Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children.

BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

Functional brain-imaging correlates of negative affectivity and the onset of first-episode depression.

BACKGROUND: The amygdala and subgenual anterior cingulate cortex (sACC) are key brain regions for the generation of negative affect. In this longitudinal fMRI study of adolescents we investigated how amygdala-sACC connectivity was correlated with negative affectivity (NA) both cross-sectionally and longitudinally, and examined its relationship to the onset of first-episode depression. METHOD: Fifty-six adolescents who were part of a larger longitudinal study of adolescent development were included. They had no history of mental illness at the time of their baseline scan (mean age 16.5 years) and had a follow-up scan 2 years later (mean age 18.8 years). We used resting-state functional-connectivity MRI to investigate whether cross-sectional and change measures of amygdala-sACC connectivity were (i) correlated with NA and its change over time, and (ii) related to the onset of first-episode depression. RESULTS: The magnitude of amygdala connectivity with sACC showed significant positive correlation with NA at both time-points. Further analysis confirmed that change in amygdala-sACC connectivity between assessments was correlated with change in NA. Eight participants developed a first episode of depression between the baseline and follow-up assessments: they showed increased amygdala-sACC connectivity at follow-up. CONCLUSIONS: Amygdala-sACC connectivity is associated with NA in adolescence, with change in connectivity between these regions showing positive correlation with change in NA. Our observation that the onset of depression was associated with an increase in connectivity between the regions provides support for the neurobiological 'scar' hypothesis of depression.

Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service.

Islet transplantation alone (ITA) is indicated for patients with type 1 diabetes (T1D) with disabling severe hypoglycaemia (SH) despite optimised medical therapy. We examined outcomes for patients referred to an islet transplant unit with recurrent SH. Retrospective case note audit of 45 patients with ≥1 SH per year who were referred to our ITA unit between 2009-2012; 36 patients attended follow-up appointments. The cohort was 52.8% male, mean (± SD) age 43.9 (± 11.4) years, and duration of diabetes 26.5 (± 12.9) years. Baseline HbA1c was 8.3% (± 1.7) (67.2 mmol/mol), median (IQR) frequency of SH was 6.0 (2.0-24.0) per/patient/year and 83.3% had impaired awareness of hypoglycaemia (IAH). 80.6% of patients were referred from other secondary diabetes services, 22.2% had completed structured education, and 30.6% were using continuous subcutaneous insulin infusion (CSII). Seventeen patients were optimised with conventional therapy; SH reduced from 2.0 (1.5-9.0) to 0.0 (0.0-0.5) episodes/patient/year; p<0.001, and there was concurrent improvement in HbA1c (8.1-7.7%; 65.0 vs. 60.7 mmol/mol; p=0.072). Ten patients were listed for transplantation as they were not optimised despite structured education, CSII, and continuous glucose monitoring (CGM). The remaining 9 had a reduction in SH [7.0 (4.8-40.5) to 4.0 (2.5-6.3) episodes/patient/year; p=0.058] and either left the service (n=5) or are still being optimised (n=4). In conclusion, 47.2% of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however 27.8% required transplantation despite access to all therapies. Provision of expertise in hypoglycaemia management is essential to focus limited transplant resources on those who need it most.

The ratio of morning cortisol to CRP prospectively predicts first-onset depression in at-risk adolescents.

RATIONALE: Early-onset adolescent depression is related to poor prognosis and a range of psychiatric and medical comorbidities later in life, making the identification of a priori risk factors for depression highly important. Increasingly, dysregulated levels of immune and neuroendocrine markers, such as C-reactive protein (CRP) and cortisol, have been demonstrated as both precursors to and consequences of depression. However, longitudinal research with adolescent populations is limited and demonstrates mixed immuno-endocrine-depression links. OBJECTIVE: This study explored the putative bidirectional relationship between salivary measures of cortisol (Cort) and CRP, including the novel Cort:CRP ratio and depression. METHODS: Participants from the randomized control trial 'Sleep and Education: learning New Skills Early' (SENSE) Study were 122 adolescents at risk for depression (73 females) aged 12-16 years (M = 12.71 years, SD = 1.01 years) assessed at baseline (T1), post-intervention (T2), and a two-year follow-up (T3). RESULTS: Logistic regression results demonstrated that adolescents with higher T1 Cort:CRPmorn ratio levels were two-fold more likely to develop a first-onset depressive disorder from T2 to T3 as compared to adolescents with lower Cort:CRPmorn ratio levels, ß = 0.73, t (36) = 2.15, p = .04, OR = 2.08. This effect was not moderated by treatment condition (ß = -1.38, t (13) = -1.33, p = .20) and did not change when controlling for known risk factors for depression, including sex, age, body-mass index, socio-economic status, T1 anxiety disorder, nor T1 sleep disturbance, anxiety, or depressive symptoms (ß = 0.91, t (31) = 2.14, p = .04). CONCLUSION: Results highlight potential immuno-endocrine dysregulation as an underlying risk factor for adolescent first-onset depression, and may inform the development of targeted, preventative biobehavioral treatment strategies for youth depression.

Salivary C-reactive protein among at-risk adolescents: A methods investigation of out of range immunoassay data.

Inflammatory markers including C-Reactive Protein (CRP) are increasingly used within research and clinical settings. Yet, varying methodologies for cleaning immunoassay data with out of range (OOR) samples may alter characteristic levels of CRP, thereby obscuring interpretation and reliability. This study investigated the influence of eight immunoassay OOR data treatment techniques on salivary CRP (sCRP) samples from at-risk adolescents. Participants from the 'Sleep and Education: learning New Skills Early' (SENSE) Study were 86 adolescents at-risk for depression (50 female), aged 14.29 years (SD = 1.04). ANOVA results showed no statistically significant differences in average morning (F(7, 590) = 1.24, p = .28) and evening (F(7, 599)=1.29, p = .25) values produced by each OOR data cleaning technique. However, varying techniques produced differences in the magnitude of Pearson's correlations between consecutive saliva samples (r's between 0.27-0.78), and influenced the significance of a sCRP diurnal pattern; two techniques produced statistically higher morning than evening sCRP levels (t(85) = 2.70, p = .01 and t(85) = 2.67, p = .01), whereas six techniques failed to find statistical differences between morning and evening sCRP levels (p's >.05). Varying techniques also produced statistically divergent associations between sCRP and age and depressive symptoms. Results from this study provide evidence for the temporal stability of sCRP among adolescents, show winsorization as an effective OOR data management technique, and highlight the influence of methodological decisions in cleaning salivary biomarker data and the need for consistency within the field.

Dispositional mindfulness is predicted by structural development of the insula during late adolescence.

Adolescence is a critical period of development, in which the increasing social and cognitive demands of independence need to be met by enhanced self-regulatory abilities. The cultivation of mindfulness has been associated with improved self-regulation in adult populations, and it is theorized that one neurodevelopmental mechanism that supports this capacity is the development of the prefrontal cortex. The current study examined the neurodevelopmental mechanisms associated with dispositional mindfulness in adolescence. Using a longitudinal within-persons design, 82 participants underwent structural magnetic resonance imaging (MRI) assessments at approximately ages 16 and 19, and also completed self-reported measurements of mindfulness at age 19. It was hypothesized that adolescents who demonstrated greater thinning of frontal cortical regions between the age of 16 and 19 would exhibit higher dispositional mindfulness levels at age 19. Results indicated that, contrary to predictions, adolescents with higher levels of mindfulness demonstrated less thinning in the left anterior insula. By contrast, higher IQ was associated with greater thinning of the right caudal middle frontal and right superior frontal regions. The involvement of insula development in mindfulness is consistent with a direct role for this structure in managing self-regulation, and in doing so concords with recent models of self-referential interoceptive awareness.

Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study.

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13-19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.