Peak alpha frequency and electroencephalographic microstates are correlated with aggression in schizophrenia.

Large scale retrospective studies have shown an association between schizophrenia and risk of violence. Overall, this increase in risk is small and does not justify or support stigmatizing public perceptions or media depictions of people with schizophrenia. Nonetheless, in some situations, some symptoms of schizophrenia can increase the risk of violent behavior. Prediction of this behavior would allow high impact preventive interventions. However, to date the neurobiological correlates of violent behavior in schizophrenia are not well understood, precluding the development of prognostic biomarkers. We used electroencephalography to measure alpha activity and microstates from 31 patients with schizophrenia and 18 age matched controls. Participants also completed multiple assessments of current aggressive tendencies and their lifetime history of aggressive acts. We found that individual alpha peak frequency was negatively correlated with aggression scores in both patients and controls (largest Spearman's r = -0.45). Furthermore, this result could be replicated in data taken from a single frontal channel suggesting that this may be possible to obtain in routine clinical settings (largest Spearman's r = -0.40). We also found that transitions between microstates corresponding to auditory and visual networks were inversely correlated with aggression scores. Finally, we found that, within patients, aggression was correlated with the degree of randomness between microstate transitions. This suggests that aggression is related to inappropriate switching between large scale brain networks and subsequent failure to appropriately integrate complicated environmental and internal stimuli. By elucidating some of the electrophysiological correlates of aggression, these data facilitate the development of prognostic biomarkers.

Recreational cannabis use over time in individuals at clinical high risk for psychosis: Lack of associations with symptom, neurocognitive, functioning, and treatment patterns.

Recreational cannabis use has recently gained considerable interest as an environmental risk factor that triggers the onset of psychosis. To date, however, the evidence that cannabis is associated with negative outcomes in individuals at clinical high risk (CHR) for psychosis is inconsistent. The present study tracked cannabis usage over a 2-year period and examined its associations with clinical and neurocognitive outcomes, along with medication rates. CHR youth who continuously used cannabis had higher neurocognition and social functioning over time, and decreased medication usage, relative to non-users. Surprisingly, clinical symptoms improved over time despite the medication decreases.

Fetal brain vulnerability to SARS-CoV-2 infection.

Whether or not SARS-CoV-2 can cross from mother to fetus during a prenatal infection has been controversial; however, recent evidence such as viral RNA detection in umbilical cord blood and amniotic fluid, as well as the discovery of additional entry receptors in fetal tissues suggests a potential for viral transmission to and infection of the fetus. Furthermore, neonates exposed to maternal COVID-19 during later development have displayed neurodevelopmental and motor skill deficiencies, suggesting the potential for consequential neurological infection or inflammation in utero. Thus, we investigated transmission potential of SARS-CoV-2 and the consequences of infection on the developing brain using human ACE2 knock-in mice. In this model, we found that viral transmission to the fetal tissues, including the brain, occurred at later developmental stages, and that infection primarily targeted male fetuses. In the brain, SARS-CoV-2 infection largely occurred within the vasculature, but also within other cells such as neurons, glia, and choroid plexus cells; however, viral replication and increased cell death were not observed in fetal tissues. Interestingly, early gross developmental differences were observed between infected and mock-infected offspring, and high levels of gliosis were seen in the infected brains 7 days post initial infection despite viral clearance at this time point. In the pregnant mice, we also observed more severe COVID-19 infections, with greater weight loss and viral dissemination to the brain, compared to non-pregnant mice. Surprisingly, we did not observe an increase in maternal inflammation or the antiviral IFN response in these infected mice, despite showing clinical signs of disease. Overall, these findings have concerning implications regarding neurodevelopment and pregnancy complications of the mother following prenatal COVID-19 exposure.

Associations Between Childhood Area-Level Social Fragmentation, Maladaptation to School, and Social Functioning Among Healthy Youth and Those at Clinical High Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Although studies have identified social fragmentation as an important risk factor for schizophrenia and other psychotic disorders, it is unknown whether it may impact social functioning. This study investigates whether social fragmentation during childhood predicts maladaptation to school as well as social functioning during childhood and adulthood. STUDY DESIGN: Data were collected from the North American Prodrome Longitudinal Study. Participants included adults at clinical high risk for psychosis (CHR-P) and healthy comparisons (HC). Maladaptation to school and social functioning during childhood were assessed retrospectively and social functioning in adulthood was assessed at baseline. STUDY RESULTS: Greater social fragmentation during childhood was associated with greater maladaptation to school (adjusted ß = 0.21; 95% CI: 0.02 to 0.40). Social fragmentation was not associated with social functioning during childhood (unadjusted ß = -0.08; 95% CI: -0.31 to 0.15). However, greater social fragmentation during childhood predicted poorer social functioning in adulthood (adjusted ß = -0.43; 95% CI: -0.79 to -0.07). Maladaptation to school mediated 15.7% of the association between social fragmentation and social functioning. The association between social fragmentation and social functioning was stronger among adults at CHR-P compared to HC (adjusted ß = -0.42; 95% CI: -0.82 to -0.02). CONCLUSIONS: This study finds that social fragmentation during childhood is associated with greater maladaptation to school during childhood, which in turn predicts poorer social functioning in adulthood. Further research is needed to disentangle aspects of social fragmentation that may contribute to social deficits, which would have implications for the development of effective interventions at the individual and community levels.

Ethnoracial discrimination and the development of suspiciousness symptoms in individuals at clinical high-risk for psychosis.

BACKGROUND AND HYPOTHESIS: While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms. STUDY DESIGN: Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms. RESULTS: CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR. CONCLUSIONS: For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome.

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Single-Shot ChAd3-MARV Vaccine in Modified Formulation Buffer Shows 100% Protection of NHPs.

Marburg virus (MARV) is a virus of high human consequence with a case fatality rate of 24-88%. The global health and national security risks posed by Marburg virus disease (MVD) underscore the compelling need for a prophylactic vaccine, but no candidate has yet reached regulatory approval. Here, we evaluate a replication-defective chimpanzee adenovirus type 3 (ChAd3)-vectored MARV Angola glycoprotein (GP)-expressing vaccine against lethal MARV challenge in macaques. The ChAd3 platform has previously been reported to protect against the MARV-related viruses, Ebola virus (EBOV) and Sudan virus (SUDV), and MARV itself in macaques, with immunogenicity demonstrated in macaques and humans. In this study, we present data showing 100% protection against MARV Angola challenge (versus 0% control survival) and associated production of GP-specific IgGs generated by the ChAd3-MARV vaccine following a single dose of 1 × 1011 virus particles prepared in a new clinical formulation buffer designed to enhance product stability. These results are consistent with previously described data using the same vaccine in a different formulation and laboratory, demonstrating the reproducible and robust protective efficacy elicited by this promising vaccine for the prevention of MVD. Additionally, a qualified anti-GP MARV IgG ELISA was developed as a critical pre-requisite for clinical advancement and regulatory approval.

Development of a Well-Characterized Cynomolgus Macaque Model of Sudan Virus Disease for Support of Product Development.

The primary objective of this study was to characterize the disease course in cynomolgus macaques exposed to Sudan virus (SUDV), to determine if infection in this species is an appropriate model for the evaluation of filovirus countermeasures under the FDA Animal Rule. Sudan virus causes Sudan virus disease (SVD), with an average case fatality rate of approximately 50%, and while research is ongoing, presently there are no approved SUDV vaccines or therapies. Well characterized animal models are crucial for further developing and evaluating countermeasures for SUDV. Twenty (20) cynomolgus macaques were exposed intramuscularly to either SUDV or sterile phosphate-buffered saline; 10 SUDV-exposed animals were euthanized on schedule to characterize pathology at defined durations post-exposure and 8 SUDV-exposed animals were not part of the scheduled euthanasia cohort. Survival was assessed, along with clinical observations, body weights, body temperatures, hematology, clinical chemistry, coagulation, viral load (serum and tissues), macroscopic observations, and histopathology. There were statistically significant differences between SUDV-exposed animals and mock-exposed animals for 26 parameters, including telemetry body temperature, clinical chemistry parameters, hematology parameters, activated partial thromboplastin time, serum viremia, and biomarkers that characterize the disease course of SUDV in cynomolgus macaques.

Development of a Well-Characterized Cynomolgus Macaque Model of Marburg Virus Disease for Support of Vaccine and Therapy Development.

Marburg virus (MARV) is a filovirus that can infect humans and nonhuman primates (NHPs), causing severe disease and death. Of the filoviruses, Ebola virus (EBOV) has been the primary target for vaccine and therapeutic development. However, MARV has an average case fatality rate of approximately 50%, the infectious dose is low, and there are currently no approved vaccines or therapies targeted at infection with MARV. The purpose of this study was to characterize disease course in cynomolgus macaques intramuscularly exposed to MARV Angola variant. There were several biomarkers that reliably correlated with MARV-induced disease, including: viral load; elevated total clinical scores; temperature changes; elevated ALT, ALP, BA, TBIL, CRP and decreased ALB values; decreased lymphocytes and platelets; and prolonged PTT. A scheduled euthanasia component also provided the opportunity to study the earliest stages of the disease. This study provides evidence for the application of this model to evaluate potential vaccines and therapies against MARV and will be valuable in improving existing models.

Immune Correlates of Protection from Filovirus Efficacy Studies in Non-Human Primates.

Non-human primate (NHP) efficacy data for several Ebola virus (EBOV) vaccine candidates exist, but definitive correlates of protection (CoP) have not been demonstrated, although antibodies to the filovirus glycoprotein (GP) antigen and other immunological endpoints have been proposed as potential CoPs. Accordingly, studies that could elucidate biomarker(s) that statistically correlate, whether mechanistically or not, with protection are warranted. The primary objective of this study was to evaluate potential CoP for Novavax EBOV GP vaccine candidate administered at different doses to cynomolgus macaques using the combined data from two separate, related studies containing a total of 44 cynomolgus macaques. Neutralizing antibodies measured by pseudovirion neutralization assay (PsVNA) and anti-GP IgG binding antibodies were evaluated as potential CoP using logistic regression models. The predictive ability of these models was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Fitted models indicated a statistically significant relationship between survival and log base 10 (log10) transformed anti-GP IgG antibodies, with good predictive ability of the model. Neither (log10 transformed) PsVNT50 nor PsVNT80 titers were statistically significant predictors of survival, though predictive ability of both models was good. Predictive ability was not statistically different between any pair of models. Models that included immunization dose in addition to anti-GP IgG antibodies failed to detect statistically significant effects of immunization dose. These results support anti-GP IgG antibodies as a correlate of protection. Total assay variabilities and geometric coefficients of variation (GCVs) based on the study data appeared to be greater for both PsVNA readouts, suggesting the increased assay variability may account for non-significant model results for PsVNA despite the good predictive ability of the models. The statistical approach to evaluating CoP for this EBOV vaccine may prove useful for advancing research for Sudan virus (SUDV) and Marburg virus (MARV) candidate vaccines.

Auditory N100 amplitude deficits predict conversion to psychosis in the North American Prodrome Longitudinal Study (NAPLS-2) cohort.

BACKGROUND: The auditory N100 is an event related potential (ERP) that is reduced in schizophrenia, but its status in individuals at clinical high risk for psychosis (CHR) and its ability to predict conversion to psychosis remains unclear. We examined whether N100 amplitudes are reduced in CHR subjects relative to healthy controls (HC), and this reduction predicts conversion to psychosis in CHR. METHODS: Subjects included CHR individuals (n = 552) and demographically similar HC subjects (n = 236) from the North American Prodrome Longitudinal Study. Follow-up assessments identified CHR individuals who converted to psychosis (CHRC; n = 73) and those who did not (CHR-NC; n = 225) over 24 months. Electroencephalography data were collected during an auditory oddball task containing Standard, Novel, and Target stimuli. N100 peak amplitudes following each stimulus were measured at electrodes Cz and Fz. RESULTS: The CHR subjects had smaller N100 absolute amplitudes than HC subjects at Fz (F(1,786) = 4.00, p 0.046). A model comparing three groups (CHRC, CHR-NC, HC) was significant for Group at the Cz electrode (F(2,531) = 3.58, p = 0.029). Both Standard (p = 0.019) and Novel (p = 0.017) stimuli showed N100 absolute amplitude reductions in CHR-C relative to HC. A smaller N100 amplitude at Cz predicted conversion to psychosis in the CHR cohort (Standard: p = 0.009; Novel: p = 0.001) and predicted shorter time to conversion (Standard: p = 0.013; Novel: p = 0.001). CONCLUSION: N100 amplitudes are reduced in CHR individuals which precedes the onset of psychosis. N100 deficits in CHR individuals predict a greater likelihood of conversion to psychosis. Our results highlight N100's utility as a biomarker of psychosis risk.

The Association Between Neighborhood Poverty and Hippocampal Volume Among Individuals at Clinical High-Risk for Psychosis: The Moderating Role of Social Engagement.

Reductions in hippocampal volume (HV) have been associated with both prolonged exposure to stress and psychotic illness. This study sought to determine whether higher levels of neighborhood poverty would be associated with reduced HV among individuals at clinical high-risk for psychosis (CHR-P), and whether social engagement would moderate this association. This cross-sectional study included a sample of participants (N  =  174, age-range = 12-33 years, 35.1% female) recruited for the second phase of the North American Prodrome Longitudinal Study. Generalized linear mixed models tested the association between neighborhood poverty and bilateral HV, as well as the moderating role of social engagement on this association. Higher levels of neighborhood poverty were associated with reduced left (ß â€…=  -0.180, P  =  .016) and right HV (ß â€…=  -0.185, P  =  .016). Social engagement significantly moderated the relation between neighborhood poverty and bilateral HV. In participants with lower levels of social engagement (n  =  77), neighborhood poverty was associated with reduced left (ß â€…=  -0.266, P  =  .006) and right HV (ß = -0.316, P  = .002). Among participants with higher levels of social engagement (n = 97), neighborhood poverty was not significantly associated with left (ß â€…=  -0.010, P  =  .932) or right HV (ß â€…=  0.087, P  =  .473). In this study, social engagement moderated the inverse relation between neighborhood poverty and HV. These findings demonstrate the importance of including broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at CHR-P.

Mismatch Negativity in Response to Auditory Deviance and Risk for Future Psychosis in Youth at Clinical High Risk for Psychosis.

Importance: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P). Objective: To examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use. Design, Setting, and Participants: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. Main Outcomes and Measures: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. Results: The CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity. Conclusions and Relevance: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Animal Models of COVID-19: Nonhuman Primates.

With the advent of the novel SARS-CoV-2, the entire world has been thrown into chaos with severe disruptions from a normal life. While the entire world was going chaotic, the researchers throughout the world were struggling to contribute to the best of their capabilities to advance the understanding of this new pandemic and fast track the development of novel therapeutics and vaccines. While various animal models have helped a lot to understand the basic physiology, nonhman primates have been promising and much more successful in modelling human diseases compared to other available clinical models. Here we describe the different aspects of modelling the SARS-CoV-2 infection in NHPs along with the associated methods used in NHP immunology.

A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 µg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.

Skin Vaccination with Ebola Virus Glycoprotein Using a Polyphosphazene-Based Microneedle Patch Protects Mice against Lethal Challenge.

Ebolavirus (EBOV) infection in humans is a severe and often fatal disease, which demands effective interventional strategies for its prevention and treatment. The available vaccines, which are authorized under exceptional circumstances, use viral vector platforms and have serious disadvantages, such as difficulties in adapting to new virus variants, reliance on cold chain supply networks, and administration by hypodermic injection. Microneedle (MN) patches, which are made of an array of micron-scale, solid needles that painlessly penetrate into the upper layers of the skin and dissolve to deliver vaccines intradermally, simplify vaccination and can thereby increase vaccine access, especially in resource-constrained or emergency settings. The present study describes a novel MN technology, which combines EBOV glycoprotein (GP) antigen with a polyphosphazene-based immunoadjuvant and vaccine delivery system (poly[di(carboxylatophenoxy)phosphazene], PCPP). The protein-stabilizing effect of PCPP in the microfabrication process enabled preparation of a dissolvable EBOV GP MN patch vaccine with superior antigenicity compared to a non-polyphosphazene polymer-based analog. Intradermal immunization of mice with polyphosphazene-based MN patches induced strong, long-lasting antibody responses against EBOV GP, which was comparable to intramuscular injection. Moreover, mice vaccinated with the MN patches were completely protected against a lethal challenge using mouse-adapted EBOV and had no histologic lesions associated with ebolavirus disease.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.

Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within 4 d in seven of eight animals receiving 50 µg of RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only approximately twofold relative to WA1/2020. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-CoV-like Sarbecovirus vaccine development.