NS. Brain MRI scans revealed abnormalities in the frontal and/or parietal lobes, as well as the temporoparietal junction, suggesting potential neuropathological correlates of these attentional deficits.

Usefulness of combined pseudo-continuous arterial spin labelling and spectroscopic analysis in schizophrenic Egyptian population sample

BackgroundSchizophrenia is a prevalent psychiatric disorder that affects 1% of the global population. Schizophrenia frequently begins in late adolescence or early adulthood, causing significant educational, social, and economic costs for people and society. Functional neuroimaging research on schizophrenia physiopathology has been beneficial. Arterial spin labelling (ASL) is one of functional magnetic resonance imaging (fMRI) technologies that assess brain function without radiation. ASL uses magnetic resonance (MR) imaging to quantify tissue-level brain perfusion non-invasively. Arterial spin labelling (ASL) is one of the functional magnetic resonance imaging (fMRI) technologies that assess the brain function without radiation hazards. ASL uses magnetic resonance (MR) imaging to quantify tissue-level brain perfusion non-invasively. Many publications were performed on role of different advanced MRI techniques in schizophrenia, but our study insisted on the added value of combined ASL and MRS over the conventional MRI in schizophrenic Egyptian population sample.Aim of the workThe purpose of this work was to evaluate the added value of combined ASL-perfusion MRI and MRS in schizophrenic patients.MethodsThis prospective case–control study was carried out on two groups: First group was 30 patients who were diagnosed clinically as schizophrenic patients, and second group was 20 healthy volunteers as a control group for comparison in the period from August 2021 till July 2022.ResultsThe majority of newly diagnosed cases had significant higher positive symptoms than chronic cases. According to arterial spin labelling (ASL) data, rCBF was noticed to be reduced in anterior cingulate, frontal lobe, and parietal lobe of both patients’ subgroups but more significant in chronically ill patients. Convergent results of decreased rCBF were also found in the parietal lobe and occipital lobe. Magnetic resonance spectroscopic analysis showed that NAA was decreased in the anterior cingulate cortex, thalami and basal ganglia of the newly diagnosed cases more than chronic cases. The ASL-MRI perfusion accurately detected the hypo-perfusion of different brain regions with sensitivity 100%, specificity 66.67%, positive predictive value 96.43%, negative predictive value 100%, and accuracy 96.67%, while MR spectroscopy showed sensitivity 100%, specificity 33.33%, positive predictive value 93.10%, negative predictive value 100%, and accuracy 93.33% in evaluation of changes of brain metabolites.ConclusionASL is a promising functional MRI technique that can produce together with MRS quantitative information about the metabolites of different brain regions. The ASL-MRI appears as a reliable non-invasive technique to measure cerebral blood flow and identify decreased rCBF without any contrast administration, and it could be repeatable which helps in early diagnosis as well as follow-up of the progression of the disease.

Gradual change of cortical representations with growing visual expertise for synthetic shapes

Abstract Objective: Visual expertise for particular categories of objects (e.g., mushrooms, birds, flowers, minerals, and so on) is known to enhance cortical responses in parts of the ventral occipitotemporal cortex. How is such additional expertise integrated into the prior cortical representation of life-long visual experience? To address this question, we presented synthetic visual objects rotating in three dimensions and recorded multivariate BOLD responses as initially unfamiliar objects gradually became familiar. Main results: An analysis of pairwise distances between multivariate BOLD responses (“representational similarity analysis,” RSA) revealed that visual objects were linearly discriminable in large parts of the ventral occipital cortex, including the primary visual cortex, as well as in certain parts of the parietal and frontal cortex. These cortical representations were present from the start, when objects were still unfamiliar, and even though objects were shown from different sides. As shapes became familiar with repeated viewing, the distribution of responses expanded to fill more of the available space. In contrast, the distribution of responses to novel shapes (which appeared only once) contracted and shifted to the margins of the available space. Conclusion: Our results revealed cortical representations of object shape and gradual changes in these representations with learning and consolidation. The cortical representations of once-viewed shapes that remained novel diverged dramatically from repeatedly viewed shapes that became familiar. This disparity was evident in both the similarity and the diversity of multivariate BOLD responses.

Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolatedfrom postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.

Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease

Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

Independent expansion, selection and hypervariability of the TBC1D3 gene family in humans.

TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 non-human primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on Chromosome 17. We find that all human copy number variation maps to two distinct clusters located at Chromosome 17q12 and that humans are highly structurally variable at this locus, differing by as many as 20 copies and ~1 Mbp in length depending on haplotypes. We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Lastly, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.

Combination antiretroviral therapy prevents SIV-induced aging in the hippocampus and neurodegeneration throughout the brain.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated neurocognitive disorders (HAND) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining acute infection, and cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16 INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and altered expression of SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions, and treatment with cART reduced GFAP expression in SIV-infected animals and thus likely decreases inflammation in the brain. Importantly, cART reversed SIV-induced accelerated aging (p16 and SIRT1) and neurodegeneration in the frontal lobe and hippocampus. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HAND.

Developmental trajectory and sex differences in auditory processing in a PTEN-deletion model of autism spectrum disorders

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.

Unveiling hierarchy and spatial distribution of O6-methylguanine-DNA methyltransferase promoter methylation in World Health Organization grade 2-3 gliomas.

This study investigated the role of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. Our findings highlighted the critical role of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. In conclusion, our study elucidates the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas, providing insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.

PFC/M1 activation and excitability: a longitudinal cohort study on fatigue symptoms in healthcare workers post-COVID-19

BackgroundFatigue is one of the most common neurological symptoms reported post coronavirus disease 2019 (COVID-19) infection. In order to establish effective early intervention strategies, more emphasis should be placed on the correlation between fatigue and cortical neurophysiological changes, especially in healthcare workers, who are at a heightened risk of COVID-19 infection.MethodsA prospective cohort study was conducted involving 29 COVID-19 medical workers and 24 healthy controls. The assessment included fatigue, sleep and health quality, psychological status, and physical capacity. Functional near-infrared spectroscopy (fNIRS) was employed to detect activation of brain regions. Bilateral primary motor cortex (M1) excitabilities were measured using single- and paired-pulse transcranial magnetic stimulation. Outcomes were assessed at 1, 3, and 6 months into the disease course.ResultsAt 1-month post-COVID-19 infection, 37.9% of patients experienced severe fatigue symptoms, dropping to 10.3% at 3 months. Interestingly, the remarkable decreased activation/excitability of bilateral prefrontal lobe (PFC) and M1 were closely linked to fatigue symptoms after COVID-19. Notably, greater increase in M1 region excitability correlated with more significant fatigue improvement. Re-infected patients exhibited lower levels of brain activation and excitability compared to single-infection patients.ConclusionsBoth single infection and reinfection of COVID-19 lead to decreased activation and excitability of the PFC and M1. The degree of excitability improvement in the M1 region correlates with a greater recovery in fatigue. Based on these findings, targeted interventions to enhance and regulate the excitability of M1 may represent a novel strategy for COVID-19 early rehabilitation. Trial registration: The Ethics Review Committee of Xijing Hospital, No. KY20232051-F-1; www.chictr.org.cn, ChiCTR2300068444.

Comparison of Brain Function and Structure in Patients with Major Depression: A Systematic Review and Meta-Analysis of MRI-Based Data.

Depression is a common mental illness worldwide. Neuroimaging techniques, such as magnetic resonance imaging and functional magnetic resonance imaging, play an essential role in diagnosing and evaluating depression. This study is based on magnetic resonance imaging (MRI)-related research to explore the comparison of brain function and structure between patients with severe depression and normal individuals, and to conduct meta-analysis. We conducted searches in various databases such as PubMed, Web of Science, Embase, and Cochrane Library to obtain research data on comparing brain function and structure between patients with severe depression and healthy individuals. The search keywords included "Major Depressive Disorder", "Brain Function", "Brain Structure", "Depression", "MRI", and "Magnetic Resonance". The quality assessment was conducted using the bias risk assessment tool recommended by the Cochrane Collaborative Network. Literature was screened following the predetermined inclusion and exclusion criteria, and Anisotropic Effect-Size Seed-Based Differential Mapping (AES-SDM) was used for systematic meta-analysis. Regression analysis was performed on age, gender, disease duration, years of education, and treatment status. After a thorough screening process, 10 documents were selected for subsequent analysis. These studies consisted of 477 study subjects, including 231 depression patients and 246 healthy individuals. The proportion of women was 36%-75%, and the disease duration was 3-60 months. The patients in 4 documents had first attacks, and the patients in the other 6 documents had multiple attacks. The baseline conditions of the 10 included documents were consistent and comparable. None of the studies reported blinding methods, and none of the results had incomplete data. The Regional homogeneity (ReHo) levels in the left precuneus (BA7), lentiform nucleus (BA48), and left prefrontal lobe (BA32) were significantly increased in the depression group, with voxel numbers of 358, 116, and 181, respectively. Conversely, the left postcentral gyrus (BA4), left cerebellar area (hemispheric lobule I, IV/V, lingual gyrus, fusiform gyrus), left fusiform gyrus (BA30), and right cingulate gyrus (BA23) were significantly reduced, with voxel numbers of 17, 50, and 124, respectively. Furthermore, regression analysis showed that gender, age, disease duration, years of education, and disease severity were potential influencing factors, and the disease duration demonstrated the most significant impact on the left cingulate gyrus (SDM = 2.777). There are significant differences in brain function and structure between patients with major depression and healthy individuals. Furthermore, our findings reveal a substantial correlation between the severity of depressive symptoms and brain function and structure indicators. These findings provide novel research directions and ideas for the diagnosis and treatment of depression.

Exploring role of prefrontal cortex region of brain in children having ADHD with machine learning: Implications and insights

Objective Attention deficit hyperactivity disorder (ADHD), is a general neurodevelopmental syndrome. This affects both adults and children, causing issues like hyperactivity, inattention, and impulsivity. Diagnosis, typically reliant on patient narratives and questionnaires, can sometimes be inaccurate, leading to distress. We propose utilizing empirical mode decomposition (EMD) for feature extraction and a machine learning (ML) algorithm to categorize ADHD and control. Method Publicly available Kaggle dataset is used for research. The EMD technique decomposes an electroencephalogram (EEG) waveform to 12 intrinsic mode functions (IMFs). Thirty-one statistical parameters are generated over the first 6 IMFs to create an input feature vector for the deep belief network (DBN) classifier. Principal component analysis (PCA) is utilized to reduce dimension. Findings Experimental results are compared on prefrontal cortex channels Fp1 and Fp2. After an in-depth evaluation of all metrics, it is observed that, in patients with ADHD, the prefrontal cortex regulates attention, behavior, and emotion. Our findings align with established neuroscience. The critical functions of the brain, such as organization, planning, attention, and decision making, are performed by the frontal lobe. Novelty Our work provides a novel approach to understanding the disorder’s underlying neurobiological mechanisms. It has the potential to deepen our understanding of the condition, improve diagnostic accuracy, personalize treatment methods, and, ultimately, improve outcomes for those affected.

The minimal computational substrate of fluid intelligence

The quantification of cognitive powers rests on identifying a behavioural task that depends on them. Such dependence cannot be assured, for the powers a task invokes cannot be experimentally controlled or constrained a priori, resulting in unknown vulnerability to failure of specificity and generalisability. Evaluating a compact version of Raven's Advanced Progressive Matrices (RAPM), a widely used clinical test of fluid intelligence, we show that LaMa, a self-supervised artificial neural network trained solely on the completion of partially masked images of natural environmental scenes, achieves representative human-level test scores a prima vista, without any task-specific inductive bias or training. Compared with cohorts of healthy and focally lesioned participants, LaMa exhibits human-like variation with item difficulty, and produces errors characteristic of right frontal lobe damage under degradation of its ability to integrate global spatial patterns. LaMa's narrow training and limited capacity suggest matrix-style tests may be open to computationally simple solutions that need not necessarily invoke the substrates of reasoning.

Supra-tentorial Ependymomas with ZFTA Fusion, YAP1 Fusion, and Astroblastomas, MN1-altered: Characteristic Imaging Features.

Supratentorial (ST) ependymoma subgroups are defined by two different fusions with different prognoses. Astroblastomas, MN1-altered, have ependymal-like histopathologic features and represent adifferential diagnosis in children. We hypothesized that ZFTA-fused ependymoma and YAP1-fused ependymoma on the one hand, and astroblastoma, MN1-altered, on the other hand, show different MRI characteristics. We retrospectively analyzed the preoperative imaging of 45patients with ST ependymoma or astroblastoma between January 2000 and September 2020, blinded to histomolecular grouping. Several characteristics, such as location, tumor volume, calcifications, solid/cystic component, and signal enhancement or diffusion were evaluated. We compared imaging characteristics according to their molecular subtype (ZFTA-fused, YAP1-fused, and astroblastoma, MN1-altered). Thirty-nine patients were classified as having an ependymoma, 35with aZFTA fusion and four with aYAP1 fusion, and six as having an astroblastoma, MN1-altered. YAP1-fused ependymomas were more likely to involve at least 3lobes than ZFTA-fused ependymomas. Astroblastomas were located in the frontal lobe in 100% of the tumors versus 49% of the ependymomas. Cerebral blood flow by arterial spin labeling was higher in astroblastomas than in ependymomas. There were no differences in the other characteristics between the molecular groups. All the tumors showed common features: intra-axial extra-ventricular tumors, very frequent contrast enhancement (39/43, 91%), acystic/necrotic component (41/45, 91%), restricted diffusion (32/36, 89%), calcifications (15/18, 83%), and peri-tumoral edema (38/44, 86%). The distinction between ST ependymoma subtypes and astroblastomas can be guided by several imaging features. These tumors share common imaging features that may help to differentiate ST ependymomas and astroblastomas from other pediatric ST tumors.