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The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental health and physical health. We explore the psychological, social, and neuroscientific effects of COVID-19 and set out the immediate priorities and longer-term strategies for mental health science research. These priorities were informed by surveys of the public and an expert panel convened by the UK Academy of Medical Sciences and the mental health research charity, MQ: Transforming Mental Health, in the first weeks of the pandemic in the UK in March, 2020. We urge UK research funding agencies to work with researchers, people with lived experience, and others to establish a high level coordination group to ensure that these research priorities are addressed, and to allow new ones to be identified over time. The need to maintain high-quality research standards is imperative. International collaboration and a global perspective will be beneficial. An immediate priority is collecting high-quality data on the mental health effects of the COVID-19 pandemic across the whole population and vulnerable groups, and on brain function, cognition, and mental health of patients with COVID-19. There is an urgent need for research to address how mental health consequences for vulnerable groups can be mitigated under pandemic conditions, and on the impact of repeated media consumption and health messaging around COVID-19. Discovery, evaluation, and refinement of mechanistically driven interventions to address the psychological, social, and neuroscientific aspects of the pandemic are required. Rising to this challenge will require integration across disciplines and sectors, and should be done together with people with lived experience. New funding will be required to meet these priorities, and it can be efficiently leveraged by the UK's world-leading infrastructure. This Position Paper provides a strategy that may be both adapted for, and integrated with, research efforts in other countries.

IntroductionThe Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) confers greater catabolism of dopamine (DA) in the prefrontal cortex (PFC) than the Met allele. Met/Met homozygotes typically outperform Val-carriers on tests of executive function (EF), perhaps resulting from increased DA bioavailability. Methamphetamine (METH) causes large releases of DA, which is associated with neurotoxicity and executive dysfunction in chronic METH users. We hypothesized that, contrary to its effect in non-METH-using populations, slower DA clearance conferred by Met/Met will relate to worse EF in METH users.Methods149 non-Hispanic White men, stratified by METH dependence (METH+/-) and COMT (Val/Val, Val/Met, Met/Met), completed three tests of EF: Wisconsin Card Sorting Test (WCST), Stroop Color-Word Test (Stroop), and Trail Making Test Part B (Trails B). Demographically-adjusted test scores were averaged to create an EF composite T-score. We examined the interaction of METH and COMT on the EF composite and individual test T-scores, controlling for premorbid functioning and alcohol use.ResultsMETH group differences in EF were evident only among Met/Met carriers (beta = -9.36, p

Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50 years) and 82 younger (

This study evaluated the effects of HIV-associated Neurocognitive Disorders (HAND) on 2 Internet-based tests of healthcare management. Study participants included 46 individuals with HIV infection, 19 of whom were diagnosed with HAND, and 21 seronegatives. Participants were administered Internet-based tests of online pharmacy and health records navigation skills in which they used mock credentials to log in to an experimenter-controlled website and independently perform a series of typical online health-related behaviors (e.g., refill a prescription, read and interpret an electronic chart note). HAND was associated with significantly lower accuracy on both the online pharmacy and health records navigation tasks. Among the HIV+ participants, poorer performance on the online healthcare navigation tasks was associated with fewer years of education, higher plasma viral load, less frequent Internet use, and lower health literacy. Findings indicate that individuals with HAND may have marked difficulties navigating the Internet to complete important health-related behaviors.

Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 (SLC39A12) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a number of cortical regions (Brodmanns area (BA) 8, 9, 44) from subjects with Sz, in BA 9 from subjects with mood disorders and in rats treated with antipsychotic drugs. In addition, we determined whether inducing the expression of SLC39A12 resulted in an increased cellular zinc uptake. SLC39A12 variant 1 and 2 mRNA was measured using quantitative PCR. Zinc uptake was measured in CHO cells transfected with human SLC39A12 variant 1 and 2. In Sz, compared with controls, SLC39A12 variant 1 and 2 mRNA was higher in all cortical regions studied. The were no differences in levels of mRNA for either variant of SLC39A12 in BA 9 from subjects with mood disorders and levels of mRNA for Slc39a12 was not different in the cortex of rats treated with antipsychotic drugs. Finally, expressing both variants in CHO-K1 cells was associated with an increase in radioactive zinc uptake. As increased levels of murine Slc39a12 mRNA has been shown to correlate with increasing cellular zinc uptake, our data would be consistent with the possibility of a dysregulated zinc homeostasis in the cortex of subjects with schizophrenia due to altered expression of SLC39A12.

BackgroundHuman immunodeficiency virus (HIV) and methamphetamine use commonly affect neurocognitive (NC) functioning. We evaluated the relationships between NC functioning and two fibroblast growth factors (FGFs) in volunteers who differed in HIV serostatus and methamphetamine dependence (MAD).MethodsA total of 100 volunteers were categorized into four groups based on HIV serostatus and MAD in the prior year. FGF-1 and FGF-2 were measured in cerebrospinal fluid by enzyme-linked immunosorbent assays along with two reference biomarkers (monocyte chemotactic protein [MCP]-1 and neopterin). Comprehensive NC testing was summarized by global and domain impairment ratings.ResultsSixty-three volunteers were HIV+ and 59 had a history of MAD. FGF-1, FGF-2, and both reference biomarkers differed by HIV and MAD status. For example, FGF-1 levels were lower in subjects who had either HIV or MAD than in HIV- and MAD- controls (P=0.003). Multivariable regression identified that global NC impairment was associated with an interaction between FGF-1 and FGF-2 (model R(2)=0.09, P=0.01): higher FGF-2 levels were only associated with neurocognitive impairment among subjects who had lower FGF-1 levels. Including other covariates in the model (including antidepressant use) strengthened the model (model R(2)=0.18, P=0.004) but did not weaken the association with FGF-1 and FGF-2. Lower FGF-1 levels were associated with impairment in five of seven cognitive domains, more than FGF-2, MCP-1, or neopterin.ConclusionThese findings provide in vivo support that HIV and MAD alter expression of FGFs, which may contribute to the NC abnormalities associated with these conditions. These cross-sectional findings cannot establish causality and the therapeutic benefits of recombinant FGF-1 need to be investigated.

FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p

HIV infection disturbs the central nervous system (CNS) through inflammation and glial activation. Evidence suggests roles for microRNA (miRNA) in host defense and neuronal homeostasis, though little is known about miRNAs' role in HIV CNS infection. MiRNAs are non-coding RNAs that regulate gene translation through post-transcriptional mechanisms. Messenger-RNA profiling alone is insufficient to elucidate the dynamic dance of molecular expression of the genome. We sought to clarify RNA alterations in the frontal cortex (FC) of HIV-infected individuals and those concurrently infected and diagnosed with major depressive disorder (MDD). This report is the first published study of large-scale miRNA profiling from human HIV-infected FC. The goals of this study were to: 1. Identify changes in miRNA expression that occurred in the frontal cortex (FC) of HIV individuals, 2. Determine whether miRNA expression profiles of the FC could differentiate HIV from HIV/MDD, and 3. Adapt a method to meaningfully integrate gene expression data and miRNA expression data in clinical samples. We isolated RNA from the FC (n = 3) of three separate groups (uninfected controls, HIV, and HIV/MDD) and then pooled the RNA within each group for use in large-scale miRNA profiling. RNA from HIV and HIV/MDD patients (n = 4 per group) were also used for non-pooled mRNA analysis on Affymetrix U133 Plus 2.0 arrays. We then utilized a method for integrating the two datasets in a Target Bias Analysis. We found miRNAs of three types: A) Those with many dysregulated mRNA targets of less stringent statistical significance, B) Fewer dysregulated target-genes of highly stringent statistical significance, and C) unclear bias. In HIV/MDD, more miRNAs were downregulated than in HIV alone. Specific miRNA families at targeted chromosomal loci were dysregulated. The dysregulated miRNAs clustered on Chromosomes 14, 17, 19, and X. A small subset of dysregulated genes had many 3' untranslated region (3'UTR) target-sites for dysregulated miRNAs. We provide evidence that certain miRNAs serve as key elements in gene regulatory networks in HIV-infected FC and may be implicated in neurobehavioral disorder. Finally, our data indicates that some genes may serve as hubs of miRNA activity.

In recent years, human immunodeficiency virus (HIV)-infected patients under highly active anti-retroviral therapy (HAART) regimens have shown a markedly improved general clinical status; however, the prevalence of mild cognitive disorders has increased. We propose that increased longevity with HIV-mediated chronic inflammation combined with the secondary effects of HAART may increase the risk of early brain aging as shown by intraneuronal accumulation of abnormal protein aggregates like amyloid β (Aβ), which might participate in worsening the neurodegenerative process and cognitive impairment in older patients with HIV. For this purpose, levels and distribution of Aβ immunoreactivity were analyzed in the frontal cortex of 43 patients with HIV (ages 38–60) and HIV− age-matched controls. Subcellular localization of the Aβ-immunoreactive material was analyzed by double labeling and confocal microscopy and by immunono-electron microscopy (EM). Compared to HIV− cases, in HIV+ cases, there was abundant intracellular Aβ immunostaining in pyramidal neurons and along axonal tracts. Cases with HIV encephalitis (HIVE) had higher levels of intraneuronal Aβ immunoreactivity compared to HIV+ cases with no HIVE. Moreover, levels of intracellular Aβ correlated with age in the group with HIVE. Double-labeling analysis showed that the Aβ-immunoreactive granules in the neurons co-localized with lysosomal markers such as cathepsin-D and LC3. Ultrastructural analysis by immuno-EM has confirmed that in these cases, intracellular Aβ was often found in structures displaying morphology similar to autophagosomes. These findings suggest that long-term survival with HIV might interfere with clearance of proteins such as Aβ and worsen neuronal damage and cognitive impairment in this population.

Patients infected with human immunodeficiency virus (HIV) have a higher risk of developing major depressive disorder (MDD) than the general population. Immunophilins FKBP51 and FKBP52 are expressed in cortical neurons and regulate the function of the glucocorticoid receptor (GR). Previous reports have shown that genetic variants in the FKBP5 gene encoding FKBP51 are linked to psychiatric disorders. We sought to determine whether immunophilins are upregulated in HIV infection. To determine whether FKBP52 and FKBP51 are associated with MDD and/or HIV, we compared protein and gene expression in autopsy tissues from the frontal cortical gray matter. The study cases were divided into five groups: control, MDD, MDD with psychosis, HIV+, and HIV+ with MDD. Gene expression and protein levels were determined by real-time PCR and Western blot analysis of fresh frozen tissues. Genotyping of previously published alleles of the FKBP5 gene was also performed. We found correlation of upregulation of both immunophilins in the HIV-infected groups. In the HIV+ population with MDD, FKBP4 expression is significantly higher while FKBP5 is more variable. After analyzing the FKBP5 gene for single nucleotide polymorphisms, we found that rs3800373 CC genotype is more frequent in the MDD and MDD/Psychosis groups. We hypothesized that the levels of FKBP51, as modulator of the nuclear translocation of GR, would be lower in MDD. Instead, an increase in FKBP51 at both the transcript (FKBP5) and protein level correlated with MDD. Increased FKBP4 expression of correlated to HIV+MDD but not to HIV without MDD.

The frequency of neurodegenerative markers among long surviving human immunodeficiency virus (HIV)-infected individuals is unknown, therefore, the present study investigated the frequency of alpha-synuclein, beta-amyloid, and HIV-associated brain pathology in the brains of older HIV-infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV-infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. Neuritic alpha-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+cases and none of the older control cases (0/18). beta-Amyloid deposits were prevalent and found in nearly all of the HIV+cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+adults, HIV-associated brain pathology does not appear elevated; however, the frequency of both alpha-synuclein and beta-amyloid is higher than that found in older healthy persons. The increased prevalence of alpha-synuclein and beta-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease.

The frequency of neurodegenerative markers among long surviving human immunodeficiency virus (HIV)-infected individuals is unknown, therefore, the present study investigated the frequency of alpha-synuclein, beta-amyloid, and HIV-associated brain pathology in the brains of older HIV-infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV-infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. Neuritic alpha-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+cases and none of the older control cases (0/18). beta-Amyloid deposits were prevalent and found in nearly all of the HIV+cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+adults, HIV-associated brain pathology does not appear elevated; however, the frequency of both alpha-synuclein and beta-amyloid is higher than that found in older healthy persons. The increased prevalence of alpha-synuclein and beta-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease.

Background: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of muscarinic M1 receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low receptor levels. Methods: We determined the distribution and number of CHRM1-positive (CHRM1+) neurons in the cortex, medial dorsal nucleus of the thalamus and regions of the hippocampus from controls (n = 12, 12 and 5, respectively) and people with schizophrenia (n = 24, 24 and 13, respectively). Results: Compared with controls, levels of CHRM1 + neurons in people with schizophrenia were lower on pyramidal cells in layer III of Brodmann areas 9 (-44%) and 17 (-45%), and in layer V in Brodmann areas 9 (-45%) and 17 (-62%). We found no significant differences in the number of CHRM1+ neurons in the medial dorsal nucleus of the thalamus or in the hippocampus. Limitations: Although diagnostic cohort sizes were typical for this type of study, they were relatively small. As well, people with schizophrenia were treated with antipsychotic drugs before death. Conclusion: The loss of CHRM1+ pyramidal cells in the cortex of people with schizophrenia may underpin derangements in the cholinergic regulation of GABAergic activity in cortical layer III and in cortical/subcortical communication via pyramidal cells in layer V., Introduction Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the population worldwide. Its peak age of onset is in early adulthood, and it is equally prevalent in [...]