Brain-based gene expression of putative risk genes for anorexia nervosa.

The etiology of anorexia nervosa (AN) remains elusive. Recent genome-wide association studies identified the first genes liked to AN which reached genome-wide significance, although our understanding of how these genes confer risk remains preliminary. Here, we leverage the Allen Human Brain Atlas to characterize the spatially distributed gene expression patterns of genes linked to AN in the non-disordered human brain, developing whole-brain maps of AN gene expression. We found that genes associated with AN are most expressed in the brain, relative to all other body tissue types, and demonstrate gene-specific expression patterns which extend to cerebellar, temporal and basal ganglia structures in particular. fMRI meta-analyses reveal that AN gene expression maps correspond with functional brain activity involved in processing and anticipating appetitive and aversive cues. Findings offer novel insights around putative mechanisms through which genes associated with AN may confer risk.

Heart rate monitoring to detect acute pain in non-verbal patients: a study protocol for a randomized controlled clinical trial.

BACKGROUND: Autism entails reduced communicative abilities. Approximately 30% of individuals with autism have intellectual disability (ID). Some people with autism and ID are virtually non-communicative and unable to notify their caregivers when they are in pain. In a pilot study, we showed that heart rate (HR) monitoring may identify painful situations in this patient group, as HR increases in acutely painful situations. OBJECTIVES: This study aims to generate knowledge to reduce the number of painful episodes in non-communicative patients' everyday lives. We will 1) assess the effectiveness of HR as a tool for identifying potentially painful care procedures, 2) test the effect of HR-informed changes in potentially painful care procedures on biomarkers of pain, and 3) assess how six weeks of communication through HR affects the quality of communication between patient and caregiver. METHODS: We will recruit 38 non-communicative patients with autism and ID residing in care homes. ASSESSMENTS: HR is measured continuously to identify acutely painful situations. HR variability and pain-related cytokines (MCP-1, IL-1RA, IL-8, TGFß1, and IL-17) are collected as measures of long-term pain. Caregivers will be asked to what degree they observe pain in their patients and how well they believe they understand their patient's expressions of emotion and pain. Pre-intervention: HR is measured 8 h/day over 2 weeks to identify potentially painful situations across four settings: physiotherapy, cast use, lifting, and personal hygiene. INTERVENTION: Changes in procedures for identified painful situations are in the form of changes in 1) physiotherapy techniques, 2) preparations for putting on casts, 3) lifting techniques or 4) personal hygiene procedures. DESIGN: Nineteen patients will start intervention in week 3 while 19 patients will continue data collection for another 2 weeks before procedure changes are introduced. This is done to distinguish between specific effects of changes in procedures and non-specific effects, such as caregivers increased attention. DISCUSSION: This study will advance the field of wearable physiological sensor use in patient care. TRIAL REGISTRATION: Registered prospectively at ClinicalTrials.gov (NCT05738278).

Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research.

Reports on the modulatory role of the neuropeptide oxytocin on social cognition and behavior have steadily increased over the last two decades, stimulating considerable interest in its psychiatric application. Basic and clinical research in humans primarily employs intranasal application protocols. This approach assumes that intranasal administration increases oxytocin levels in the central nervous system via a direct nose-to-brain route, which in turn acts upon centrally-located oxytocin receptors to exert its behavioral effects. However, debates have emerged on whether intranasally administered oxytocin enters the brain via the nose-to-brain route and whether this route leads to functionally relevant increases in central oxytocin levels. In this review we outline recent advances from human and animal research that provide converging evidence for functionally relevant effects of the intranasal oxytocin administration route, suggesting that direct nose-to-brain delivery underlies the behavioral effects of oxytocin on social cognition and behavior. Moreover, advances in previously debated methodological issues, such as pre-registration, reproducibility, statistical power, interpretation of non-significant results, dosage, and sex differences are discussed and integrated with suggestions for the next steps in translating intranasal oxytocin into psychiatric applications.

The effect of intranasal oxytocin on processing emotional stimuli during alcohol withdrawal: A randomized placebo-controlled double-blind clinical trial.

Alcohol dependence is associated with difficulties in processing emotional stimuli, which can lead to interpersonal problems. The neuropeptide oxytocin has been shown to modulate the processing of emotional stimuli, however, oxytocin treatment has not yet been examined in patients with withdrawal symptoms during alcohol detoxification. The aim of the present study was to investigate the effect of oxytocin on the reading the mind in the eyes test (RMET), which indexes theory of mind ability, during a three-day period of alcohol detoxification at an addiction treatment centre in Norway. We performed a randomized, double-blind, placebo-controlled trial in 39 patients fulfilling criteria for ICD-10 diagnosis of alcohol dependence admitted for alcohol detoxification and withdrawal treatment. Participants were randomized to receive either intranasal oxytocin (24 IU) or placebo, twice daily for three days. We evaluated RMET performance on day 2 and day 3 of detoxification and differences in RMET scores between day 2 and day 3 of detoxification. Frequentist and Bayesian statistical inference suggested that oxytocin administration during alcohol withdrawal in alcohol-dependent patients did not improve RMET performance. However, exploratory analyses provided preliminary evidence that oxytocin might improve performance on the RMET negative emotion subscale (uncorrected p value = 0.038), and that oxytocin treatment might show the most promise for those with high levels of alcohol consumption (i.e., ≥20 alcohol units per day; uncorrected p value = 0.023). Moreover, alcohol consumption levels significantly predicted RMET performance on day 2, but not on day 3, of withdrawal.

Misinformation About COVID-19 Vaccines on Social Media: Rapid Review.

BACKGROUND: The development of COVID-19 vaccines has been crucial in fighting the pandemic. However, misinformation about the COVID-19 pandemic and vaccines is spread on social media platforms at a rate that has made the World Health Organization coin the phrase infodemic. False claims about adverse vaccine side effects, such as vaccines being the cause of autism, were already considered a threat to global health before the outbreak of COVID-19. OBJECTIVE: We aimed to synthesize the existing research on misinformation about COVID-19 vaccines spread on social media platforms and its effects. The secondary aim was to gain insight and gather knowledge about whether misinformation about autism and COVID-19 vaccines is being spread on social media platforms. METHODS: We performed a literature search on September 9, 2021, and searched PubMed, PsycINFO, ERIC, EMBASE, Cochrane Library, and the Cochrane COVID-19 Study Register. We included publications in peer-reviewed journals that fulfilled the following criteria: original empirical studies, studies that assessed social media and misinformation, and studies about COVID-19 vaccines. Thematic analysis was used to identify the patterns (themes) of misinformation. Narrative qualitative synthesis was undertaken with the guidance of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 Statement and the Synthesis Without Meta-analysis reporting guideline. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal tool. Ratings of the certainty of evidence were based on recommendations from the Grading of Recommendations Assessment, Development and Evaluation Working Group. RESULTS: The search yielded 757 records, with 45 articles selected for this review. We identified 3 main themes of misinformation: medical misinformation, vaccine development, and conspiracies. Twitter was the most studied social media platform, followed by Facebook, YouTube, and Instagram. A vast majority of studies were from industrialized Western countries. We identified 19 studies in which the effect of social media misinformation on vaccine hesitancy was measured or discussed. These studies implied that the misinformation spread on social media had a negative effect on vaccine hesitancy and uptake. Only 1 study contained misinformation about autism as a side effect of COVID-19 vaccines. CONCLUSIONS: To prevent these misconceptions from taking hold, health authorities should openly address and discuss these false claims with both cultural and religious awareness in mind. Our review showed that there is a need to examine the effect of social media misinformation on vaccine hesitancy with a more robust experimental design. Furthermore, this review also demonstrated that more studies are needed from the Global South and on social media platforms other than the major platforms such as Twitter and Facebook. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021277524; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021277524. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.31219/osf.io/tyevj.

Multimodal imaging improves brain age prediction and reveals distinct abnormalities in patients with psychiatric and neurological disorders.

The deviation between chronological age and age predicted using brain MRI is a putative marker of overall brain health. Age prediction based on structural MRI data shows high accuracy in common brain disorders. However, brain aging is complex and heterogenous, both in terms of individual differences and the underlying biological processes. Here, we implemented a multimodal model to estimate brain age using different combinations of cortical area, thickness and sub-cortical volumes, cortical and subcortical T1/T2-weighted ratios, and cerebral blood flow (CBF) based on arterial spin labeling. For each of the 11 models we assessed the age prediction accuracy in healthy controls (HC, n = 750) and compared the obtained brain age gaps (BAGs) between age-matched subsets of HC and patients with Alzheimer's disease (AD, n = 54), mild (MCI, n = 90) and subjective (SCI, n = 56) cognitive impairment, schizophrenia spectrum (SZ, n = 159) and bipolar disorder (BD, n = 135). We found highest age prediction accuracy in HC when integrating all modalities. Furthermore, two-group case-control classifications revealed highest accuracy for AD using global T1-weighted BAG, while MCI, SCI, BD and SZ showed strongest effects in CBF-based BAGs. Combining multiple MRI modalities improves brain age prediction and reveals distinct deviations in patients with psychiatric and neurological disorders. The multimodal BAG was most accurate in predicting age in HC, while group differences between patients and HC were often larger for BAGs based on single modalities. These findings indicate that multidimensional neuroimaging of patients may provide a brain-based mapping of overlapping and distinct pathophysiology in common disorders.

Registration, reporting, and replication in clinical trials: The case of anorexia nervosa.

OBJECTIVE: Treatment outcomes for anorexia nervosa (AN) remain modest, and recent research suggests that clinical trials may be of limited methodological quality. With increasing evidence illustrating the irreproducibility of psychological research, no research to date has systematically examined the cumulative effect of bias in research relating to the treatment of AN. METHOD: We identified all AN trials listed on ClinicalTrials.gov between 2000 and 2018 and examined rates of (a) the noncompletion of clinical trials, the (b) nonpublication of trials once listed as completed, (c) the nonprospective registration of clinical trials, and (d) the nonreplication of findings. RESULTS: We note that of 201 trials listed on ClinicalTrials.gov, only 101 have been completed, and of those, only 41 have been published. Moreover, of these 41 published trials, only eight demonstrated evidence of prospective trial registration, and only seven have had their primary findings replicated in other studies. DISCUSSION: These results illustrate the profound cumulative effect of methodological bias in registered trials for AN, which may have a significant impact both on what appears in the current evidence base, and on the reproducibility of studies comprising this evidence base.

Treatment outcomes for anorexia nervosa: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To determine the impact of specialized treatments, relative to comparator treatments, upon the weight and psychological symptoms of anorexia nervosa (AN) at end-of-treatment (EOT) and follow-up. METHODS: Randomized controlled trials (RCTs) between January 1980 and December 2017 that reported the effects of at least two treatments on AN were screened. Weight and psychological symptoms were analyzed separately for each study. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed, and studies were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) criteria and Cochrane risk of bias tool. RESULTS: We identified 35 eligible RCTs, comprising data from 2524 patients. Meta-analyses revealed a significant treatment effect on weight outcomes at EOT [g = 0.16, 95% CI (0.05-0.28), p = 0.006], but not at follow-up [g = 0.11, 95% CI (-0.04 to 0.27), p = 0.15]. There was no significant treatment effect on psychological outcomes at either EOT [g = -0.03, 95% CI (-0.14 to 0.08), p = 0.63], or follow-up [g = -0.001, 95% CI (-0.11 to 0.11), p = 0.98]. There was no strong evidence of publication bias or significant moderator effects for illness duration, mean age, year of publication, comparator group category, or risk of bias (all p values > 0.05). CONCLUSIONS: Current specialized treatments are more adept than comparator interventions at imparting change in weight-based AN symptoms at EOT, but not at follow-up. Specialized treatments confer no advantage over comparator interventions in terms of psychological symptoms. Future precision treatment efforts require a specific focus on the psychological symptoms of AN.

Oxytocin system dysfunction as a common mechanism underlying metabolic syndrome and psychiatric symptoms in schizophrenia and bipolar disorders.

There is growing interest in using intranasal oxytocin (OT) to treat social dysfunction in schizophrenia and bipolar disorders (i.e., psychotic disorders). While OT treatment results have been mixed, emerging evidence suggests that OT system dysfunction may also play a role in the etiology of metabolic syndrome (MetS), which appears in one-third of individuals with psychotic disorders and associated with increased mortality. Here we examine the evidence for a potential role of the OT system in the shared risk for MetS and psychotic disorders, and its prospects for ameliorating MetS. Using several studies to demonstrate the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, we show that OT system dysfunction may be one common mechanism underlying MetS and psychotic disorders. Given the critical need to better understand metabolic dysregulation in these disorders, future OT trials assessing behavioural and cognitive outcomes should additionally include metabolic risk factor parameters.

Saliva oxytocin measures do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men.

Oxytocin plays an important role in social behavior. Thus, there has been significant research interest for the role of the oxytocin system in several psychiatric disorders, and the potential of intranasal oxytocin administration to treat social dysfunction. Measurement of oxytocin concentrations in saliva are sometimes used to approximate peripheral levels of oxytocin; however, the validity of this approach is unclear. In this study, saliva and plasma oxytocin was assessed after two doses of Exhalation Delivery System delivered intranasal oxytocin (8 IU and 24 IU), intravenous oxytocin (1 IU) and placebo in a double-dummy, within-subjects design with men. We found that intranasal oxytocin (8 IU and 24 IU) administration increased saliva oxytocin concentrations in comparison to saliva oxytocin concentration levels after intravenous and placebo administration. Additionally, we found that saliva oxytocin concentrations were not significantly associated with plasma oxytocin concentrations after either intranasal or intravenous oxytocin administration. Altogether, we suggest that saliva oxytocin concentrations do not accurately index peripheral oxytocin after intranasal or intravenous oxytocin administration, at least in men. The data indicates that elevated oxytocin saliva levels after nasal delivery primarily reflect exogenous administered oxytocin that is cleared from the nasal cavity to the oropharynx, and is therefore a weak surrogate for peripheral blood measurements.

Bayesian alternatives for common null-hypothesis significance tests in psychiatry: a non-technical guide using JASP.

BACKGROUND: Despite its popularity as an inferential framework, classical null hypothesis significance testing (NHST) has several restrictions. Bayesian analysis can be used to complement NHST, however, this approach has been underutilized largely due to a dearth of accessible software options. JASP is a recently developed open-source statistical package that facilitates both Bayesian and NHST analysis using a graphical interface. This article provides an applied introduction to Bayesian inference with Bayes factors using JASP. METHODS: We use JASP to compare and contrast Bayesian alternatives for several common classical null hypothesis significance tests: correlations, frequency distributions, t-tests, ANCOVAs, and ANOVAs. These examples are also used to illustrate the strengths and limitations of both NHST and Bayesian hypothesis testing. RESULTS: A comparison of NHST and Bayesian inferential frameworks demonstrates that Bayes factors can complement p-values by providing additional information for hypothesis testing. Namely, Bayes factors can quantify relative evidence for both alternative and null hypotheses. Moreover, the magnitude of this evidence can be presented as an easy-to-interpret odds ratio. CONCLUSIONS: While Bayesian analysis is by no means a new method, this type of statistical inference has been largely inaccessible for most psychiatry researchers. JASP provides a straightforward means of performing reproducible Bayesian hypothesis tests using a graphical "point and click" environment that will be familiar to researchers conversant with other graphical statistical packages, such as SPSS.

Reliability of basal plasma vasopressin concentrations in healthy male adults.

OBJECTIVE: The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) play important and interrelated roles in modulating mammalian social behaviour. While the OT system has received considerable research attention for its potential to treat psychiatric symptoms, comparatively little is known about the role of the AVP system in human social behaviour. To better understand the intraindividual stability of basal AVP, the present study assessed the reproducibility of basal plasma AVP concentrations. METHODS: Basal plasma AVP was assessed at four sampling points separated by 8 days, on average, in 16 healthy adult males. RESULTS: Only one out of six comparisons revealed strong evidence for reproducibility of basal AVP concentrations (visit 2 vs. visit 4: r=0.8, p0.1). The concordance correlation coefficient [0.15, 95% CI (-0.55, 0.73)] also revealed poor overall reproducibility. CONCLUSION: Poor reliability of basal AVP concentrations suggests future work covarying AVP with trait markers should proceed with careful consideration of intraindividual fluctuations.

Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis.

BACKGROUND: Autonomic nervous system (ANS) dysfunction is a putative underlying mechanism for increased cardiovascular disease risk in individuals with psychiatric disorders. Previous studies suggest that this risk may be related to psychotropic medication use. In the present study we systematically reviewed and analyzed published studies of heart rate variability (HRV), measuring ANS output, to determine the effect of psychiatric illness and medication use. METHODS: We searched for studies comparing HRV in physically healthy adults with a diagnosed psychiatric disorder to controls and comparing HRV pre- and post-treatment with a psychotropic medication. RESULTS: In total, 140 case-control (mood, anxiety, psychosis, dependent disorders, k = 151) and 30 treatment (antidepressants, antipsychotics; k = 43) studies were included. We found that HRV was reduced in all patient groups compared to controls (Hedges g = -0.583) with a large effect for psychotic disorders (Hedges g = -0.948). Effect sizes remained highly significant for medication-free patients compared to controls across all disorders. Smaller and significant reductions in HRV were observed for specific antidepressants and antipsychotics. LIMITATIONS: Study quality significantly moderated effect sizes in case-control analyses, underscoring the importance of assessing methodological quality when interpreting HRV findings. CONCLUSION: Combined findings confirm substantial reductions in HRV across psychiatric disorders, and these effects remained significant even in medication-free individuals. Reductions in HRV may therefore represent a significant mechanism contributing to elevated cardiovascular risk in individuals with psychiatric disorders. The negative impact of specific medications on HRV suggest increased risk for cardiovascular disease in these groups, highlighting a need for treatment providers to consider modifiable cardiovascular risk factors to attenuate this risk.

A Meta-analysis of Theory of Mind in Alcohol Use Disorders.

AIM: Research into Theory of Mind (ToM) in alcohol use disorder (AUD) is sparse and the extant findings contradictory. The objective of this paper was to conduct a meta-analysis to determine whether individuals with AUD show ToM deficits across the available published literature. METHOD: A comprehensive literature search was performed with the PsychInfo, PubMed and Web Science databases for studies from 1990 to March 2015, pairing the keywords 'alcohol' and 'theory of mind'. Results were filtered and eight studies met the inclusion criteria and were included in the final meta-analysis. RESULTS: Results showed that individuals with AUD (n = 187) displayed reduced ToM compared to controls (n = 187). Hedges' g was -1.62 [(-2.28, -0.96), SE = 0.66, P < 0.01], which is indicative of a large effect size. The percentage of males had a significant impact on the effect size, Q = 7.90, P = 0.005, while IQ and level of education did not. CONCLUSIONS: Results of this study suggest that AUD may be associated with impaired understanding of others' intentions and emotions, which can leave an individual vulnerable to misinterpreting social cues. Clinical care implications of the findings, limitations of the study, and suggestions for future research are discussed.

Heart rate variability during social interactions in children with and without psychopathology: a meta-analysis.

BACKGROUND: The inability to regulate autonomic activity during social interactions is believed to contribute to social and emotional dysregulation in children. Research has employed heart rate variability (HRV) during both socially engaging and socially disengaging dyadic tasks between children and adults to assess this. METHODS: We conducted a meta-analysis including evidence from 18 studies comprising 1,544 children who were categorized as either healthy or at risk/diagnosed with psychopathology. Within these groups, we assessed the impact of social engagement and disengagement tasks on HRV. RESULTS: Results showed that social engagement tasks left HRV unaltered to a baseline. Social disengagement, however, was associated with decreases in HRV. In a task that included disengagement and then engagement, HRV was reduced during disengagement but was then restored during the reunion phase (engagement). Children at risk or with a diagnosis for psychopathology, however, failed to show any change in HRV during dyadic social interaction tasks. This was despite a social stressor, the Trier Social Stress Test, causing significantly reduced HRV in both groups. CONCLUSIONS: This meta-analysis provides support to suggest HRV may provide a worthwhile context specific marker for the effective regulation of dyadic social interactions in children.

Redefining effect size interpretations for psychotherapy RCTs in depression.

INTRODUCTION: Effect sizes are often used to interpret the magnitude of a result and in power calculations when planning research studies. However, as effect size interpretations are context-dependent, Jacob Cohen's suggested guidelines for what represents a small, medium, and large effect are unlikely to be suitable for a diverse range of research populations and interventions. Our objective here is to determine empirically-derived effect size thresholds associated with psychotherapy randomized controlled trials (RCTs) in depression by calculating the effect size distribution. METHODS: We extracted effect sizes from 366 RCTs provided by the systematic review of Cuijpers and colleagues (2020) on psychotherapy for depressive disorders across all age groups. The 50th percentile effect size, as this represents a medium effect size, and the 25th (small) and 75th (large) percentile effect sizes were calculated to determine empirically-derived effect size thresholds. RESULTS: After adjusting for publication bias, 0.27, 0.53, and 0.86 represent small, medium, and large effect sizes, respectively, for psychotherapy treatment for depressive disorders. DISCUSSION: The effect size distribution for psychotherapy treatment of depression indicates that observed effect size thresholds are larger than Cohen's suggested effect size thresholds (0.2, 0.5, and 0.8). These results have implications for the interpretation of study effects and the planning of future studies via power analyses, which often use effect size thresholds.

The interplay of oxytocin and sex hormones.

The neuropeptide oxytocin has historically been associated with reproduction and maternal behavior. However, more recent research has uncovered that oxytocin has a much wider range of roles in physiology and behavior. Despite the excitement surrounding potential therapeutical applications of intranasally administered oxytocin, the results of these intervention studies have been inconsistent. Various reasons for these mixed results have been proposed, which tend to focus on methodological issues, such as study design. While methodological issues are certainly important, emerging evidence suggests that the interaction between oxytocin and sex hormones may also account for these varied findings. To better understand the purpose and function of the interaction of oxytocin with sex hormones, with a focus on estrogens, progesterone, and testosterone, we conducted a comprehensive thematic review via four perspectives: evolutionary, developmental, mechanistic, and survival. Altogether, this synergistic approach highlights the critical function of sex hormone activity for accomplishing the diverse roles of oxytocin via the modulation of oxytocin release and oxytocin receptor activity, which is also likely to contribute to the heterogeneity of outcomes after oxytocin administration.