Efficacy and moderators of efficacy of cognitive behavioural therapies with a trauma focus in children and adolescents: an individual participant data meta-analysis of randomised trials.

BACKGROUND: Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators. METHODS: This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6-18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954. FINDINGS: We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=-13·17, 95% CI -17·84 to -8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=-0·15, 95% CI -0·29 to -0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms. INTERPRETATION: This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress. FUNDING: Swiss National Science Foundation.

Efficacy and moderators of efficacy of trauma-focused cognitive behavioural therapies in children and adolescents: protocol for an individual participant data meta-analysis from randomised trials.

INTRODUCTION: Trauma-focused cognitive behavioural therapies are the first-line treatment for posttraumatic stress disorder (PTSD) in children and adolescents. Nevertheless, open questions remain with respect to efficacy: why does this first-line treatment not work for everyone? For whom does it work best? Individual clinical trials often do not provide sufficient statistical power to examine and substantiate moderating factors. To overcome the issue of limited power, an individual participant data meta-analysis of randomised trials evaluating forms of trauma-focused cognitive behavioural therapy in children and adolescents aged 6-18 years will be conducted. METHODS AND ANALYSIS: We will update the National Institute for Health and Care Excellence guideline literature search from 2018 with an electronic search in the databases PsycINFO, MEDLINE, Embase, Cochrane Central Register of Controlled Trials and CINAHL with the terms (trauma* OR stress*) AND (cognitive therap* OR psychotherap*) AND (trial* OR review*). Electronic searches will be supplemented by a comprehensive grey literature search in archives and trial registries. Only randomised trials that used any manualised psychological treatment-that is a trauma-focused cognitive behavioural therapy for children and adolescents-will be included. The primary outcome variable will be child-reported posttraumatic stress symptoms (PTSS) post-treatment. Proxy-reports (teacher, parent and caregiver) will be analysed separately. Secondary outcomes will include follow-up assessments of PTSS, PTSD diagnosis and symptoms of comorbid disorders such as depression, anxiety-related and externalising problems. Random-effects models applying restricted maximum likelihood estimation will be used for all analyses. We will use the Revised Cochrane Risk of Bias tool to measure risk of bias. ETHICS AND DISSEMINATION: Contributing study authors need to have permission to share anonymised data. Contributing studies will be required to remove patient identifiers before providing their data. Results will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42019151954.

CACNA1C methylation: association with cortisol, perceived stress, rs1006737 and childhood trauma in males.

Aim: We investigated morning cortisol, stress, rs1006737 and childhood trauma relationship with CACNA1C methylation. Materials & methods: Morning cortisol release, childhood trauma and perceived stress were collected and genotyping for rs1006737 conducted in 103 adult males. Genomic DNA extracted from saliva was bisulphite converted and using pyrosequencing methylation determined at 11 CpG sites within intron 3 of CACNA1C. Results: A significant negative correlation between waking cortisol and overall mean methylation was found and a positive correlation between CpG5 methylation and perceived stress. Conclusion:CACNA1C methylation levels may be related to cortisol release and stress perception. Future work should evaluate the influence of altered CACNA1C methylation on stress reactivity to investigate this as a potential mechanism for mental health vulnerability.

Dopamine and Working Memory: Genetic Variation, Stress and Implications for Mental Health.

At the molecular level, the neurotransmitter dopamine (DA) is a key regulatory component of executive function in the prefrontal cortex (PFC) and dysfunction in dopaminergic (DAergic) circuitry has been shown to result in impaired working memory (WM). Research has identified multiple common genetic variants suggested to impact on the DA system functionally and also behaviourally to alter WM task performance. In addition, environmental stressors impact on DAergic tone, and this may be one mechanism by which stressors confer vulnerability to the development of neuropsychiatric conditions. This chapter aims to evaluate the impact of key DAergic gene variants suggested to impact on both synaptic DA levels (COMT, DAT1, DBH, MAOA) and DA receptor function (ANKK1, DRD2, DRD4) in terms of their influence on visuospatial WM. The role of stressors and interaction with the genetic background is discussed in addition to discussion around some of the implications for precision psychiatry. This and future work in this area aim to disentangle the neural mechanisms underlying susceptibility to stress and their impact and relationship with cognitive processes known to influence mental health vulnerability.

The effect of ANKK1 Taq1A and DRD2 C957T polymorphisms on executive function: A systematic review and meta-analysis.

Research in healthy adults suggests that C957T polymorphism of the dopamine D2 receptor encoding DRD2 and the Taq1A polymorphism of the neighbouring gene ankyrin repeat and kinase domain containing 1 (ANKK1) alter dopaminergic signalling and may influence prefrontally-mediated executive functions. A systematic review and meta-analysis was carried out on the evidence for the association of DRD2 C957T and ANKK1 Taq1A polymorphisms in performance on tasks relating to the three core domains of executive function: working memory, response inhibition and cognitive flexibility in healthy adults. CINAHL, MEDLINE, PsycARTICLES and PsychINFO databases were searched for predefined key search terms associated with the two polymorphisms and executive function. Studies were included if they investigated a healthy adult population with the mean age of 18-65 years, no psychiatric or neurological disorder and only the healthy adult arm were included in studies with any case-control design. Data from 17 independent studies were included in meta-analysis, separated by the Taq1A and C957T polymorphisms and by executive function tests: working memory (Taq1A, 6 samples, n = 1270; C957 T, 6 samples, n = 977), cognitive flexibility (C957 T, 3 samples, n = 620), and response inhibition (C957 T, 3 samples, n = 598). The meta-analyses did not establish significant associations between these gene polymorphisms of interest and any of the executive function domains. Theoretical implications and methodological considerations of these findings are discussed.

Overnight retention of emotional memories is influenced by BDNF Val66Met but not 5-HTTLPR.

Emotional memory may be modulated by BDNF Val66Met and 5-HTTLPR polymorphisms. However, the influence of these genetic variants on the overnight retention of emotional memories has not been investigated in humans. Thirty-six healthy female students were selected to participate in this study based on 5-HTTLPR genotype status (L'/L', L'/S', S'/S'). Participants were also genotyped for BDNF Val66Met (Val/Val, Met carriers). We measured recognition performance for positive, neutral and negative images before and after overnight sleep. We found a significant interaction between BDNF Val66Met genotype group and image valence on post-sleep recognition performance. This interaction was driven by greater memory for negative and positive images, relative to neutral images, in Met carriers. We also found that longer Rapid Eye Movement (REM) sleep duration predicted greater post-sleep recognition performance for negative images in Met carriers, but not in Val homozygotes. We observed no influence of 5-HTTLPR polymorphisms on post- sleep recognition performance for positive, neutral or negative images. Our findings support a modulatory role for BDNF Val66Met in overnight emotional memory retention in females. We discuss the implications of this finding for understanding the influence of BDNF Val66Met on depression vulnerability.

Elevated cortisol awakening response associated with early life stress and impaired executive function in healthy adult males.

Experiencing early life stress (ELS) and subsequent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in the aetiology of mental health disorders. However, the exact mechanisms linking HPA-axis dysregulation with the development of psychopathology have not been fully delineated. Progress in this area is hampered by the complex and often conflicting associations found between markers of HPA-axis function and risk factors for mental health disorders such as impaired executive function (EF) and ELS. This study investigated the association of the cortisol awakening response (CAR) with ELS and EF in a healthy adult male population (n=109, aged 21-63). As previous inconsistencies in CAR and ELS association studies may be the result of not considering ELS-related factors such as cumulative exposure, type of stressor and developmental timing of ELS, these were also investigated. The main findings were that the CAR was significantly elevated in individuals reporting ELS compared to those reporting no ELS (p=0.007) and that an elevated CAR predicted poorer problem solving/planning (p=0.046). Cumulative exposure, type of stressor and developmental timing of ELS were also found to impact significantly on the CAR. These results suggest that ELS is associated with chronic changes in HPA-axis function and that these changes may be associated with impairments in problem solving/planning. Future work should investigate further the neurobiological mechanisms linking ELS, the CAR and EF and their role in conferring risk for the development of mental health disorders.

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress.

INTRODUCTION: Previous research has indicated that variation in genes encoding catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) may influence cognitive function and that this may confer vulnerability to the development of mental health disorders such as schizophrenia. However, increasing evidence suggests environmental factors such as early life stress may interact with genetic variants in affecting these cognitive outcomes. This study investigated the effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress in healthy adults. METHODS: One hundred and twenty-two healthy adult males (mean age 35.2 years, range 21-63) were enrolled in the study. Cognitive function was assessed using Cambridge Neuropsychological Test Automated Battery and early life stress was assessed using the Childhood Traumatic Events Scale (Pennebaker & Susman, 1988). RESULTS: DRD2 C957T was significantly associated with executive function, with CC homozygotes having significantly reduced performance in spatial working memory and spatial planning. A significant genotype-trauma interaction was found in Rapid Visual Information Processing test, a measure of sustained attention, with CC carriers who had experienced early life stress exhibiting impaired performance compared to the CC carriers without early life stressful experiences. There were no significant findings for COMT Val158Met. CONCLUSIONS: This study supports previous findings that DRD2 C957T significantly affects performance on executive function related tasks in healthy individuals and shows for the first time that some of these effects may be mediated through the impact of childhood traumatic events. Future work should aim to clarify further the effect of stress on neuronal systems that are known to be vulnerable in mental health disorders and more specifically what the impact of this might be on cognitive function.

The assessment of post-vasectomy pain in mice using behaviour and the Mouse Grimace Scale.

BACKGROUND: Current behaviour-based pain assessments for laboratory rodents have significant limitations. Assessment of facial expression changes, as a novel means of pain scoring, may overcome some of these limitations. The Mouse Grimace Scale appears to offer a means of assessing post-operative pain in mice that is as effective as manual behavioural-based scoring, without the limitations of such schemes. Effective assessment of post-operative pain is not only critical for animal welfare, but also the validity of science using animal models. METHODOLOGY/PRINCIPAL FINDINGS: This study compared changes in behaviour assessed using both an automated system ("HomeCageScan") and using manual analysis with changes in facial expressions assessed using the Mouse Grimace Scale (MGS). Mice (n = 6/group) were assessed before and after surgery (scrotal approach vasectomy) and either received saline, meloxicam or bupivacaine. Both the MGS and manual scoring of pain behaviours identified clear differences between the pre and post surgery periods and between those animals receiving analgesia (20 mg/kg meloxicam or 5 mg/kg bupivacaine) or saline post-operatively. Both of these assessments were highly correlated with those showing high MGS scores also exhibiting high frequencies of pain behaviours. Automated behavioural analysis in contrast was only able to detect differences between the pre and post surgery periods. CONCLUSIONS: In conclusion, both the Mouse Grimace Scale and manual scoring of pain behaviours are assessing the presence of post-surgical pain, whereas automated behavioural analysis could be detecting surgical stress and/or post-surgical pain. This study suggests that the Mouse Grimace Scale could prove to be a quick and easy means of assessing post-surgical pain, and the efficacy of analgesic treatment in mice that overcomes some of the limitations of behaviour-based assessment schemes.

Fear and exploration in European starlings (Sturnus vulgaris): a comparison of hand-reared and wild-caught birds.

The revision of EU legislation will ban the use of wild-caught animals in scientific procedures. This change is partially predicated on the assumption that captive-rearing produces animals with reduced fearfulness. Previously, we have shown that hand-reared starlings (Sturnus vulgaris) indeed exhibit reduced fear of humans compared to wild-caught conspecifics. Here, we asked whether this reduction in fear in hand-reared birds is limited to fear of humans or extends more generally to fear of novel environments and novel objects. Comparing 6-8 month old birds hand-reared in the lab with age-matched birds caught from the wild as fledged juveniles a minimum of 1 month previously, we examined the birds' initial reactions in a novel environment (a small cage) and found that wild-caught starlings were faster to initiate movement compared to the hand-reared birds. We interpret this difference as evidence for greater escape motivation in the wild-caught birds. In contrast, we found no differences between hand-reared and wild-caught birds when tested in novel object tests assumed to measure neophobia and exploratory behaviour. Moreover, we found no correlations between individual bird's responses in the different tests, supporting the idea that these measure different traits (e.g. fear and exploration). In summary, our data show that developmental origin affects one measure of response to novelty in young starlings, indicative of a difference in either fear or coping style in a stressful situation. Our data contribute to a growing literature demonstrating effects of early-life experience on later behaviour in a range of species. However, since we did not find consistent evidence for reduced fearfulness in hand-reared birds, we remain agnostic about the welfare benefits of hand-rearing as a method for sourcing wild birds for behavioural and physiological research.