Recreational Marijuana Use, Adolescent Cognitive Development, and Schizophrenia Susceptibility

BACKGROUND: We investigated how low marijuana (MJ) use levels, the typical use pattern in most adolescent users, affect cognitive maturation and schizophrenia risk. METHODS: In two complementary adolescent samples where the majority reported minimal MJ use, we compared cognitive performances before and after MJ use initiation. The Iowa sample (40 first-degree relatives and 54 second-degree relatives of patients with schizophrenia and 117 control subjects with no schizophrenia family history) underwent a battery of standardized neuropsychological tests at 0, 18, and 36 months. Based on self-administered Timeline Followback interviews, 26.5% of adolescents had emergent MJ use (eMJ) during follow-up. The second sample (n = 3463), derived from a birth cohort, received substance use and sustained attention assessments between ages 10 and 15 years. Mixed linear models and regression analyses tested the effects of eMJ on longitudinal changes in cognitive performance. RESULTS: In the Iowa sample, longitudinal changes in 5 of 8 cognitive domains were significantly associated with eMJ. On sustained attention, visuospatial working memory, and executive sequencing, adolescents with eMJ showed less age-expected improved performance. In addition, first-degree relatives with eMJ were less improved on processing speed and executive reasoning than first-degree relatives without eMJ. In the birth cohort, greater intraindividual variability in reaction times (indicative of poorer sustained attention) was significantly associated with more frequent MJ use and with recreational use levels. CONCLUSIONS: Nonheavy MJ use disrupts normal adolescent maturation and compounds aberrant adolescent maturation associated with familial schizophrenia risk. These findings underscore the importance of reducing adolescent MJ access in the context of increased availability to high-potency MJ

Risk of thyroid dysfunction associated with mRNA and inactivated COVID-19 vaccines: a population-based study of 2.3 million vaccine recipients

Background: In view of accumulating case reports of thyroid dysfunction following COVID-19 vaccination, we evaluated the risks of incident thyroid dysfunction following inactivated (CoronaVac) and mRNA (BNT162b2) COVID-19 vaccines using a population-based dataset. / Methods: We identified people who received COVID-19 vaccination between 23 February and 30 September 2021 from a population-based electronic health database in Hong Kong, linked to vaccination records. Thyroid dysfunction encompassed anti-thyroid drug (ATD)/levothyroxine (LT4) initiation, biochemical picture of hyperthyroidism/hypothyroidism, incident Graves’ disease (GD), and thyroiditis. A self-controlled case series design was used to estimate the incidence rate ratio (IRR) of thyroid dysfunction in a 56-day post-vaccination period compared to the baseline period (non-exposure period) using conditional Poisson regression. / Results: A total of 2,288,239 people received at least one dose of COVID-19 vaccination (57.8% BNT162b2 recipients and 42.2% CoronaVac recipients). 94.3% of BNT162b2 recipients and 92.2% of CoronaVac recipients received the second dose. Following the first dose of COVID-19 vaccination, there was no increase in the risks of ATD initiation (BNT162b2: IRR 0.864, 95% CI 0.670–1.114; CoronaVac: IRR 0.707, 95% CI 0.549–0.912), LT4 initiation (BNT162b2: IRR 0.911, 95% CI 0.716–1.159; CoronaVac: IRR 0.778, 95% CI 0.618–0.981), biochemical picture of hyperthyroidism (BNT162b2: IRR 0.872, 95% CI 0.744–1.023; CoronaVac: IRR 0.830, 95% CI 0.713–0.967) or hypothyroidism (BNT162b2: IRR 1.002, 95% CI 0.838–1.199; CoronaVac: IRR 0.963, 95% CI 0.807–1.149), GD, and thyroiditis. Similarly, following the second dose of COVID-19 vaccination, there was no increase in the risks of ATD initiation (BNT162b2: IRR 0.972, 95% CI 0.770–1.227; CoronaVac: IRR 0.879, 95%CI 0.693–1.116), LT4 initiation (BNT162b2: IRR 1.019, 95% CI 0.833–1.246; CoronaVac: IRR 0.768, 95% CI 0.613–0.962), hyperthyroidism (BNT162b2: IRR 1.039, 95% CI 0.899–1.201; CoronaVac: IRR 0.911, 95% CI 0.786–1.055), hypothyroidism (BNT162b2: IRR 0.935, 95% CI 0.794–1.102; CoronaVac: IRR 0.945, 95% CI 0.799–1.119), GD, and thyroiditis. Age- and sex-specific subgroup and sensitivity analyses showed consistent neutral associations between thyroid dysfunction and both types of COVID-19 vaccines. / Conclusions: Our population-based study showed no evidence of vaccine-related increase in incident hyperthyroidism or hypothyroidism with both BNT162b2 and CoronaVac

Sequential algorithm to stratify liver fibrosis risk in overweight/obese metabolic dysfunction-associated fatty liver disease

BackgroundNon-diabetic overweight/obese metabolic dysfunction-associated fatty liver disease (MAFLD) represents the largest subgroup with heterogeneous liver fibrosis risk. Metabolic dysfunction promotes liver fibrosis. Here, we investigated whether incorporating additional metabolic risk factors into clinical evaluation improved liver fibrosis risk stratification among individuals with non-diabetic overweight/obese MAFLD.Materials and methodsComprehensive metabolic evaluation including 75-gram oral glucose tolerance test was performed in over 1000 participants from the New Hong Kong Cardiovascular Risk Factor Prevalence Study (HK-NCRISPS), a contemporary population-based study of HK Chinese. Hepatic steatosis and fibrosis were evaluated based on controlled attenuation parameter and liver stiffness (LS) measured using vibration-controlled transient elastography, respectively. Clinically significant liver fibrosis was defined as LS ≥8.0 kPa. Our findings were validated in an independent pooled cohort comprising individuals with obesity and/or polycystic ovarian syndrome.ResultsOf the 1020 recruited community-dwelling individuals, 312 (30.6%) had non-diabetic overweight/obese MAFLD. Among them, 6.4% had LS ≥8.0 kPa. In multivariable stepwise logistic regression analysis, abnormal serum aspartate aminotransferase (AST) (OR 7.95, p<0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5 (OR 5.01, p=0.008) were independently associated with LS ≥8.0 kPa, in a model also consisting of other metabolic risk factors including central adiposity, hypertension, dyslipidaemia and prediabetes. A sequential screening algorithm using abnormal AST, followed by elevated HOMA-IR, was developed to identify individuals with LS ≥8.0 kPa, and externally validated with satisfactory sensitivity (>80%) and negative predictive value (>90%).ConclusionA sequential algorithm incorporating AST and HOMA-IR levels improves fibrosis risk stratification among non-diabetic overweight/obese MAFLD individuals

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies

Altered Small-World Brain Networks in Schizophrenia Patients during Working Memory Performance

Impairment of working memory (WM) performance in schizophrenia patients (SZ) is well-established. Compared to healthy controls (HC), SZ patients show aberrant blood oxygen level dependent (BOLD) activations and disrupted functional connectivity during WM performance. In this study, we examined the small-world network metrics computed from functional magnetic resonance imaging (fMRI) data collected as 35 HC and 35 SZ performed a Sternberg Item Recognition Paradigm (SIRP) at three WM load levels. Functional connectivity networks were built by calculating the partial correlation on preprocessed time courses of BOLD signal between task-related brain regions of interest (ROIs) defined by group independent component analysis (ICA). The networks were then thresholded within the small-world regime, resulting in undirected binarized small-world networks at different working memory loads. Our results showed: 1) at the medium WM load level, the networks in SZ showed a lower clustering coefficient and less local efficiency compared with HC; 2) in SZ, most network measures altered significantly as the WM load level increased from low to medium and from medium to high, while the network metrics were relatively stable in HC at different WM loads; and 3) the altered structure at medium WM load in SZ was related to their performance during the task, with longer reaction time related to lower clustering coefficient and lower local efficiency. These findings suggest brain connectivity in patients with SZ was more diffuse and less strongly linked locally in functional network at intermediate level of WM when compared to HC. SZ show distinctly inefficient and variable network structures in response to WM load increase, comparing to stable highly clustered network topologies in HC

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Career Development in Schizophrenia: A Heuristic Framework

Adults with schizophrenia continue to have poor rates of competitive employment. We have learned how to support individuals in the workplace with supported employment (SE); but have paid limited attention to early vocational identity development, work antecedents, illness characteristics, and career preferences. Vocational identity development is an important and natural condition of human growth for all persons and is well-researched in career counseling. For young adults with schizophrenia, the predictor of positive work outcome with the most evidence has been that working competitively prior to illness leads to better chances for work post-diagnosis. A heuristic framework is proposed to conceptualize how pre-illness vocational development (paid and unpaid) plus life cycle supports can provide direction to the individual in their work recovery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44318/1/10597_2005_Article_5004.pd