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The International Journal of... Aug 2023Implicit cognitive markers may assist with the prediction of suicidality beyond clinical risk factors. The aim of this study was to investigate neural correlates...
BACKGROUND
Implicit cognitive markers may assist with the prediction of suicidality beyond clinical risk factors. The aim of this study was to investigate neural correlates associated with the Death/Suicide Implicit Association Test (DS-IAT) via event-related potentials (ERP) in suicidal adolescents.
METHODS
Thirty inpatient adolescents with suicidal ideations and behaviors (SIBS) and 30 healthy controls from the community were recruited. All participants underwent 64-channel electroencephalography, DS-IAT, and clinical assessments. Hierarchical generalized linear models with spatiotemporal clustering were used to identify significant ERPs associated with the behavioral outcome of DS-IAT (D scores) and group differences.
RESULTS
Behavioral results (D scores) showed that the adolescents with SIBS had stronger implicit associations between "death" and "self" than the healthy group (P = .02). Within adolescents with SIBS, participants with stronger implicit associations between "death" and "self" reported more difficulty in controllability of suicidal ideation in the past 2 weeks based on the Columbia-Suicide Severity Rating Scale (P = .03). For the ERP data, the D scores and N100 component over the left parieto-occipital cortex had significant correlations. Significant group differences without behavioral correlation were observed for a second N100 cluster (P = .01), P200 (P = .02), and late positive potential (5 clusters, all P ≤ .02). Exploratory predictive models combining both neurophysiological and clinical measures distinguished adolescents with SIBS from healthy adolescents.
CONCLUSIONS
Our results suggest that N100 may be a marker of attentional resources involved in the distinction of stimuli that are congruent or incongruent to associations between death and self. Combined clinical and ERP measures may have utility in future refinements of assessment and treatment approaches for adolescents with suicidality.
Topics: Humans; Adolescent; Suicidal Ideation; Suicide; Evoked Potentials; Risk Factors; Electroencephalography
PubMed: 37422891
DOI: 10.1093/ijnp/pyad039 -
Annals of Neurology Sep 2023Unawareness of a deficit, anosognosia, can occur for visual or motor deficits and lends insight into awareness itself; however, lesions associated with anosognosia occur...
OBJECTIVE
Unawareness of a deficit, anosognosia, can occur for visual or motor deficits and lends insight into awareness itself; however, lesions associated with anosognosia occur in many different brain locations.
METHODS
We analyzed 267 lesion locations associated with either vision loss (with and without awareness) or weakness (with and without awareness). The network of brain regions connected to each lesion location was computed using resting-state functional connectivity from 1,000 healthy subjects. Both domain specific and cross-modal associations with awareness were identified.
RESULTS
The domain-specific network for visual anosognosia demonstrated connectivity to visual association cortex and posterior cingulate while motor anosognosia was defined by insula, supplementary motor area, and anterior cingulate connectivity. A cross-modal anosognosia network was defined by connectivity to the hippocampus and precuneus (false discovery rate p < 0.05).
INTERPRETATION
Our results identify distinct network connections associated with visual and motor anosognosia and a shared, cross-modal network for awareness of deficits centered on memory-related brain structures. ANN NEUROL 2023;94:434-441.
Topics: Humans; Awareness; Brain; Agnosia; Cerebral Cortex; Gyrus Cinguli; Magnetic Resonance Imaging
PubMed: 37289520
DOI: 10.1002/ana.26709 -
BioRxiv : the Preprint Server For... Aug 2023Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous...
Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer's disease and Parkinson's disease genome-wide association studies (GWAS), such as apolipoprotein E (), and leucine-rich repeat kinase 2 () in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.
PubMed: 37577533
DOI: 10.1101/2023.07.31.551097 -
Psychiatry Research. Neuroimaging Oct 2023Individuals with schizophrenia (SZ) show aberrant activations, assessed via functional magnetic resonance imaging (fMRI), during auditory oddball tasks. However,...
Individuals with schizophrenia (SZ) show aberrant activations, assessed via functional magnetic resonance imaging (fMRI), during auditory oddball tasks. However, associations with cognitive performance and genetic contributions remain unknown. This study compares individuals with SZ to healthy volunteers (HVs) using two cross-sectional data sets from multi-center brain imaging studies. It examines brain activation to auditory oddball targets, and their associations with cognitive domain performance, schizophrenia polygenic risk scores (PRS), and genetic variation (loci). Both sample 1 (137 SZ vs. 147 HV) and sample 2 (91 SZ vs. 98 HV), showed hypoactivation in SZ in the left-frontal pole, and right frontal orbital, frontal pole, paracingulate, intracalcarine, precuneus, supramarginal and hippocampal cortices, and right thalamus. In SZ, precuneus activity was positively related to cognitive performance. Schizophrenia PRS showed a negative correlation with brain activity in the right-supramarginal cortex. GWA analyses revealed significant single-nucleotide polymorphisms associated with right-supramarginal gyrus activity. RPL36 also predicted right-supramarginal gyrus activity. In addition to replicating hypoactivation for oddball targets in SZ, this study identifies novel relationships between regional activity, cognitive performance, and genetic loci that warrant replication, emphasizing the need for continued data sharing and collaborative efforts.
Topics: Humans; Schizophrenia; Cross-Sectional Studies; Brain; Cerebral Cortex; Frontal Lobe
PubMed: 37690161
DOI: 10.1016/j.pscychresns.2023.111710 -
Molecular Neurodegeneration Feb 2024Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated...
BACKGROUND
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms.
METHODS
In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0-30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects.
RESULTS
The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ([Formula: see text] = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] = 0.03, 95%CI = 0.01-0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ([Formula: see text] s = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] s = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] s = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13-49% of variance in cognitive and functional scales and 6-14% of variance in neuropsychiatric scales.
CONCLUSION
Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.
Topics: Humans; Activities of Daily Living; Autopsy; Brain; Chronic Traumatic Encephalopathy; Cognition; Neurodegenerative Diseases; tau Proteins
PubMed: 38317248
DOI: 10.1186/s13024-023-00697-2 -
The World Journal of Biological... Mar 2024Corticosteroids are widely prescribed for a variety of medical conditions. Accumulating evidence suggests that their use may be associated with adverse psychiatric... (Review)
Review
OBJECTIVES
Corticosteroids are widely prescribed for a variety of medical conditions. Accumulating evidence suggests that their use may be associated with adverse psychiatric effects, including mania. In this systematic review, we aim to critically evaluate the existing literature on the association between corticosteroid use and the emergence of mania.
METHODS
We conducted a comprehensive search of major electronic databases (PubMed, Embase, Cochrane Library) for relevant studies published up to the date of the search (12th January 2023). Inclusion criteria involve studies that investigate the association between corticosteroid use and the emergence of mania in adult patients. The primary outcome is the prevalence of (hypo)mania following corticosteroid administration. Secondary outcomes include potential risk factors, dose-response relationships, and differences among various corticosteroid formulations.
RESULTS
The identified studies were subjected to a systematic selection process and data extraction by an independent reviewer. A total of 47 articles met the inclusion criteria for our systematic review.
CONCLUSION
Our findings suggest that mania is a common side-effect of corticosteroid use, particularly in prednisone equivalent doses above 40 mg. These findings hold practical significance for clinicians and provide insights into potential interventions, including careful monitoring, dose adjustments, and consideration of psychotropic medications when managing corticosteroid-induced mania.
Topics: Adult; Humans; Mania; Adrenal Cortex Hormones; Prednisone
PubMed: 38363330
DOI: 10.1080/15622975.2024.2312572 -
Aging and Disease Aug 2023Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a...
Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman's partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology.
PubMed: 37548931
DOI: 10.14336/AD.2023.0707 -
The Journal of Allergy and Clinical... Oct 2023Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids.
OBJECTIVES
We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores.
METHODS
Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated.
RESULTS
Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level.
CONCLUSIONS
OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.
Topics: Humans; Transcriptome; Asthma; Gene Expression Profiling; Biomarkers; Adrenal Cortex Hormones
PubMed: 37315813
DOI: 10.1016/j.jaci.2023.05.023 -
Brain Communications 2023Post-stroke depression affects about 30% of stroke patients and often hampers functional recovery. The diagnosis of depression encompasses heterogeneous symptoms at...
Post-stroke depression affects about 30% of stroke patients and often hampers functional recovery. The diagnosis of depression encompasses heterogeneous symptoms at emotional, motivational, cognitive, behavioural or somatic levels. Evidence indicates that depression is caused by disruption of bio-aminergic fibre tracts between prefrontal and limbic or striatal brain regions comprising different functional networks. Voxel-based lesion-symptom mapping studies reported discrepant findings regarding the association between infarct locations and depression. Inconsistencies may be due to the usage of sum scores, thereby mixing different symptoms of depression. In this cross-sectional study, we used multivariate support vector regression for lesion-symptom mapping to identify regions significantly involved in distinct depressive symptom domains and global depression. MRI lesion data were included from 200 patients with acute first-ever ischaemic stroke (mean 0.9 ± 1.5 days of post-stroke). The Montgomery-Åsberg Depression Rating interview assessed depression severity in five symptom domains encompassing motivational, emotional and cognitive symptoms deficits, anxiety and somatic symptoms and was examined 8.4 days of post-stroke (±4.3). We found that global depression severity, irrespective of individual symptom domains, was primarily linked to right hemispheric lesions in the dorsolateral prefrontal cortex and inferior frontal gyrus. In contrast, when considering distinct symptom domains individually, the analyses yielded much more sensitive results in regions where the correlations with the global depression score yielded no effects. Accordingly, motivational deficits were associated with lesions in orbitofrontal cortex, dorsolateral prefrontal cortex, pre- and post-central gyri and basal ganglia, including putamen and pallidum. Lesions affecting the dorsal thalamus, anterior insula and somatosensory cortex were significantly associated with emotional symptoms such as sadness. Damage to the dorsolateral prefrontal cortex was associated with concentration deficits, cognitive symptoms of guilt and self-reproach. Furthermore, somatic symptoms, including loss of appetite and sleep disturbances, were linked to the insula, parietal operculum and amygdala lesions. Likewise, anxiety was associated with lesions impacting the central operculum, insula and inferior frontal gyrus. Interestingly, symptoms of anxiety were exclusively left hemispheric, whereas the lesion-symptom associations of the other domains were lateralized to the right hemisphere. In conclusion, this large-scale study shows that in acute stroke patients, differential post-stroke depression symptom domains are associated with specific structural correlates. Our findings extend existing concepts on the neural underpinnings of depressive symptoms, indicating that differential lesion patterns lead to distinct depressive symptoms in the first weeks of post-stroke. These findings may facilitate the development of personalized treatments to improve post-stroke rehabilitation.
PubMed: 37908237
DOI: 10.1093/braincomms/fcad275 -
BMC Medicine Jul 2023Inflammation has been implicated in the pathology of schizophrenia and may cause neuronal cell death and dendrite loss. Neuroimaging studies have highlighted...
BACKGROUND
Inflammation has been implicated in the pathology of schizophrenia and may cause neuronal cell death and dendrite loss. Neuroimaging studies have highlighted longitudinal brain structural changes in patients with schizophrenia, yet it is unclear whether this is related to inflammation. We aim to address this question, by relating brain structural changes with the transcriptional profile of inflammation markers in the early stage of schizophrenia.
METHODS
Thirty-eight patients with first-episode schizophrenia and 51 healthy controls were included. High-resolution T1-weighted magnetic resonance imaging (MRI) and clinical assessments were performed at baseline and 2 ~ 6 months follow-up for all subjects. Changes in the brain structure were analyzed using surface-based morphological analysis and correlated with the expression of immune cells-related gene sets of interest reported by previous reviews. Transcriptional data were retrieved from the Allen Human Brain Atlas. Furthermore, we examined the brain structural changes and peripheral inflammation markers in association with behavioral symptoms and cognitive functioning in patients.
RESULTS
Patients exhibited accelerated cortical thickness decrease in the left frontal cortices, less decrease or an increase in the superior parietal lobule and right lateral occipital lobe, and increased volume in the bilateral pallidum, compared with controls. Changes in cortical thickness correlated with the transcriptional level of monocyte across cortical regions in patients (r = 0.54, p < 0.01), but not in controls (r = - 0.05, p = 0.76). In addition, cortical thickness change in the left superior parietal lobule positively correlated with changes in digital span-backward test scores in patients.
CONCLUSIONS
Patients with schizophrenia exhibit regional-specific cortical thickness changes in the prefrontal and parietooccipital cortices, which is related to their cognitive impairment. Inflammation may be an important factor contributing to cortical thinning in first-episode schizophrenia. Our findings suggest that the immunity-brain-behavior association may play a crucial role in the pathogenesis of schizophrenia.
Topics: Humans; Schizophrenia; Magnetic Resonance Imaging; Brain; Cognition; Cerebral Cortex
PubMed: 37424013
DOI: 10.1186/s12916-023-02963-y