Sustaining attention in affective contexts during adolescence: age-related differences and association with elevated symptoms of depression and anxiety.

Sustained attention, a key cognitive skill that improves during childhood and adolescence, tends to be worse in some emotional and behavioural disorders. Sustained attention is typically studied in non-affective task contexts; here, we used a novel task to index performance in affective versus neutral contexts across adolescence (N = 465; ages 11-18). We asked whether: (i) performance would be worse in negative versus neutral task contexts; (ii) performance would improve with age; (iii) affective interference would be greater in younger adolescents; (iv) adolescents at risk for depression and higher in anxiety would show overall worse performance; and (v) would show differential performance in negative contexts. Results indicated that participants performed more poorly in negative contexts and showed age-related performance improvements. Those at risk of depression performed more poorly than those at lower risk. However, there was no difference between groups as a result of affective context. For anxiety there was no difference in performance as a function of severity. However, those with higher anxiety showed less variance in their reaction times to negative stimuli than those with lower anxiety. One interpretation is that moderate levels of emotional arousal associated with anxiety make individuals less susceptible to the distracting effects of negative stimuli.

Age-related changes in the impact of valence on self-referential processing in female adolescents and young adults.

Adolescence is a period of self-concept development. In the current study, females aged 11-30 years (N = 210) completed two self-referential tasks. In a memory task, participants judged the descriptiveness of words for themselves or a familiar other and their recognition of these words was subsequently measured. In an associative-matching task, participants associated neutral shapes to either themselves or a familiar other and the accuracy of their matching judgements was measured. In the evaluative memory task, participants were more likely to remember self-judged than other-judged words and there was an age-related decrease in the size of this self-reference effect. Negative self-judgements showed a quadratic association with age, peaking around age 19. Participants were more likely to remember positive than negative words and there was an age-related increase in the magnitude of this positivity bias. In the neutral shapes task, there were no age-related changes in the self-reference effect. Overall, adolescent girls showed enhanced processing of self-relevant stimuli when it could be used to inform their self-concept and especially when it was negative.

Susceptibility to prosocial and antisocial influence in adolescence.

INTRODUCTION: Adolescents are particularly susceptible to social influence and previous studies have shown that this susceptibility decreases with age. The current study used a cross-sectional experimental paradigm to investigate the effect of age and puberty on susceptibility to both prosocial and antisocial influence. METHODS: Participants (N = 520) aged 11-18 from London and Cambridge (United Kingdom) rated how likely they would be to engage in a prosocial (e.g. "help a classmate with their work") or antisocial (e.g. "make fun of a classmate") act. They were then shown the average rating (in fact fictitious) that other adolescents had given to the same question, and were then asked to rate the same behaviour again. RESULTS: Both prosocial and antisocial influence decreased linearly with age, with younger adolescents being more socially influenced when other adolescents' ratings were more prosocial and less antisocial than their own initial rating. Both antisocial and prosocial influence significantly decreased across puberty for boys but not girls (independent of age). CONCLUSIONS: These findings suggest that social influence declines with increasing maturity across adolescence. However, the exact relationship between social influence and maturity is dependent on the nature of the social influence and gender. Understanding when adolescents are most susceptible to different types of social influence, and how this might influence their social behaviour, has important implications for understanding adolescent social development.

Atypical interference effect of action observation in autism spectrum conditions.

BACKGROUND: Observing incongruent actions interferes with ongoing action execution. This 'interference effect' is larger for observed biological actions than for non-biological actions. The current study used virtual reality to investigate the biological specificity of interference effects of action observation in autism spectrum conditions (ASC). METHOD: High-functioning adults with ASC and age- and IQ-matched healthy controls performed horizontal sinusoidal arm movements whilst observing arm movements conducted by a virtual reality agent with either human or robot form, which moved with either biological motion or at a constant velocity. In another condition, participants made the same arm movements while observing a real human. Observed arm movements were either congruent or incongruent with executed arm movements. An interference effect was calculated as the average variance in the incongruent action dimension during observation of incongruent compared with congruent movements. RESULTS: Control participants exhibited an interference effect when observing real human and virtual human agent incongruent movements but not when observing virtual robot agent movements. Individuals with ASC differed from controls in that they showed no interference effects for real human, virtual human or virtual robot movements. CONCLUSIONS: The current study demonstrates atypical interference effects in ASC.

Applications of pathology-assisted image analysis of immunohistochemistry-based biomarkers in oncology.

Immunohistochemistry-based biomarkers are commonly used to understand target inhibition in key cancer pathways in preclinical models and clinical studies. Automated slide-scanning and advanced high-throughput image analysis software technologies have evolved into a routine methodology for quantitative analysis of immunohistochemistry-based biomarkers. Alongside the traditional pathology H-score based on physical slides, the pathology world is welcoming digital pathology and advanced quantitative image analysis, which have enabled tissue- and cellular-level analysis. An automated workflow was implemented that includes automated staining, slide-scanning, and image analysis methodologies to explore biomarkers involved in 2 cancer targets: Aurora A and NEDD8-activating enzyme (NAE). The 2 workflows highlight the evolution of our immunohistochemistry laboratory and the different needs and requirements of each biological assay. Skin biopsies obtained from MLN8237 (Aurora A inhibitor) phase 1 clinical trials were evaluated for mitotic and apoptotic index, while mitotic index and defects in chromosome alignment and spindles were assessed in tumor biopsies to demonstrate Aurora A inhibition. Additionally, in both preclinical xenograft models and an acute myeloid leukemia phase 1 trial of the NAE inhibitor MLN4924, development of a novel image algorithm enabled measurement of downstream pathway modulation upon NAE inhibition. In the highlighted studies, developing a biomarker strategy based on automated image analysis solutions enabled project teams to confirm target and pathway inhibition and understand downstream outcomes of target inhibition with increased throughput and quantitative accuracy. These case studies demonstrate a strategy that combines a pathologist's expertise with automated image analysis to support oncology drug discovery and development programs.

Puberty and risky decision-making in male adolescents.

Pubertal development is a potential trigger for increases in risk-taking behaviours during adolescence. Here, we sought to investigate the relationship between puberty and neural activation during risky decision-making in males using functional magnetic resonance imaging (fMRI). Forty-seven males aged 12.5-14.5 years completed an fMRI risk-taking task (BART) and reported their tendencies for risky decision-making using a self-report questionnaire. Puberty was assessed through self-reported pubertal status and salivary testosterone levels. Testosterone concentration, but not physical pubertal status, was positively correlated with self-reported risk-taking behaviour, while neither was correlated with BART performance. Across the whole sample, participants had greater activation of the bilateral nucleus accumbens and right caudate on trials when they made a successful risky decision compared to trials when they made a safe choice or when their risky decision was unsuccessful. There was a negative correlation between pubertal stage and brain activation during unsuccessful risky decision-making trials compared within unsuccessful control trials. Males at a lower stage of pubertal development showed increased activation in the left insula, right cingulate cortex, dorsomedial prefrontal cortex (dmPFC), right putamen and right orbitofrontal cortex (OFC) relative to more pubertally mature males during trials when they chose to take a risk and the balloon popped compared to when they watched the computer make an unsuccessful risky decision. Less pubertally mature males also showed greater activation in brain regions including the dmPFC, right temporal and frontal cortices, right OFC, right hippocampus and occipital cortex in unsuccessful risky trials compared to successful risky trials. These results suggest a puberty-related shift in neural activation within key brain regions when processing outcomes of risky decisions, which may reduce their sensitivity to negative feedback, and in turn contribute to increases in adolescent risk-taking behaviours.

The influence of prior expectations on facial expression discrimination in schizophrenia.

BACKGROUND: Belief inflexibility is a thinking style observed in patients with schizophrenia, in which patients tend to refute evidence that runs counter to their prior beliefs. This bias has been related to a dominance of prior expectations (prior beliefs) over incoming sensory evidence. In this study we investigated the reliance on prior expectations for the processing of emotional faces in schizophrenia. METHOD: Eighteen patients with schizophrenia and 18 healthy controls were presented with sequences of emotional (happy, fearful, angry or neutral) faces. Perceptual decisions were biased towards a particular expression by a specific instruction at the start of each sequence, referred to as the context in which stimuli occurred. Participants were required to judge the emotion on each face and the effect of the context on emotion discrimination was investigated. RESULTS: For threatening emotions (anger and fear), there was a performance cost for facial expressions that were incongruent with, and perceptually close to, the expression named in the instruction. For example, for angry faces, participants in both groups made more errors and reaction times (RTs) were longer when they were asked to look out for fearful faces compared with the other contexts. This bias against sensory evidence that runs counter to prior information was stronger in the patients, evidenced by a group by context interaction in accuracy and RTs for anger and fear respectively. CONCLUSIONS: Overall, the present data suggest an overdependence on prior expectations for threatening stimuli, reflecting belief inflexibility, in schizophrenia.

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.

Neural correlates of social influence on risk perception during development.

Studies have shown that adolescents are more likely than adults to take risks in the presence of peers than when alone, and that young adolescents' risk perception is more influenced by other teenagers than by adults. The current fMRI study investigated the effect of social influence on risk perception in female adolescents (aged 12-14) and adults (aged 23-29). Participants rated the riskiness of everyday situations and were then informed about the (alleged) risk ratings of a social influence group (teenagers or adults), before rating each situation again. The results showed that adolescents adjusted their ratings to conform with others more than adults did, and both age groups were influenced more by adults than by teenagers. When there was a conflict between the participants' own risk ratings and the ratings of the social influence group, activation was increased in the posterior medial frontal cortex, dorsal cingulate cortex and inferior frontal gyrus in both age groups. In addition, there was greater activation during no-conflict situations in the right middle frontal gyrus and bilateral parietal cortex in adults compared with adolescents. These results suggest that there are behavioral and neural differences between adolescents and adults in conflict and no-conflict social situations.

The effect of social preference on academic diligence in adolescence.

In the current study, we were interested in whether adolescents show a preference for social stimuli compared with non-social stimuli in the context of academic diligence, that is, the ability to expend effort on tedious tasks that have long-term benefits. Forty-five female adolescents (aged 11-17) and 46 female adults (aged 23-33) carried out an adapted version of the Academic Diligence Task (ADT). We created two variations of the ADT: a social ADT and non-social ADT. Individuals were required to freely split their time between an easy, boring arithmetic task and looking at a show-reel of photographs of people (in the social ADT) or landscapes (in the non-social ADT). Individuals also provided enjoyment ratings for both the arithmetic task and the set of photographs they viewed. Adolescents reported enjoying the social photographs significantly more than the non-social photographs, with the converse being true for adults. There was no significant difference in the time spent looking at the social photographs between the adolescents and adults. However, adults spent significantly more time than adolescents looking at the non-social photographs, suggesting that adolescents were less motivated to look at the non-social stimuli. Further, the correlation between self-reported enjoyment of the pictures and choice behaviour in the ADT was stronger for adults than for adolescents in the non-social condition, revealing a greater discrepancy between self-reported enjoyment and ADT choice behaviour for adolescents. Our results are discussed within the context of the development of social cognition and introspective awareness between adolescence and adulthood.

Central cancellation of self-produced tickle sensation.

A self-produced tactile stimulus is perceived as less ticklish than the same stimulus generated externally. We used fMRI to examine neural responses when subjects experienced a tactile stimulus that was either self-produced or externally produced. More activity was found in somatosensory cortex when the stimulus was externally produced. In the cerebellum, less activity was associated with a movement that generated a tactile stimulus than with a movement that did not. This difference suggests that the cerebellum is involved in predicting the specific sensory consequences of movements, providing the signal that is used to cancel the sensory response to self-generated stimulation.

An interference effect of observed biological movement on action.

It has been proposed that actions are intrinsically linked to perception and that imagining, observing, preparing, or in any way representing an action excites the motor programs used to execute that same action. There is neurophysiological evidence that certain brain regions involved in executing actions are activated by the mere observation of action (the so-called "mirror system;" ). However, it is unknown whether this mirror system causes interference between observed and simultaneously executed movements. In this study we test the hypothesis that, because of the overlap between action observation and execution, observed actions should interfere with incongruous executed actions. Subjects made arm movements while observing either a robot or another human making the same or qualitatively different arm movements. Variance in the executed movement was measured as an index of interference to the movement. The results demonstrate that observing another human making incongruent movements has a significant interference effect on executed movements. However, we found no evidence that this interference effect occurred when subjects observed a robotic arm making incongruent movements. These results suggest that the simultaneous activation of the overlapping neural networks that process movement observation and execution infers a measurable cost to motor control.

PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis.

PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kδi. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kδi-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Eµ-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kδi imparted significant therapeutic responses in Eµ-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim-/- Eµ-Tcl1 Tg leukemias demonstrated resistance to PI3Kδi-induced apoptosis were refractory to PI3Kδi in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kδi, both alone and in combination therapy regimes.

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia.

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

Four-year PhDs in neuroscience: an assessment after four years.

In 1996, as an innovation for the UK, the Wellcome Trust set up two 'American style' four-year PhD programmes in neuroscience, with an initial year of broad training followed by a three-year PhD. Here, some of the first cohort of students, who are soon to graduate and the coordinators of the programmes, give their views on this experiment in neuroscience research training.

Somatosensory activations during the observation of touch and a case of vision-touch synaesthesia.

In this study, we describe a new form of synaesthesia in which visual perception of touch elicits conscious tactile experiences in the perceiver. We describe a female subject (C) for whom the observation of another person being touched is experienced as tactile stimulation on the equivalent part of C's own body. Apart from this clearly abnormal synesthetic experience, C is healthy and normal in every other way. In this study, we investigate whether C's 'mirrored touch' synesthetic experience is caused by overactivity in the neural system that responds to the observation of touch. A functional MRI experiment was designed to investigate the neural system involved in the perception of touch in a group of 12 non-synesthetic control subjects and in C. We investigated neural activity to the observation of touch to a human face or neck compared with the observation of touch to equivalent regions on an object. Furthermore, to investigate the somatosensory topography of the activations during observation of touch, we compared activations when observing a human face or neck being touched with activations when the subjects themselves were touched on their own face or neck. The results demonstrated that the somatosensory cortex was activated in the non-synesthetic subjects by the mere observation of touch and that this activation was somatotopically organized such that observation of touch to the face activated the head area of primary somatosensory cortex, whereas observation of touch to the neck did not. Moreover, in non-synesthetic subjects, the brain's mirror system-comprising premotor cortex, superior temporal sulcus and parietal cortex-was activated by the observation of touch to another human more than to an object. C's activation patterns differed in three ways from those of the non-synesthetic controls. First, activations in the somatosensory cortex were significantly higher in C when she observed touch. Secondly, an area in left premotor cortex was activated in C to a greater extent than in the non-synesthetic group. Thirdly, the anterior insula cortex bilaterally was activated in C, but there was no evidence of such activation in the non-synesthetic group. The results suggest that, in C, the mirror system for touch is overactive, above the threshold for conscious tactile perception.

Perception and recognition of faces in adolescence.

Most studies on the development of face cognition abilities have focussed on childhood, with early maturation accounts contending that face cognition abilities are mature by 3-5 years. Late maturation accounts, in contrast, propose that some aspects of face cognition are not mature until at least 10 years. Here, we measured face memory and face perception, two core face cognition abilities, in 661 participants (397 females) in four age groups (younger adolescents (11.27-13.38 years); mid-adolescents (13.39-15.89 years); older adolescents (15.90-18.00 years); and adults (18.01-33.15 years)) while controlling for differences in general cognitive ability. We showed that both face cognition abilities mature relatively late, at around 16 years, with a female advantage in face memory, but not in face perception, both in adolescence and adulthood. Late maturation in the face perception task was driven mainly by protracted development in identity perception, while gaze perception abilities were already comparatively mature in early adolescence. These improvements in the ability to memorize, recognize and perceive faces during adolescence may be related to increasing exploratory behaviour and exposure to novel faces during this period of life.

BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma.

Genetic recombination during B-cell development regularly results in the generation of autoreactive, potentially pathogenic B-cell receptors (BCRs). Consequently, multiple mechanisms link inappropriate BCR specificity to clonal deletion. Similar pathways remain in malignant B cells, offering the potential for targeting BCR signaling. Recently, small molecule inhibitors have realized this potential and, therefore, a deeper understanding of BCR-induced signaling networks in malignant cells is vital. The BH3-only protein Bim has a key role in BCR-induced apoptosis, but it has long been proposed that additional BH3-only proteins also contribute, although conclusive proof has been lacking. Here, we comprehensively characterized the mechanism of BCR-induced apoptosis in Eµ-Myc murine lymphoma cells. We demonstrate the upregulation of Bim, Bik, and Noxa during BCR signaling in vitro and that intrinsic apoptosis has a prominent role in anti-BCR antibody therapy in vivo. Furthermore, lymphomas deficient in these individual BH3-only proteins display significant protection from BCR-induced cell death, whereas combined loss of Noxa and Bim offers enhanced protection in comparison with loss of Bim alone. Some but not all of these effects were reversed upon inhibition of Syk or MEK. These observations indicate that BCR signaling elicits maximal cell death through upregulation of multiple BH3-only proteins; namely Bim, Bik, and Noxa.

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1.

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukaemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA) is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1(L) to MCL-1(s) in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested that Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumour cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-x(L) antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-x(L) antagonists may have therapeutic utility for CLL.

How do we predict the consequences of our actions? A functional imaging study.

Humans are readily able to distinguish expected and unexpected sensory events. Whether a single mechanism underlies this ability is unknown. The most common type of expected sensory events are those generated as a consequence of self-generated actions. Using H2 15O PET, we studied brain responses to such predictable sensory events (tones) and to similar unpredictable events and especially how the processing of predictable sensory events is modified by the context of a causative self-generated action. Increases in activity when the tones were unpredictable were seen in the inferior and superior temporal lobe bilaterally, the right parahippocampal gyrus and right parietal cortex. Self-generated actions produced activity in a number of motor and premotor areas, including dorsolateral prefrontal cortex. We observed an interaction between the predictability of stimuli and self-generated actions in several areas, including the medial posterior cingulate cortex, left insula, dorsomedial thalamus, superior colliculus and right inferior temporal cortex. This modulation of activity associated with stimulus predictability in the context of self-generated actions implies that these areas may be involved in self-monitoring processes. Detection of expected stimuli and the detection of the sensory consequences of self-generated actions appear to be functionally distinct processes, and are carried out in different cortical areas. These observations support theoretical approaches to cognition that postulate the existence of a self-monitoring system.