Mechanical stretch triggers rapid epithelial cell division through Piezo1.

Despite acting as a barrier for the organs they encase, epithelial cells turn over at some of the fastest rates in the body. However, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How does the number of dying cells match those dividing to maintain constant numbers? When epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. However, it is unclear how epithelial cell division is controlled to balance cell death at the steady state. Here we show that mammalian epithelial cell division occurs in regions of low cell density where cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the Piezo1 channel. To stimulate cell division, stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at the steady state, the type of mechanical force controls the outcome: stretch induces cell division, whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion and apoptosis in crowded regions and cell division in sparse regions.

The impact of a complex school nutrition intervention on double burden of malnutrition among Thai primary school children: a 2-year quasi-experiment.

OBJECTIVE: This study assessed the impacts of the Dekthai Kamsai programme on overweight/obesity, underweight and stunting among male and female primary school students. STUDY DESIGN: A quasi-experiment was conducted in 16 intervention and 19 control schools across Thailand in 2018 and 2019. In total, 896 treated and 1779 control students from grades 1 to 3 were recruited. In intervention schools, a set of multifaceted intervention components were added into school routine practices. Anthropometric outcomes were measured at baseline and at the beginning and end of every school term. METHODS: Propensity score matching with linear and Poisson difference-in-difference analyses were used to adjust for the non-randomisation and to analyse the intervention's effects over time. RESULTS: Compared with controls, the increases in mean BMI-for-age Z-score (BAZ) and the incidence rate of overweight/obesity were lower in the intervention schools at the 3rd, 4th and 8th measurements and the 3rd measurement, respectively. The decrease in mean height-for-age Z-score (HAZ) was lower at the 4th measurement. The decrease in the incidence rate of wasting was lower at the 5th, 7th and 8th measurements. The favourable impacts on BAZ and HAZ were found in both sexes, while the favourable impact on overweight/obesity and unfavourable impact on wasting were found in girls. CONCLUSIONS: This intervention might be effective in reducing BAZ, overweight/obesity, poor height gain, but not wasting. These findings highlight the benefits of a multifaceted school nutrition intervention and a need to incorporate tailor-made interventions for wasting to comprehensively address the double burden of malnutrition.

Padres Preparados, Jóvenes Saludables: intervention impact of a randomized controlled trial on Latino father and adolescent energy balance-related behaviors.

BACKGROUND: Studies have shown associations among food and activity behaviors and body weight of Latino fathers and adolescents. However, few Latino father-focused interventions have been designed to improve energy balance-related behaviors (EBRBs) and weight status among early adolescents. Thus, this efficacy study aims to evaluate the Padres Preparados, Jóvenes Saludables (Padres) youth obesity prevention program for positive changes in EBRBs (fruit, vegetable, sugar-sweetened beverage (SSB), sweet/salty snack, and fast-food consumption, physical activity, and screen time) and weight status among low-income Latino fathers and adolescents (10-14 years). METHODS: A two-arm (treatment versus delayed-treatment control group) randomized controlled trial was conducted to evaluate the efficacy of 8 weekly experiential learning sessions (2.5 hours each) based on social cognitive theory. The sessions included food preparation, parenting skills, nutrition, and physical activity. The program was delivered to father-adolescent dyads (mothers were encouraged to attend) in trusted community-based settings in a Midwest metropolitan area between 2017 and 2019. In March 2020, in-person implementation was discontinued due to COVID-19 pandemic restrictions, which limited the sample size. Father/adolescent dyads were randomized to treatment or control group within each site. Surveys and measurements were completed by fathers and adolescents to assess changes in food and activity behaviors from baseline to post-intervention. Adolescents also completed 24-hour dietary recall interviews at baseline and post-intervention. Intervention effects were assessed using linear regression mixed models adjusted for covariates and accounting for clustering of participants within sites. RESULTS: Data from 147 father/adolescent dyads who completed at least the baseline data collection were used. No significant differences were observed for baseline to post-intervention changes in adolescents' and fathers' EBRBs or weight status between treatment and control groups. Fathers' SSB and fast food intakes were not statistically significant (p = 0.067 and p = 0.090, respectively). CONCLUSIONS: The Padres program resulted in no significant improvements in adolescent and father EBRBs and weight status. Additional Latino father-focused interventions are needed to examine intervention effects on EBRBs among Latino adolescents. TRIAL REGISTRATION: The Padres Preparados, Jóvenes Saludables study is registered with the U.S. National Library of Medicine, ClinicalTrials.gov Identifier: NCT03469752 (19/03/2018).

Scale-up of reverse electrodialysis for energy generation from high concentration salinity gradients.

Whilst reverse electrodialysis (RED) has been extensively characterised for saline gradient energy from seawater/river water (0.5 M/0.02 M), less is known about RED stack design for high concentration salinity gradients (4 M/0.02 M), important to closed loop applications (e.g. thermal-to-electrical, energy storage). This study therefore focuses on the scale-up of RED stacks for high concentration salinity gradients. Higher velocities were required to attain a maximum Open Circuit Voltage (OCV) for 4 M/0.02 M, which gives a measure of the electrochemical potential of the cell. The experimental OCV was also much below the theoretical OCV, due to the greater boundary layer resistance observed, which is distinct from 0.5 M/0.02 M. However, negative net power density (net produced electrical power divided by total membrane area) was demonstrated with 0.5 M/0.02 M for larger stacks using shorter residence times (three stack sizes tested: 10 × 10cm, 10 × 20cm and 10 × 40cm). In contrast, the highest net power density was observed at the shortest residence time for the 4 M/0.02 M concentration gradient, as the increased ionic flux compensated for the pressure drop. Whilst comparable net power densities were determined for the 10 × 10cm and 10 × 40cm stacks using the 4 M/0.02 M concentration gradient, the osmotic and ionic transport mechanisms are distinct. Increasing cell pair number improved maximum current density. This subsequently increased power density, due to the reduction in boundary layer resistance, and may therefore be used to improve thermodynamic efficiency and power density from RED for high concentrations. Although comparable power densities may be achieved for small and large stacks, large stacks maybe preferred for high concentration salinity gradients due to the comparative benefit in thermodynamic efficiency in single pass. The greater current achieved by large stacks may also be complemented by an increase in cell pair number and current density optimisation to increase power density and reduce exergy losses.

Membrane distillation for concentrated blackwater: Influence of configuration (air gap, direct contact, vacuum) on selectivity and water productivity.

Water recovery from concentrated blackwater has been studied using air gap (AGMD), direct contact (DCMD) and vacuum membrane distillation (VMD) to deliver decentralised sanitation. Whilst good water quality was achieved with each configuration, differences in the rejection of volatile compounds was observed. VMD exhibited the highest rejection of volatiles, specifically ammoniacal nitrogen, of all the configurations but fouling inhibited total flux. DCMD exhibited a temperature dependent volatile rejection which resulted in poor rejection at lower feed temperatures (≤40 °C). AGMD was identified as the most promising configuration for application within decentralised sanitation, since the rejection of volatiles was consistent over a range of operating temperatures with ammonia rejection directly related to solution pH. An increase in organic colloids and particles due to faecal contamination reduced COD removal due to the induction of wetting, but was shown to be offset by adoption of a smaller pore size (0.1 µm), and when complemented with upstream solid-liquid separation within a fully integrated system, will provide a robust sanitation solution. Importantly, this work has shown that AGMD can recover water from concentrated blackwater close to international discharge and reuse regulations in a single stage process; this is significant as blackwater consists of only urine and faeces, and is thus 40 times more concentrated than municipal sewage. It is proposed that the water quality produced reflects a step change to delivering safe sanitation, and is complemented by a simple method for heat recovery integration this is similarly advantageous for resource constrained environments common to decentralised sanitation solutions.

Transitioning from electrodialysis to reverse electrodialysis stack design for energy generation from high concentration salinity gradients.

In this study, stack design for high concentration gradient reverse electrodialysis operating in recycle is addressed. High concentration gradients introduce complex transport phenomena, which are exacerbated when recycling feeds; a strategy employed to improve system level energy efficiency. This unique challenge indicates that membrane properties and spacer thickness requirements may differ considerably from reverse electrodialysis for lower concentration gradients (e.g. seawater/river water), drawing closer parallels to electrodialysis stack design. Consequently, commercially available electrodialysis and reverse electrodialysis stack design was first compared for power generation from high concentration gradients. Higher gross power densities were identified for the reverse electrodialysis stack, due to the use of thinner membranes characterised by a higher permselectivity, which improved current. However, energy efficiency of the electrodialysis stack was twice that recorded for the reverse electrodialysis stack at low current densities, which was attributed to: (i) an increased residence time provided by the larger intermembrane distance, and (ii) reduced exergy losses of the electrodialysis membranes, which provided comparatively lower water permeance. Further in-depth investigation into membrane properties and spacer thickness identified that membranes characterised by an intermediate water permeability and ohmic resistance provided the highest power density and energy efficiency (Neosepta ACS/CMS), while wider intermembrane distances up to 0.3 mm improved energy efficiency. This study confirms that reverse electrodialysis stacks for high concentration gradients in recycle therefore demand design more comparable to electrodialysis stacks to drive energy efficiency, but when selecting membrane properties, the trade-off with permselectivity must also be considered to ensure economic viability.

Wavelength-Selective Photopolymerization of Hybrid Acrylate-Oxetane Liquid Crystals.

We report on the wavelength-selective photopolymerization of a hybrid acrylate-oxetane cholesteric liquid crystal monomer mixture. By controlling the sequence and rate of the orthogonal free-radical and cationic photopolymerization reactions, it is possible to control the degree of phase separation in the resulting liquid crystal interpenetrating networks. We show that this can be used to tune the reflective color of the structurally colored coatings produced. Conversely, the structural color can be used to monitor the degree of phase separation. Our new photopolymerization procedure allows for structuring liquid crystal networks in three dimensions, which has great potential for fabricating liquid crystal polymer materials with programmable functional properties.

Epoxide and oxetane based liquid crystals for advanced functional materials.

Liquid crystalline elastomers (LCEs) and liquid crystalline networks (LCNs) are classes of polymers very suitable for fabricating advanced functional materials. Two main pathways to obtain LCEs and LCNs have gained the most attention in the literature, namely the two-step crosslinking of LC side-chain polymers and the photoinitiated free-radical polymerisation of acrylate LC monomers. These liquid crystal polymers have demonstrated remarkable properties resulting from their anisotropic shapes, being used in soft robotics, responsive surfaces and as photonic materials. In this review, we will show that LCs with cyclic ethers as polymerisable groups can be an attractive alternative to the aforementioned reactive acrylate mesogens. These epoxide and oxetane based reactive mesogens could offer a number of advantages over their acrylate-based counterparts, including oxygen insensitivity, reduced polymerisation shrinkage, improved alignment, lower processing viscosity and potentially extended resistivity. In this review, we summarise the research on these materials from the past 30 years and offer a glimpse into the potential of these cyclic ether mesogens.

Ultrafiltration pretreatment enhances membrane distillation flux, resilience and permeate quality during water recovery from concentrated blackwater (urine/faeces).

In this study, the pretreatment of concentrated blackwater using ultrafiltration (UF) was shown to improve the permeability, selectivity and robustness of membrane distillation (MD) for application to wastewater treatment. Concentrated blackwater comprises urine and faeces, with minimal flushwater added. The faecal contribution increased the soluble organic fraction and introduced coarse and colloidal particles into the urine, which increased resistance to filtration during dead-end UF. Ultrafiltration removed the particulate and colloidal fractions (MW > 500 kDa) from the blackwater, which permitted similar permeability and robustness for MD to that observed with urine (29.9 vs 25.9 kg m-2 h-1), which comprises a lower colloidal organic concentration. Without UF pretreatment, a higher density organic layer formed on the MD surface (197 vs 70 gCOD m-2) which reduced mass transfer, and transformed the contact angle from hydrophobic to hydrophilic (144.9° to 49.8°), leading to pore wetting and a dissipation in product water quality due to breakthrough. In comparison, with UF pretreatment, MD delivered permeate water quality to standards satisfactory for discharge or reuse. This is particularly timely as the ISO standard for non-sewered sanitation has been adopted by several countries at a national level, and to date there are relatively few technologies to achieve the treatment standard. Membrane distillation provides a robust means for concentrated blackwater treatment, and since the energy required for separation is primarily heat, this advanced treatment can be delivered into areas with more fragile power networks.

Managing power dissipation in closed-loop reverse electrodialysis to maximise energy recovery during thermal-to-electric conversion.

Whilst the efficiency of reverse electrodialysis (RED) for thermal-to-electrical conversion has been theoretically demonstrated for low-grade waste heat, the specific configuration and salinity required to manage power generation has been less well described. This study demonstrates that operating RED by recycling feed solutions provides the most suitable configuration for energy recovery from a fixed solution volume, providing a minimum unitary cost for energy production. For a fixed membrane area, recycling feeds achieves energy efficiency seven times higher than single pass (conventional operation), and with an improved power density. However, ionic transport, water flux and concentration polarisation introduce complex temporal effects when concentrated brines are recirculated, that are not ordinarily encountered in single pass systems. Regeneration of the concentration gradient at around 80% energy dissipation was deemed most economically pragmatic, due to the increased resistance to mass transport beyond this threshold. However, this leads to significant exergy destruction that could be improved by interventions to better control ionic build up in the dilute feed. Further improvements to energy efficiency were fostered through optimising current density for each brine concentration independently. Whilst energy efficiency was greatest at lower brine concentrations, the work produced from a fixed volume of feed solution was greatest at higher saline concentrations. Since the thermal-to-electrical conversion proposed is governed by volumetric heat utilisation (distillation to reset the concentration gradient), higher brine concentrations are therefore recommended to improve total system efficiency. Importantly, this study provides new evidence for the configuration and boundary conditions required to realise RED as a practical solution for application to sources of low-grade waste heat in industry.

Hybrid membrane distillation reverse electrodialysis configuration for water and energy recovery from human urine: An opportunity for off-grid decentralised sanitation.

The integration of membrane distillation with reverse electrodialysis has been investigated as a sustainable sanitation solution to provide clean water and electrical power from urine and waste heat. Reverse electrodialysis was integrated to provide the partial remixing of the concentrate (urine) and diluate (permeate) produced from the membrane distillation of urine. Broadly comparable power densities to those of a model salt solution (sodium chloride) were determined during evaluation of the individual and combined contribution of the various monovalent and multivalent inorganic and organic salt constituents in urine. Power densities were improved through raising feed-side temperature and increasing concentration in the concentrate, without observation of limiting behaviour imposed by non-ideal salt and water transport. A further unique contribution of this application is the limited volume of salt concentrate available, which demanded brine recycling to maximise energy recovery analogous to a battery, operating in a 'state of charge'. During recycle, around 47% of the Gibbs free energy was recoverable with up to 80% of the energy extractable before the concentration difference between the two solutions was halfway towards equilibrium which implies that energy recovery can be optimised with limited effect on permeate quality. This study has provided the first successful demonstration of an integrated MD-RED system for energy recovery from a limited resource, and evidences that the recovered power is sufficient to operate a range of low current fluid pumping technologies that could help deliver off-grid sanitation and clean water recovery at single household scale.

Does adherence to child care nutrition and physical activity best practices differ by child care provider's participation in support programs and training?

INTRODUCTION: To date, gaps exist in our understanding of how child care provider participation in various support programs is associated with the reported implementation of nutrition and physical activity best practices by child care providers. Thus, the purpose of the current study was to compare implementation of nutrition and physical activity best practices among child care providers engaged in the Child and Adult Food Care Program (CACFP), Parent AWARE, and other training opportunities, to implementation among providers who do not participate in each of these opportunities. METHODS: Cross-sectional analysis of survey data collected from a stratified-random sample of licensed family-home and center-based child care settings (Family-homes n=394; Centers n= 224) in XXX from Month-Month 20XX. Descriptive statistics and multiple regression models were used to characterize differences in adherence to best practices based on program participation (CACFP, Parent AWARE, training) and type of child care setting (center versus family-home). Surveys measured self-reported engagement in nutrition and PA best practices as well as participation in CACFP, Parent Aware, and training opportunities. RESULTS: Center-based child care providers participating in CACFP adhered to more nutrition and PA best practices than those not involved in CACFP. Further, with one exception, participating in Parent AWARE and engagement in training were positively associated with adherence to nutrition practices in center and family-home setting, and with adherence to PA practices in family homes. CONCLUSIONS: Child care providers should be encouraged to participate in available support programs; advocates should work to identify and remove barriers to support program participation.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder.

BACKGROUND: Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals. METHOD: In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging. RESULTS: Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety-threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC. CONCLUSIONS: Poor vmPFC safety-threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.Declaration of interestNone.

Robust analysis of stepped wedge trials using cluster-level summaries within periods.

In stepped-wedge trials (SWTs), the intervention is rolled out in a random order over more than 1 time-period. SWTs are often analysed using mixed-effects models that require strong assumptions and may be inappropriate when the number of clusters is small. We propose a non-parametric within-period method to analyse SWTs. This method estimates the intervention effect by comparing intervention and control conditions in a given period using cluster-level data corresponding to exposure. The within-period intervention effects are combined with an inverse-variance-weighted average, and permutation tests are used. We present an example and, using simulated data, compared the method to (1) a parametric cluster-level within-period method, (2) the most commonly used mixed-effects model, and (3) a more flexible mixed-effects model. We simulated scenarios where period effects were common to all clusters, and when they varied according to a distribution informed by routinely collected health data. The non-parametric within-period method provided unbiased intervention effect estimates with correct confidence-interval coverage for all scenarios. The parametric within-period method produced confidence intervals with low coverage for most scenarios. The mixed-effects models' confidence intervals had low coverage when period effects varied between clusters but had greater power than the non-parametric within-period method when period effects were common to all clusters. The non-parametric within-period method is a robust method for analysing SWT. The method could be used by trial statisticians who want to emphasise that the SWT is a randomised trial, in the common position of being uncertain about whether data will meet the assumptions necessary for mixed-effect models.

Predictors and consequences of health anxiety symptoms: a novel twin modeling study.

OBJECTIVE: The question of how to best conceptualize health anxiety (HA) from a diagnostic and etiological perspective remains debated. The aim was to examine the relationship between HA and the symptoms of anxiety and obsessive-compulsive-related disorders in a normative twin population. METHOD: Four hundred and ninety-six monozygotic adult twin pairs from the Australian Twin Registry participated in the study (age, 34.4 ± 7.72 years; 59% females). Validated scales were used to assess each domain. We applied a twin regression methodology-ICE FALCON-to determine whether there was evidence consistent with 'causal' relationships between HA and other symptoms by fitting and comparing model estimates. RESULTS: Estimates were consistent with higher levels of obsessing ('unwanted thoughts') (P = 0.008), social anxiety (P = 0.03), and body dysmorphic symptoms (P = 0.008) causing higher levels of HA symptoms, and with higher levels of HA symptoms causing higher levels of physical/somatic anxiety symptoms (P = 0.001). CONCLUSION: Obsessional thoughts, body dysmorphic concerns, and social anxiety symptoms may have a causal influence on HA. To report physical/somatic anxiety appears to be a consequence of the underlying presence of HA-related fears. Should our results be confirmed by longitudinal studies, the evaluation and treatment of HA may benefit from the consideration of these identified risk factors.

A Comparison of Vocational Engagement Among Young People with Psychosis, Depression and Borderline Personality Pathology.

Poor vocational engagement is well documented among young people experiencing first-episode psychosis (FEP). The aim of the present study was to establish and compare rates of vocational engagement across young people with first-episode psychosis, depression, and borderline personality pathology. A file audit was used to collect vocational data of young people aged 15-25 entering tertiary mental health treatment in 2011. Rates of vocational engagement were similar across groups, indicating that like those with FEP, young people with depression and borderline personality pathology experience impaired vocational engagement and are in need of targeted vocational interventions. Post hoc analysis indicated that that the depression group had significantly more people who were partially vocationally engaged compared with the psychosis group, suggesting that vocational interventions might need to be targeted differently across different diagnostic groups. Future research should explore risk factors for vocational disengagement across diagnostic groups in order to inform intervention development.

A systematic review and meta-analysis of prospective transition from major depression to bipolar disorder.

OBJECTIVE: Some people with major depressive disorder (MDD) may be at a pre-onset stage for bipolar disorder (BD), where early identification or prevention efforts may be feasible. We aimed to identify rates and characteristics predictive of transition to BD in prospective follow-up studies of people with MDD. METHODS: Using a systematic search strategy, we identified studies with a diagnostic ascertainment of MDD and BD of an adequate standard, and where the minimum length of follow-up was 6 months. We examined the incidence and point prevalence of BD and the pooled odds ratios (OR) for baseline predictors. RESULTS: From 5554 unique publications, 56 were included. Nearly a quarter of adults (22.5%) and adolescents with MDD followed up for a mean length of 12-18 years developed BD, with the greatest risk of transition being in the first 5 years. The meta-analysis identified that transition from MDD to BD was predicted by family history of BD (OR = 2.89, 95% CI: 2.01-4.14, N = 7), earlier age of onset of depression (g = -0.33, SE = 0.05, N = 6) and presence of psychotic symptoms (OR = 4.76, 95% CI: 1.79-12.66, N = 5). CONCLUSIONS: Participants with the identified risk factors merit closer observation and may benefit from prevention efforts, especially if outcomes broader than BD are considered.

The effects of stress-tension on depression and anxiety symptoms: evidence from a novel twin modelling analysis.

BACKGROUND: Negative mood states are composed of symptoms of depression and anxiety, and by a third factor related to stress, tension and irritability. We sought to clarify the nature of the relationships between the factors by studying twin pairs. METHOD: A total of 503 monozygotic twin pairs completed the Depression Anxiety Stress Scales (DASS), an instrument that assesses symptoms of depression, anxiety and stress-tension. We applied a recently developed twin regression methodology - Inference about Causation from Examination of FAmiliaL CONfounding (ICE FALCON) - to test for evidence consistent with the existence of 'causal' influences between the DASS factors. RESULTS: There was evidence consistent with the stress-tension factor having a causal influence on both the depression (p < 0.0001) and anxiety factors (p = 0.001), and for the depression factor having a causal influence on the anxiety factor (p < 0.001). CONCLUSIONS: Our findings suggest a critical role for stress-tension in the structure of negative mood states, and that interventions that target it may be particularly effective in reducing depression and anxiety symptoms.

Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi trial): study design and rationale.

Although lung volume reduction surgery improves survival in selected patients with emphysema, there has been ongoing interest in developing and evaluating bronchoscopic approaches to try to reduce lung volumes with less morbidity and mortality. The placement of endobronchial valves is one such technique, and although some patients have had a significant improvement, responses have been inconsistent because collateral ventilation prevents lobar atelectasis. We describe the protocol of a trial (ISRCTN04761234) aimed to show that a responder phenotype, patients with heterogeneous emphysema and intact interlobar fissures on CT scanning, can be identified prospectively, leading to a consistent benefit in clinical practice.

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.