Estradiol effects on an emotional interference task in adolescents with current and remitted depression.

Attentional biases to emotional stimuli are thought to reflect vulnerability for mood disorder onset and maintenance. This study examined the association between the endogenous sex hormone estradiol and emotional attentional biases in adolescent females with either current or remitted depression. Three groups of participants (mean age ± SD) completed the Emotional Interrupt Task: 1) 20 adolescent females (15.1 ± 1.83 years) currently diagnosed with Major Depressive Disorder (MDD), 2) 16 adolescent females (16.4 ± 1.31 years) who had experienced at least one episode of MDD in their lifetime but currently met criteria for MDD in remission, and 3) 30 adolescent female (15.4 ± 1.83 years) healthy controls. Attentional interference (AI) scores were calculated as differences in target response reaction time between trials with emotional facial expressions versus neutral facial expressions. Estradiol levels were assayed by Salimetrics LLC using saliva samples collected within 30 min of waking on assessment days. Robust multiple regression with product terms evaluated estradiol's main effect on AI scores, as well as hypothesized estradiol × diagnostic group interactions. Although neither mean estradiol levels nor mean AI scores in the current-MDD and remitted-MDD groups differed from controls, the relationship between estradiol and overall AI score differed between control adolescents and the remitted-MDD group. Specifically, the remitted-MDD adolescents performed worse (i.e., showed greater attentional interference) when they had higher estradiol; no significant relationship existed in the current-MDD group. Because this finding was driven by angry and not happy stimuli, it appears higher estradiol levels were associated with greater susceptibility to the attention-capturing effects of negatively-valenced emotional content in girls at risk for MDD from prior history.

Electrical brain activations in young children during a probabilistic reward-learning task are associated with behavioral strategy.

Both adults and children learn through feedback which events and choices in the environment are associated with higher probability of reward. This probability reward-learning ability is thought to be supported by the development of fronto-striatal reward circuits. Recent developmental studies have applied computational models of reward learning to investigate such learning in children. However, there has been limited development of task tools capable of measuring the cascade of neural reward-learning processes in children. Using a child-version of a probabilistic reward-learning task while recording event-related-potential (ERP) measures of electrical brain activity, this study examined key processes of reward learning in preadolescents (n=30), namely: (1) reward-feedback sensitivity, as measured by the early reward-related frontal ERP positivity, (2) rapid attentional shifting of processing toward favored visual stimuli, as measured by the N2pc component, and (3) longer-latency attention-related responses to reward feedback as a function of behavior strategies (i.e., Win-Stay-Lose-Shift), as measured by the central-parietal P300. Consistent with our prior work in adults, the behavioral findings indicate that preadolescents could learn stimulus-reward outcome associations, but at varying levels of performance. Neurally, poor preadolescent learners (those with slower learning rates) showed greater reward-related positivity amplitudes relative to good learners, suggesting greater reward sensitivity. We also found attention shifting towards to-be-chosen stimuli, as evidenced by the N2pc, but not to more highly rewarded stimuli. Lastly, we found an effect of behavioral learning strategies (i.e., Win-Stay-Lose-Shift) on the feedback-locked P300 over the parietal cortex. These findings provide novel insights into the key neural processes underlying reinforcement learning in preadolescents.

Neural correlates of non-specific skin conductance responses during resting state fMRI.

Skin conductance responses (SCRs) reliably occur in the absence of external stimulation. However, the neural correlates of these non-specific SCRs have been less explored than brain activity associated with stimulus-elicited SCRs. This study modeled spontaneous skin conductance responses observed during an unstructured resting state fMRI scan in 58 adolescents. A Finite Impulse Response (FIR) fMRI model was used to detect any type of hemodynamic response shape time-locked to non-specific SCRs; the shape of these responses was then carefully characterized. The strongest evidence for signal change was found in several sub-regions of sensorimotor cortex. There also was evidence for engagement of discrete areas within the lateral surfaces of the parietal lobe, cingulate cortex, fronto-insular operculum, and both visual and auditory primary processing areas. The hemodynamic profile measured by FIR modeling clearly resembled an event-related response. However, it was a complex response, best explained by two quickly successive, but opposing neuronal impulses across all brain regions - a brief positive response that begins several seconds prior to the SCR with a much longer negative neuronal impulse beginning shortly after the SCR onset. Post hoc exploratory analyses linked these two hemodynamic response phases to different emotion-related individual differences. In conclusion, this study shows the neural correlates of non-specific SCRs are a widespread, cortical network of brain regions engaged in a complex, seemingly biphasic fashion. This bimodal response profile should be considered in replication studies that attempt to directly link brain activity to possible homeostatic mechanisms or seek evidence for alternative mechanisms.

Adolescent sex differences in cortico-subcortical functional connectivity during response inhibition.

Numerous lines of evidence have shown that cognitive processes engaged during response inhibition tasks are associated with structure and functional integration of regions within fronto-parietal networks. However, while prior studies have started to characterize how intrinsic connectivity during resting state differs between boys and girls, comparatively less is known about how functional connectivity differs between males and females when brain function is exogenously driven by the processing demands of typical Go/No-Go tasks that assess both response inhibition and error processing. The purpose of this study was to characterize adolescent sex differences and possible changes in sexually dimorphic regional functional connectivity across adolescent development in both cortical and subcortical brain connectivity elicited during a visual Go/No-Go task. A total of 130 healthy adolescents (ages 12-25 years) performed a Go/No-Go task during functional magnetic resonance imaging. High model-order group independent component analysis was used to characterize whole-brain network functional connectivity during response inhibition and then a univariate technique used to evaluate differences related to sex and age. As predicted and similar to previously described findings from non-task-driven resting state connectivity studies, functional connectivity sex differences were observed in several subcortical regions, including the amygdala, caudate, thalamus, and cortical regions, including inferior frontal gyrus engaged most strongly during successful response inhibition and/or error processing. Importantly, adolescent boys and girls exhibited different normative profiles of age-related changes in several default mode networks of regions and anterior cingulate cortex. These results suggest that cortical-subcortical functional networks supporting response inhibition operate differently between sexes during adolescence.

A preliminary study of association between adolescent estradiol level and dorsolateral prefrontal cortex activity during emotion regulation.

Non-human primate models have been useful in clarifying estradiol's role in cognitive processing. These animal studies indicate estradiol impacts cognitive processes supported by regions within dorsolateral prefrontal cortex (DLPFC). Although human functional neuroimaging studies have begun to find similar relationships between estradiol in women for some forms of 'cold' cognitive control, to date no studies have examined the relationship between estradiol and DLPFC function in the context of active attempts to regulate one's emotions. Here, we asked whether peripheral 17-beta estradiol levels in adolescent girls in different pubertal developmental stages (age = 14.9 years ± 1.74) were related to engagement of DLPFC regions during the use of a cognitive strategy for regulating emotion known as reappraisal using functional Magnetic Resonance Imaging. Findings indicated that higher estradiol levels predicted greater DLPFC activity during the down-regulation of negative emotion using reappraisal. This is the first report of an association between estradiol level and DLPFC activity during cognitive reappraisal of negative emotion. The study suggests a possibility that estradiol might positively contribute to regulatory function of a cortical system important for emotional experiences.

Adolescent maturation of the relationship between cortical gyrification and cognitive ability.

There are changes to the degree of cortical folding from gestation through adolescence into young adulthood. Recent evidence suggests that degree of cortical folding is linked to individual differences in general cognitive ability in healthy adults. However, it is not yet known whether age-related cortical folding changes are related to maturation of specific cognitive abilities in adolescence. To address this, we examined the relationship between frontoparietal cortical folding as measured by a Freesurfer-derived local gyrification index (lGI) and performance on subtests from the Wechsler Abbreviated Scale of Intelligence and scores from Conner's Continuous Performance Test-II in 241 healthy adolescents (ages 12-25 years). We hypothesized that age-related lGI changes in the frontoparietal cortex would contribute to cognitive development. A secondary goal was to explore if any gyrification-cognition relationships were either test-specific or sex-specific. Consistent with previous studies, our results showed a reduction of frontoparietal local gyrification with age. Also, as predicted, all cognitive test scores (i.e., Vocabulary, Matrix Reasoning, the CPT-II Commission, Omission, Variabiltiy, d') showed age × cognitive ability interaction effects in frontoparietal and temporoparietal brain regions. Mediation analyses confirmed a causal role of age-related cortical folding changes only for CPT-II Commission errors. Taken together, the results support the functional significance of cortical folding, as well as provide the first evidence that cortical folding maturational changes play a role in cognitive development.

Frontal-striatum dysfunction during reward processing: Relationships to amotivation in schizophrenia.

Schizophrenia is characterized by deficits of context processing, thought to be related to dorsolateral prefrontal cortex (DLPFC) impairment. Despite emerging evidence suggesting a crucial role of the DLPFC in integrating reward and goal information, we do not know whether individuals with schizophrenia can represent and integrate reward-related context information to modulate cognitive control. To address this question, 36 individuals with schizophrenia (n = 29) or schizoaffective disorder (n = 7) and 27 healthy controls performed a variant of a response conflict task (Padmala & Pessoa, 2011) during fMRI scanning, in both baseline and reward conditions, with monetary incentives on some reward trials. We used a mixed state-item design that allowed us to examine both sustained and transient reward effects on cognitive control. Different from predictions about impaired DLPFC function in schizophrenia, we found an intact pattern of increased sustained DLPFC activity during reward versus baseline blocks in individuals with schizophrenia at a group level but blunted sustained activations in the putamen. Contrary to our predictions, individuals with schizophrenia showed blunted cue-related activations in several regions of the basal ganglia responding to reward-predicting cues. Importantly, as predicted, individual differences in anhedonia/amotivation symptoms severity were significantly associated with reduced sustained DLPFC activation in the same region that showed overall increased activity as a function of reward. These results suggest that individual differences in motivational impairments in schizophrenia may be related to dysfunction of the DLPFC and striatum in motivationally salient situations.

Anhedonia is associated with reduced incentive cue related activation in the basal ganglia.

Research has shown that reward incentives improve cognitive control in motivationally salient situations. Much previous work in this domain has focused on incentive cue-related activity in a number of brain regions, including the dorsolateral prefrontal cortex (DLPFC) and striatum. However, the more sustained changes in functional brain activity during task contexts with incentives have been relatively less explored. Here, we examined both the cue-related and sustained effects of rewards (i.e., monetary incentives) on cognitive control, with a particular focus on the roles of the DLPFC and striatum, using a mixed state-item design. We investigated whether variability in a reward-related trait (i.e., anhedonia) would modulate the sustained and/or the cue-related transient aspects of motivated cognitive control. Twenty-seven healthy individuals performed a modified response conflict task (Padmala & Pessoa, Journal of Cognitive Neuroscience, 23, 3419-3432, 2011) during scanning, in which participants were asked to categorize images as either houses or buildings with either congruent or incongruent overlaid words. Participants performed a baseline condition without knowledge of monetary incentives, followed by reward blocks with monetary incentives on some cued trials (reward cues) for fast and correct responses. We replicated previous work by showing increases in both sustained activity during reward versus baseline blocks and transient. cue-related activity in bilateral DLPFC and the basal ganglia. Importantly, healthy individuals with higher anhedonia showed less of an increase in trial-by-trial activity as a function of reward in the lateral globus pallidus. Together, our results suggest that reduced hedonic experience may be related to abnormality of reward cue-related activity in the basal ganglia.

A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder.

Mentalizing has been examined both in autism spectrum disorder (ASD) and schizophrenia (SCZ) primarily by either cognitive-linguistic (referred to as verbal) or emotion recognition from eyes (referred to as visual) mentalizing tasks. Each type of task is thought to measure different aspects of mentalizing. Differences in clinical features and developmental courses of each disorder may predict distinct patterns of mentalizing performance across dis orders on each type of task. To test this, a meta-analysis was conducted using 37 studies that assessed mentalizing either verbally or visually in adults with SCZ or ASD. We found that the estimated effect sizes of impairments in verbal and visual mentalizing tasks for both clinical groups were statistically large and at a similar level (overall Hedges' g = 0.73-1.05). For each disorder, adults with SCZ showed a trend towards larger impairments on verbal (overall Hedges' g = 0.99) than on visual mentalizing task (overall Hedges' g = 0.73; Qbet = 3.45, p =.06, df =1). Adults with ASD did not show different levels of impairment on the verbal versus visual tasks (Qbet = 0.08, p =.78, df =1). These results suggest that both clinical groups share, at least in part, some common cognitive processing deficits associated with mentalizing impairments.

Spared and impaired aspects of motivated cognitive control in schizophrenia.

The ability to upregulate cognitive control in motivationally salient situations was examined in individuals with schizophrenia (patients) and healthy controls. Fifty-four patients and 39 healthy controls were recruited. A computerized monetary response conflict task required participants to identity a picture, over which was printed a matching (congruent), neutral, or incongruent word. This baseline condition was followed by an incentive condition, in which participants were given the opportunity to win money on reward-cued trials. These reward-cued trials were interleaved with nonreward cued trials. Reaction times (RT) were examined for both incentive context effects (difference in RT between baseline and nonreward cue trials in the incentive condition) and incentive cue effects (difference in RT between nonreward and reward cue trials in the incentive condition). Compared with baseline, controls showed a speeding of responses during both the nonreward (incentive context effect) and reward cued (incentive cue effect) trials during the incentive condition, but with a larger incentive context than incentive cue effect, suggesting a reliance on proactive control strategies. Although patients also showed a speeding of responses to both nonreward and reward cued trials, they showed a significantly smaller incentive context effect than controls, suggesting a reduction in the use of proactive control and a greater reliance on the use of "just-in-time," reactive control strategies. These results are discussed in light of the relationship between motivation and cognitive impairments in schizophrenia, and the potential role of impairments in prefrontally mediated active maintenance mechanisms.

The effect of emotional context on facial emotion ratings in schizophrenia.

Individuals with schizophrenia show deficits both in facial emotion recognition and context processing (Kohler, C.G., Walker, J.B., Martin, E.A., Healey, K.M., Moberg, P.J., 2010. Facial emotion perception in schizophrenia: a meta-analytic review. Schizophr. Bull. 36, 1009-1019). Recent evidence suggests context information can affect facial emotion recognition (Aviezer, H., Bentin, S., Hassin, R.R., Meschino, W.S., Kennedy, J., Grewal, S., Esmail, S., Cohen, S., Moscovitch, M., 2009. Not on the face alone: perception of contextualized face expressions in Huntington's disease. Brain 132, 1633-1644). Thus, individuals with schizophrenia may have deficits in facial emotion processing, at least in part, due to impairments in processing context information (Green, M.J., Waldron, J.H., Coltheart, M., 2007. Emotional context processing is impaired in schizophrenia. Cogn. Neuropsychiatry 12, 259-280.). We used a novel experimental task, the Emotion Context Processing Task (ECPT) to examine the influences of emotional context (IAPS pictures) on the processing of subtle surprised faces in schizophrenia. One of the task conditions included a manipulation designed to determine whether enhancing attention to the context (by requiring a categorization judgment on the context pictures) would facilitate the influence of context on facial emotion processing in schizophrenia. In addition, we tested whether deficits on a non-social context processing would predict deficits in the influence of context on facial emotion processing in schizophrenia. We administered the Dot Probe Expectancy Task (a non-social context processing task) and the ECPT to individuals with schizophrenia (n=35) and healthy controls (n=32). Individuals with schizophrenia showed an intact influence of context information on facial emotion recognition. The manipulation designed to enhance attention to emotional context reduced the effect of context for both groups. In schizophrenia, better processing of non-social context was associated with a stronger influence of context on valence ratings of facial expressions in the negative context condition. These results suggest in schizophrenia, similar mechanisms may influence the processing of context for both social and non-social information.

The effect of context processing on different aspects of social cognition in schizophrenia.

BACKGROUND: It is well known that individuals with schizophrenia have impaired social cognition. The construct of social cognition involves several components, including perception, interpretation, and the ability to integrate context (Adolphs R. The neurobiology of social cognition. Curr Opin Neurobiol. 2001;11:231-239; Brothers L. The social brain: a project for integrating primate behavior and neurophysiology in a new domain. Concepts Neurosci. 1990;1:27-61). Importantly, a number of studies have suggested that deficits in context processing underlie cognitive dysfunction in schizophrenia (Penn DL, Corrigan PW, Bentall RP, Racenstein JM, Newman L. Social cognition in schizophrenia. Psychol Bull. 1997;121(1):114-132; Green MF, Nuechterlein KH. Should schizophrenia be treated as a neurocognitive disorder? Schizophr Bull. 1999;25:309-319). Thus, the purpose of the current study was to investigate the relationship between context processing and different aspects of social cognition in schizophrenia. METHOD: Individuals with schizophrenia (n = 41) and the healthy controls (n = 32) participated in this study. The participants completed 2 sections of The Awareness of Social Inference Test: (1) social inference minimal (SI-M) and (2) social inference enriched (SI-E). They also completed face and voice emotion discrimination tasks. In addition, we used the AX-Continuous Performance Test (AX-CPT) to measure context processing and the n-back task to measure working memory more generally. RESULTS: AX-CPT performance in schizophrenia was positively correlated with both SI-M and SI-E performance but not with either the face or the voice discrimination. Furthermore, the correlation between AX-CPT performance and SI-M/SI-E performance was significantly stronger in individuals with schizophrenia than in controls. CONCLUSION: These results suggest that impairments in context processing are related to inferential components of social cognition in schizophrenia but not to the ability to recognition facial or vocal emotion. As such, deficits in context processing may contribute to deficits in both "hot" and "cold" aspects of cognition in schizophrenia.

Social functioning deficits in young people at risk for schizophrenia.

OBJECTIVE: Impairment in social functioning is a central feature of schizophrenia and is known to be evident before the onset of psychosis, acting as a potential vulnerability marker. The aim of the present study was to test the hypothesis that social impairment is simultaneously a state and trait marker of risk for schizophrenia and schizophrenia-related disorder. METHOD: Social functioning was examined in three groups: ultra-high-risk subjects (UHR, n =32), genetic high-risk subjects (GHR, n =32), and age- and IQ-matched healthy controls (HC, n =30). Social functioning was assessed using the Social Functioning Scale (SFS), and prodromal symptoms were assessed in high-risk subjects using the Comprehensive Assessment of At-Risk Mental States (CAARMS). RESULTS: Both the UHR and GHR groups exhibited significantly impaired social functioning compared with the HC group, and the UHR group was more impaired than the GHR group. In the UHR group, duration of prodromal symptoms was related to impaired 'interpersonal behaviour'. Positive and negative symptoms were not significantly associated with social functioning, whereas disorganized and general symptoms were significantly correlated with poor 'independence-competence' in UHR individuals. CONCLUSION: The findings support the hypothesis that impairment in social functioning is both a trait and state marker of risk for schizophrenia and other psychotic disorders, implying that social impairment constitutes a mediating vulnerability indicator of psychotic disorders including schizophrenia.

Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia.

BACKGROUND: Although a deficit in social cognition is regarded as an early indicator of schizophrenia, few studies have investigated social cognition in ultra-high-risk (UHR) individuals. METHODS: Our investigation involved subjects at UHR for psychosis (N=33) and an age- and IQ-matched healthy control (HC) group (N=36). Two types of theory of mind (ToM) tasks and a neuropsychological test battery were measured. RESULTS: Compared to the HC group, the UHR group performed significantly worse for ToM tasks, with the effect size at an intermediate level (0.64-0.68). Furthermore, the UHR group showed impaired performance in the executive and working memory tests, but not verbal memory tests. These deficits for ToM tests observed in the UHR group were significantly correlated with set-shifting tasks. CONCLUSIONS: Deficits in social cognition may be modest at the prodromal stage of schizophrenia and may be attributed to prefrontal dysfunction. To prevent or delay transition to psychosis, there is a need for specific preventive strategies targeting social functioning for the UHR group.