Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

Unravelling the complex nature of resilience factors and their changes between early and later adolescence.

BACKGROUND: Childhood adversity (CA) is strongly associated with mental health problems. Resilience factors (RFs) reduce mental health problems following CA. Yet, knowledge on the nature of RFs is scarce. Therefore, we examined RF mean levels, RF interrelations, RF-distress pathways, and their changes between early (age 14) and later adolescence (age 17). METHODS: We studied 10 empirically supported RFs in adolescents with (CA+; n = 631) and without CA (CA-; n = 499), using network psychometrics. RESULTS: All inter-personal RFs (e.g. friendships) showed stable mean levels between age 14 and 17, and three of seven intra-personal RFs (e.g. distress tolerance) changed in a similar manner in the two groups. The CA+ group had lower RFs and higher distress at both ages. Thus, CA does not seem to inhibit RF changes, but to increase the risk of persistently lower RFs. At age 14, but not 17, the RF network of the CA+ group was less positively connected, suggesting that RFs are less likely to enhance each other than in the CA- group. Those findings underpin the notion that CA has a predominantly strong proximal effect. RF-distress pathways did not differ in strength between the CA+ and the CA- group, which suggests that RFs have a similarly protective strength in the two groups. Yet, as RFs are lower and distress is higher, RF-distress pathways may overall be less advantageous in the CA+ group. Most RF interrelations and RF-distress pathways were stable between age 14 and 17, which may help explain why exposure to CA is frequently found to have a lasting impact on mental health. CONCLUSIONS: Our findings not only shed light on the nature and changes of RFs between early and later adolescence, but also offer some accounts for why exposure to CA has stronger proximal effects and is often found to have a lasting impact on mental health.

Identifying key targets for interventions to improve psychological wellbeing: replicable results from four UK cohorts.

BACKGROUND: An increasing importance is being placed on mental health and wellbeing at individual and population levels. While there are several interventions that have been proposed to improve wellbeing, more evidence is needed to understand which aspects of wellbeing are most influential. This study aimed to identify key items that signal improvement of mental health and wellbeing. METHODS: Using network analysis, we identified the most central items in the graph network estimated from the well-established Warwick-Edinburgh Mental Well-being Scale (WEMWBS). Results were compared across four major UK cohorts comprising a total of 47,578 individuals: the Neuroscience in Psychiatry Network, the Scottish Schools Adolescent Lifestyle and Substance Use Survey, the Northern Ireland Health Survey, and the National Child Development Study. RESULTS: Regardless of gender, the three items most central in the network were related to positive self-perception and mood: 'I have been feeling good about myself'; 'I have been feeling confident'; and 'I have been feeling cheerful'. Results were consistent across all four cohorts. CONCLUSIONS: Positive self-perception and positive mood are central to psychological wellbeing. Psychotherapeutic and public mental health interventions might best promote psychological wellbeing by prioritising the improvement of self-esteem, self-confidence and cheerfulness. However, empirical testing of interventions using these key targets is needed.

Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study.

BACKGROUND: To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms. METHODS: IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms. RESULTS: Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose-response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68-0.95); that for IL-6 was 1.20 (95% CI, 1.03-1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship. CONCLUSIONS: The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people.

Adolescent friendships predict later resilient functioning across psychosocial domains in a healthy community cohort.

BACKGROUND: Adolescence is a key time period for the emergence of psychosocial and mental health difficulties. To promote adolescent adaptive ('resilient') psychosocial functioning (PSF), appropriate conceptualisation and quantification of such functioning and its predictors is a crucial first step. Here, we quantify resilient functioning as the degree to which an individual functions better or worse than expected given their self-reported childhood family experiences, and relate this to adolescent family and friendship support. METHOD: We used Principal Component and regression analyses to investigate the relationship between childhood family experiences and PSF (psychiatric symptomatology, personality traits and mental wellbeing) in healthy adolescents (the Neuroscience in Psychiatry Network; N = 2389; ages 14-24). Residuals from the relation between childhood family experiences and PSF reflect resilient functioning; the degree to which an individual is functioning better, or worse, than expected given their childhood family experiences. Next, we relate family and friendship support with resilient functioning both cross-sectionally and 1 year later. RESULTS: Friendship and family support were positive predictors of immediate resilient PSF, with friendship support being the strongest predictor. However, whereas friendship support was a significant positive predictor of later resilient functioning, family support had a negative relationship with later resilient PSF. CONCLUSIONS: We show that friendship support, but not family support, is an important positive predictor of both immediate and later resilient PSF in adolescence and early adulthood. Interventions that promote the skills needed to acquire and sustain adolescent friendships may be crucial in increasing adolescent resilient PSF.

Mood, anxiety and psychotic phenomena measure a common psychopathological factor.

BACKGROUND: Psychotic phenomena are common in the general population but are excluded from diagnostic criteria for mild to moderate depression and anxiety despite their co-occurrence and shared risk factors. We used item response theory modelling to examine whether the co-occurrence of depressive, anxiety and psychotic phenomena is best explained by: (1) a single underlying factor; (2) two separate, uncorrelated factors; (3) two separate yet linked factors; or (4) two separate domains along with an underlying 'common mental distress' (CMD) factor. We defined where, along any latent continuum, the psychopathological items contributed most information. METHOD: We performed a secondary analysis of cross-sectional, item-level information from measures of depression, anxiety and psychotic experiences in 6617 participants aged 13 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and 977 participants aged 18 years from the ROOTS schools-based sample. We replicated results from one sample in the other and validated the latent factors against an earlier parental measure of mental state. RESULTS: In both cohorts depression, anxiety and psychotic items were best represented as a bi-factor model with a single, unitary CMD factor on which psychotic items conveyed information about the more severe end (model 4); residual variation remained for psychotic items. The CMD factor was significantly associated with the prior parental measure. CONCLUSIONS: Psychotic phenomena co-occur with depression and anxiety in teenagers and may be a marker of severity in a single, unitary dimension of CMD. Psychotic phenomena should be routinely included in epidemiological assessments of psychiatric morbidity, otherwise the most severe symptomatology remains unmeasured.

Breakfast consumption and physical activity in British adolescents.

Studies show an inverse relationship between breakfast frequency and weight gain. This may reflect poor eating habits generally and associated low physical activity (PA) or direct impacts of breakfast on mechanisms leading to lethargy and reduced PA. The relationship between breakfast frequency and PA is inconclusive. We aimed to determine whether breakfast frequency is associated with PA levels in British adolescents independent of body composition and socio-economic status (SES). Habitual breakfast frequency (self-report questionnaire) was assessed in 877 adolescents (43% male, age 14·5 (SD 0·5) years old). PA was measured over 5 d (accelerometry, average counts/ min; cpm). Associations between daily PA and breakfast frequency were assessed using linear regression adjusted for body fat percentage and SES. Effect modification by sex and associations with PA during the morning (06.00-12.00 hours) were explored. For boys, there were no significant associations between breakfast frequency and PA. For girls, less frequent breakfast consumption was significantly associated with lower PA (cpm) during the morning (occasional v. frequent b - 6·1 (95% CI - 11·1, -1·1), P = 0·017) when adjusted for body fat percentage and SES. There were no associations between PA and breakfast consumption over the whole day; however, for girls, less frequent breakfast consumption may be associated with lower PA levels during the morning, suggesting that breakfast consumption should perhaps be taken into consideration when aiming to promote PA in adolescent girls.

The interplay between adolescent friendship quality and resilient functioning following childhood and adolescent adversity.

Background: Child and adolescent adversity ('CA') is a major predictor of mental health problems in adolescence and early adulthood. However, not all young people who have experienced CA develop psychopathology; their mental health functioning can be described as resilient. We previously found that resilient functioning in adolescence following CA is facilitated by adolescent friendships.However, during adolescence, friendships undergo significant change. It is unknown whether resilient functioning after CA fluctuates with these normative changes in friendship quality. Methods: We used Latent Change Score Modelling in a large sample of adolescents (i.e. the ROOTS cohort; N=1238) to examine whether and how emergent friendship quality and resilient functioning at ages 14 and 17 inter-relate and change together. Results: We found that friendships quality and resilient functioning had strong associations at age 14, although friendships at 14 did not predict higher resilient functioning at 17. Higher resilient functioning in 14-year-olds with a history of CA was associated with a positive change in friendships from age 14 to 17. Finally, improvements in friendship quality and resilient functioning went hand in hand, even when taking into account baseline levels of both, the change within friendship quality or resilient functioning over time, and the association between resilient functioning and change in friendship quality over time. Conclusions: We show that friendship quality and resilient functioning after CA inter-relate and change together between ages 14 and 17. Our results suggest that improving friendship quality or resilient functioning within this timeframe may benefit this vulnerable adolescent group, and this should be tested in future research.

Embracing the positive: an examination of how well resilience factors at age 14 can predict distress at age 17.

One-in-two people suffering from mental health problems develop such distress before or during adolescence. Research has shown that distress can predict itself well over time. Yet, little is known about how well resilience factors (RFs), i.e. those factors that decrease mental health problems, predict subsequent distress. Therefore, we investigated which RFs are the best indicators for subsequent distress and with what accuracy RFs predict subsequent distress. We examined three interpersonal (e.g. friendships) and seven intrapersonal RFs (e.g. self-esteem) and distress in 1130 adolescents, at age 14 and 17. We estimated the RFs and a continuous distress-index using factor analyses, and ordinal distress-classes using factor mixture models. We then examined how well age-14 RFs and age-14 distress predict age-17 distress, using stepwise linear regressions, relative importance analyses, as well as ordinal and linear prediction models. Low brooding, low negative and high positive self-esteem RFs were the most important indicators for age-17 distress. RFs and age-14 distress predicted age-17 distress similarly. The accuracy was acceptable for ordinal (low/moderate/high age-17 distress-classes: 62-64%), but low for linear models (37-41%). Crucially, the accuracy remained similar when only self-esteem and brooding RFs were used instead of all ten RFs (ordinal = 62%; linear = 37%); correctly predicting for about two-in-three adolescents whether they have low, moderate or high distress 3 years later. RFs, and particularly brooding and self-esteem, seem to predict subsequent distress similarly well as distress can predict itself. As assessing brooding and self-esteem can be strength-focussed and is time-efficient, those RFs may be promising for risk-detection and translational intervention research.

Cognitive behavioral therapy may have a rehabilitative, not normalizing, effect on functional connectivity in adolescent depression.

BACKGROUND: Whether the differences in brain structure and function, characteristic of adult major depressive disorder (MDD1), are present in adolescent MDD is still unclear, but it has been shown that cognitive behavioral therapy (CBT2) affects resting-state functional connectivity in both adult and adolescent MDD patients, with the claim that CBT has a normalizing effect on MDD-related functional disruption, but this has not been directly tested. METHODS: 128 adolescent MDD patients and 40 adolescent controls were enrolled in the study. We investigated pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity. We also investigated the longitudinal effects of CBT on resting-state functional connectivity, and the relationship between pre-treatment functional disruption and CBT-related changes to resting-state functional connectivity was assessed by the correlation of pre-treatment cross-sectional effects and longitudinal CBT-related effects across multiple brain regions. RESULTS: Patients had greater cortical thickness and white matter volume within fronto-limbic regions of the brain. Patients had greater pre-treatment resting-state functional connectivity within the default-mode, fronto-limbic, central-executive, and salience networks. CBT increased resting-state functional connectivity of the subgenual anterior cingulate and amygdala seeds with predominantly frontal regions. Regions showing the greatest pre-treatment functional disruption showed the weakest CBT-related changes. LIMITATIONS: For ethical reasons, there was no placebo group. CONCLUSIONS: Adolescent MDD is associated with structural and functional differences also seen in adult patients. CBT-related changes in resting-state functional connectivity do not appear to show a normalizing effect, but instead indicate rehabilitative effects on resting-state functional connectivity.

A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

OBJECTIVES: To determine if, in the short term, depressed adolescents attending routine NHS Child and Adolescent Mental Health Services (CAMHS), and receiving ongoing active clinical care, treatment with selective serotonin reuptake inhibitors (SSRIs) plus cognitive behaviour therapy (CBT) compared with SSRI alone, results in better healthcare outcomes. DESIGN: A pragmatic randomised controlled trial (RCT) was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention (BII) prior to randomisation. SETTING: Six English CAMHS participated in the study. PARTICIPANTS: A total of 208 patients aged between 11 and 17 years were recruited and randomised. INTERVENTIONS: All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT. MAIN OUTCOME MEASURES: The duration of the trial was a 12-week treatment phase, followed by a 16-week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical global impression of response to treatment. Information on resource use was collected in interview at baseline and at the 12- and 28-week follow-up assessments using the Child and Adolescent Service Use Schedule (CA-SUS). RESULTS: Of the 208 patients randomised, 200 (96%) completed the trial to the primary end-point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated. Overall, 193 (93%) participants had been assessed at one or more time points. Clinical characteristics indicated that the trial was conducted on a severely depressed group. There was significant recovery at all time points in both arms. The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at any time point. This lack of difference held when baseline and treatment characteristics where taken into account (age, sex, severity, co-morbid characteristics, quality and quantity of CBT treatment, number of clinic attendances). The SSRI + CBT group was somewhat more expensive over the 28 weeks than the SSRI-only group (p=0.057) and no more cost-effective. Over the trial period there was on average a decrease in suicidal thoughts and self-harm compared with levels recorded at baseline. There was no significant increase in disinhibition, irritability and violence compared with levels at baseline. Around 20% (n=40) of patients in the trial were non-responders. Of these, 17 (43%) showed no improvement by 28 weeks and 23 (57%) were considered minimally (n=10) or moderately to severely worse (n=13). CONCLUSIONS: For moderately to severely depressed adolescents who are non-responsive to a BII, the addition of CBT to fluoxetine plus routine clinical care does not improve outcome or confer protective effects against adverse events and is not cost-effective. SSRIs (mostly fluoxetine) are not likely to result in harmful adverse effects. The findings are broadly consistent with existing guidelines on the treatment of moderate to severe depression. Modification is advised for those presenting with moderate (6-8 symptoms) to severe depressions (>8 symptoms) and in those with either overt suicidal risk and/or high levels of personal impairment. In such cases, the time allowed for response to psychosocial interventions should be no more than 2-4 weeks, after which fluoxetine should be prescribed. Further research should focus on evaluating the efficacy of specific psychological treatments against brief psychological intervention, determining the characteristics of patients with severe depression who are non-responsive to fluoxetine, relapse prevention in severe depression and improving tools for determining treatment responders and non-responders.

A Network Model of Resilience Factors for Adolescents with and without Exposure to Childhood Adversity.

Resilience factors (RFs) help prevent mental health problems after childhood adversity (CA). RFs are known to be related, but it is currently unknown how their interrelations facilitate mental health. Here, we used network analysis to examine the interrelations between ten RFs in 14-year-old adolescents exposed ('CA'; n = 638) and not exposed to CA ('no-CA'; n = 501). We found that the degree to which RFs are assumed to enhance each other is higher in the no-CA compared to the CA group. Upon correction for general distress levels, the global RF connectivity also differed between the two groups. More specifically, in the no-CA network almost all RFs were positively interrelated and thus may enhance each other, whereas in the CA network some RFs were negatively interrelated and thus may hamper each other. Moreover, the CA group showed more direct connections between the RFs and current distress. Therefore, CA seems to influence how RFs relate to each other and to current distress, potentially leading to a dysfunctional RF system. Translational research could explore whether intervening on negative RF interrelations so that they turn positive and RFs can enhance each other, may alter 'RF-mental distress' relations, resulting in a lower risk for subsequent mental health problems.

Do corticosteroids damage the brain?

Corticosteroids are an essential component of the body's homeostatic system. In common with other such systems, this implies that corticosteroid levels in blood and, more importantly, in the tissues remain within an optimal range. It also implies that this range may vary according to circumstance. Lack of corticosteroids, such as untreated Addison's disease, can be fatal in humans. In this review, we are principally concerned with excess or disturbed patterns of circulating corticosteroids in the longer or shorter term, and the effects they have on the brain.

Multiple markers of cortical morphology reveal evidence of supragranular thinning in schizophrenia.

In vivo structural neuroimaging can reliably identify changes to cortical morphology and its regional variation but cannot yet relate these changes to specific cortical layers. We propose, however, that by synthesizing principles of cortical organization, including relative contributions of different layers to sulcal and gyral thickness, regional patterns of variation in thickness of different layers across the cortical sheet and profiles of layer variation across functional hierarchies, it is possible to develop indirect morphological measures as markers of more specific cytoarchitectural changes. We developed four indirect measures sensitive to changes specifically occurring in supragranular cortical layers, and applied these to test the hypothesis that supragranular layers are disproportionately affected in schizophrenia. Our findings from the four different measures converge to indicate a predominance of supragranular thinning in schizophrenia, independent of medication and illness duration. We propose that these indirect measures offer novel ways of identifying layer-specific cortical changes, offering complementary in vivo observations to existing post-mortem studies.

Objectively measured physical activity and longitudinal changes in adolescent body fatness: an observational cohort study.

BACKGROUND: The data regarding prospective associations between physical activity (PA) and adiposity in youth are inconsistent. OBJECTIVE: The objective of this study was to investigate associations between baseline levels of objectively measured PA and changes in adiposity over 2.5 years from mid-to-late adolescence. METHODS: This was an observational cohort study in 728 school students (43% boys) from Cambridgeshire, United Kingdom. Fat mass index (FMI, kg m(-2) ) was estimated at baseline (mean ± standard deviation age: 15 ± 0.3 years) and follow-up (17.5 ± 0.3 years) by anthropometry and bioelectrical impedance. Habitual PA was assessed at baseline by ≥3 d combined heart rate and movement sensing. Average daily PA energy expenditure (PAEE) and the time (min d(-1) ) spent in light, moderate and vigorous intensity PA (LPA, MPA and VPA, respectively) was estimated. Multilevel models were used to investigate associations between baseline PA and change in FMI (ΔFMI). Adjustment for baseline age, sex, follow-up duration, area-level socioeconomic status, season of PA assessment, sedentary time, energy intake and sleep duration was made; baseline FMI was also added in a second model. RESULTS: FMI increased significantly over follow-up (0.6 ± 1.2 kg m(-2) , P < 0.001). Baseline PAEE and LPA positively predicted ΔFMI in overfat participants (P ≤ 0.030), as did VPA in initially normal fat participants (P ≤ 0.044). There were further positive associations between PAEE and ΔFMI in normal fat participants, and between MPA and ΔFMI in both fat groups, when adjusted for baseline FMI (P ≤ 0.024). CONCLUSIONS: Baseline PAEE and its subcomponents were positively associated with small and unlikely clinically relevant increases in ΔFMI. These counter-intuitive findings may be explained by behavioural changes during the course of study follow-up.

Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age.

The relation between blood and cerebrospinal fluid (CSF) concentrations of cortisol, dehydroepiandrosterone (DHEA), and its sulfate (DHEAS) was measured in 62 subjects aged 3-85 yr old, fitted with ventriculo-peritoneal or lumbar-peritoneal shunts for a variety of diagnoses. There were 36 males and 36 females. Forty-eight subjects were not taking exogenous corticosteroids; the other 14 were receiving either systemic or local steroids. A single sample of blood and CSF was taken from each subject within 10 min for measurement of cortisol, DHEA, and DHEAS. The proportional levels of cortisol (5.8%) and DHEA (5.4%) in the CSF compared with those in the blood were similar in subjects not taking steroids. However, CSF DHEAS levels were only 0.15% of those in the blood. Because DHEAS blood levels were so much greater than DHEA, DHEAS in the CSF was still higher than DHEA despite the reduced penetration of the sulfated steroid. The blood/CSF ratios were similar in subjects taking steroids. There were significant correlations in steroid-free subjects between blood and CSF levels for DHEA (r = 0.65) and DHEAS (r = 0.88) but not for cortisol (r = 0.26). Steroid treatment significantly lowered blood cortisol, DHEA and DHEAS, and CSF DHEA, but not CSF cortisol or DHEAS compared with an age- and sex-matched sample of steroid-free subjects. In steroid-free adults (18 yr and over; n = 37), blood cortisol showed no age-related change. However, CSF cortisol was markedly raised in a proportion of steroid-free subjects over the age of 60 yr. Levels of corticoid-binding globulin in plasma did not alter with age. As expected, there were significant age-related decrements in both blood DHEA and DHEAS. CSF DHEA (r = 0.42) and CSF DHEAS (r = 0.39) were significantly negatively correlated with age. In steroid-free juveniles (n = 11) there were no age-related changes in either blood or CSF cortisol, but significant increases with age in DHEA and DHEAS in both blood and CSF. Calculation of the cortisol/DHEA and cortisol/ DHEAS molar ratios in the CSF showed both to be raised in the very young (3-8 yr) and the elderly (60 yr and over) by a factor of 4-5 compared with young adults aged 18-39. There were no sex differences in any of the parameters measured. These findings show that the relation between levels in the blood and CSF differ for each of these three neuroactive steroids. The brain is exposed to relatively high levels of DHEA and DHEAS during later childhood and early adulthood but to relatively or absolutely high levels of cortisol during infancy and older age. In view of the known antiglucocorticoid action of DHEA and DHEAS, and the direct action of these steroids on membrane-bound transmitter events (such as gamma-aminobutyric acidA receptors), these changes may have important implications for age-related alterations in brain function.

Psychosocial and endocrine features of chronic first-episode major depression in 8-16 year olds.

BACKGROUND: Psychoendocrine processes may have a role in explaining individual differences in the outcome of major depression in 8-16-year-old school children. METHODS: Salivary cortisol and dehydroepiandrosterone (DHEA) levels at 8:00 AM and 8:00 PM, life events, and comorbidity were assessed at presentation, 36, and 72 weeks in 47 (60%) of 78 clinically referred subjects with a first episode of major depression. Comparisons were made between chronic and nonchronic major depression. RESULTS: Chronic depression was characterized by being older, cortisol hypersecretion at 8:00 PM at all three assessments, increasing depression-dependent life events over the follow-up period, and comorbid obsessive-compulsive disorder (OCD) at presentation and at 36 weeks. Chronicity may be best predicted by increasing depression-dependent events over the 72-week period. Such events are more likely in cases with evening cortisol hypersecretion at entry and persistent OCD. Variations in DHEA levels were not associated with chronicity or increasing life events. CONCLUSIONS: During adolescence, but not childhood, the persistence of major depression may occur through an increase of risk for further and particular types of depression-dependent undesirable life events (personal disappointments and/or dangers to the self), that are more likely in those subjects with persisting cortisol hypersecretion and unresolved comorbid OCD.

Efflux of 6-deoxy-D-glucose from Plasmodium falciparum-infected erythrocytes via two saturable carriers.

Glucose transport in human erythrocytes infected with the malaria parasite, Plasmodium falciparum, has been studied using 6-deoxy-D-glucose (6DOG) as a non-metabolised glucose analogue. Inhibition studies using cytochalasin B, a powerful inhibitor of the erythrocyte glucose transporter, GLUT1, indicate that in the infected red blood cell (IRBC), glucose is transported via a saturable carrier. However, inhibition is not as complete as in the uninfected erythrocyte. The synergistic inhibition effect of 6DOG entry by niflumic acid, an inhibitor of the non-specific malaria-induced pore, in the presence of cytochalasin B suggests that some glucose may also enter the infected erythrocytes through the pore, if entry via the carrier is blocked. The time course of 6DOG efflux from infected erythrocytes in the presence of cytochalasin B did not follow simple first-order kinetics. To elucidate the kinetic mechanism of 6DOG efflux from the infected erythrocytes, the concentration dependence of efflux was determined. Eight two-compartment kinetic models were simulated, involving first-order pore diffusion and carrier-mediated saturable diffusion in two systems, one ductless and one assuming the existence of a parasitophorous duct. The only two models showing reasonable fits to the efflux data each involve two saturable carriers. It is likely that one of the saturable carriers is associated with the parasite itself. Evidence that the parasite carrier has different inhibitor sensitivities from that of GLUT1 is presented.

Characterization of macromolecular transport pathways in malaria-infected erythrocytes.

We have previously provided evidence for a pathway in Plasmodium falciparum-infected erythrocytes, coined the parasitophorous duct pathway, which provides serum (macro)molecules direct access to intraerythrocytic parasites . The present study addresses the purity of the fluorescent macromolecules used to define the duct pathway and provides ultrastructural evidence for its presence. The fluorescent tracers used to characterize transport remain intact during their incubation with infected erythrocytes. Transport of macromolecules in the external medium or host cell cytosol to the intracellular parasites is shown to occur by two distinct pathways. Fluorescent dextrans in the erythrocyte cytosol are ingested by the parasite via a specialized organelle, the cytostome, and are transported to the parasite food vacuole. Transport through this pathway occurs throughout the asexual life cycle. By contrast, fluorescent dextrans in the external medium bypass the erythrocyte cytosol, and are internalized by the parasite by a process resembling fluid-phase endocytosis. Serial sections of mature parasites fixed and stained by various methods for transmission electron microscopy reveal areas of apparent membrane continuity between the erythrocyte membrane and the parasitophorous vacuolar membrane that surrounds the parasite, that could leave the parasites exposed to the external medium. Using carboxylate and amidine-modified fluorescent latex spheres and laser scanning confocal microscopy, macromolecules up to 50-70 nm in diameter are found to have direct access to intraerythrocytic parasites. This size exclusion is consistent with the dimensions of the parasitophorous duct pathway revealed by electron microscopy. This investigation reports for the first time the existence of two, distinct macromolecular transport pathways in malaria-infected erythrocytes.