Adolescent transformations of behavioral and neural processes as potential targets for prevention.

Adolescence is a transitional period in development that is marked by a distinct, typical behavioral profile of high rates of exploration, novelty-seeking, and emotional lability. While these behaviors generally assist the adolescent transition to independence, they can also confer vulnerability for excessive risk-taking and psychopathology, particularly in the context of specific environmental or genetic influences. As prevention research depends on the identification of targets of vulnerability, the following review will discuss the interplay among motivational systems including reward-related, avoidance-related, and regulatory processes in typical and atypical adolescent development. Each set of processes will be discussed in relation to their underlying neural correlates and distinct developmental trajectories. Evidence suggests that typical adolescent behavior and the risk for atypical development are mediated by heightened adolescent responsiveness of reward-related and avoidance-related systems under specific conditions, concurrent with poor modulation by immature regulatory processes. Finally, we will propose strategies to exploit heightened reward processing to reinforce inhibitory control, which is an essential component of regulatory processes in prevention interventions.

The influence of emotional stimuli on attention orienting and inhibitory control in pediatric anxiety.

BACKGROUND: Anxiety disorders are highly prevalent in children and adolescents, and are associated with aberrant emotion-related attention orienting and inhibitory control. While recent studies conducted with high-trait anxious adults have employed novel emotion-modified antisaccade tasks to examine the influence of emotional information on orienting and inhibition, similar studies have yet to be conducted in youths. METHODS: Participants were 22 children/adolescents diagnosed with an anxiety disorder, and 22 age-matched healthy comparison youths. Participants completed an emotion-modified antisaccade task that was similar to those used in studies of high-trait anxious adults. This task probed the influence of abruptly appearing neutral, happy, angry, or fear stimuli on orienting (prosaccade) or inhibitory (antisaccade) responses. RESULTS: Anxious compared to healthy children showed facilitated orienting toward angry stimuli. With respect to inhibitory processes, threat-related information improved antisaccade accuracy in healthy but not anxious youth. These findings were not linked to individual levels of reported anxiety or specific anxiety disorders. CONCLUSIONS: Findings suggest that anxious relative to healthy children manifest enhanced orienting toward threat-related stimuli. In addition, the current findings suggest that threat may modulate inhibitory control during adolescent development.

Clinical Validation of a Circulating Tumor Cell Assay Using Density Centrifugation and Automated Immunofluorescence Microscopy.

OBJECTIVES: The US Food and Drug Administration (FDA)-approved CELLSEARCH assay (Menarini Silicon Biosystems) for circulating tumor cells (CTCs) relies on expression of an epithelial cell adhesion molecule to enrich for CTCs. We sought to validate a CTC assay (RareCyte) for clinical use that instead collects a buffy coat preparation enriched for CTCs. METHODS: Normal peripheral blood specimens spiked with cultured breast and prostate cancer cells and 47 clinical samples were used to validate assay performance. Specimens were enriched for buffy coat cells and applied onto 8 glass slides. The slides were immunofluorescently stained and imaged by automated microscopy and computer-aided image analysis. RESULTS: The assay was 100% specific for detecting spiked tumor cells. For samples spiked with 25, 50, and 125 cells, the percentage coefficients of variation were 42%, 21%, and 3.7%, respectively. Linearity studies demonstrated a slope of 0.99, an intercept of 1.6, and R2 of 0.96. Recoveries at the 25-, 50-, and 125-cell levels were 92%, 111%, and 100%, respectively. Clinical samples run on both CELLSEARCH and RareCyte correlated with an R2 of 0.8 after log-transformation and demonstrated 87.5% concordance using the CELLSEARCH criteria for predicting adverse outcomes. CONCLUSIONS: The RareCyte CTC assay has comparable performance to the FDA-cleared method and is ready for further clinical validation studies.

The influence of context valence in the neural coding of monetary outcomes.

The emotional significance of objects and events depends on the context in which they occur. Using functional magnetic resonance imaging, we examined the modulation of neural responses to monetary outcomes while subjects performed a decision-making task in a positive and a negative economic context. Neural responses indicated a relative regional specialization in the neural coding of outcome valence and followed three distinct patterns. The nucleus accumbens (NAc) and orbital frontal cortex (OFC) appeared to code the most extreme outcome in each context, with a potentiated response for favorable outcomes by a positive context. The amygdala and insula appeared to also code highly salient outcomes, but showed a potentiated response to unfavorable outcomes occurring in a negative context. The medial prefrontal cortex (medPFC), on the other hand, only coded favorable responses occurring in a positive context. Moreover, the medPFC showed large inter-individual variability when responding to outcomes in a negative context, suggesting that its role in a negative context may depend on a number of individual factors. The results of this work provide evidence of complex valence-based regional dissociations that are influenced by contextual factors.

Neural substrates of reward magnitude, probability, and risk during a wheel of fortune decision-making task.

Economic decision-making involves the weighting of magnitude and probability of potential gains/losses. While previous work has examined the neural systems involved in decision-making, there is a need to understand how the parameters associated with decision-making (e.g., magnitude of expected reward, probability of expected reward and risk) modulate activation within these neural systems. In the current fMRI study, we modified the monetary wheel of fortune (WOF) task [Ernst, M., Nelson, E.E., McClure, E.B., Monk, C.S., Munson, S., Eshel, N., et al. (2004). Choice selection and reward anticipation: an fMRI study. Neuropsychologia 42(12), 1585-1597.] to examine in 25 healthy young adults the neural responses to selections of different reward magnitudes, probabilities, or risks. Selection of high, relative to low, reward magnitude increased activity in insula, amygdala, middle and posterior cingulate cortex, and basal ganglia. Selection of low-probability, as opposed to high-probability reward, increased activity in anterior cingulate cortex, as did selection of risky, relative to safe reward. In summary, decision-making that did not involve conflict, as in the magnitude contrast, recruited structures known to support the coding of reward values, and those that integrate motivational and perceptual information for behavioral responses. In contrast, decision-making under conflict, as in the probability and risk contrasts, engaged the dorsal anterior cingulate cortex whose role in conflict monitoring is well established. However, decision-making under conflict failed to activate the structures that track reward values per se. Thus, the presence of conflict in decision-making seemed to significantly alter the pattern of neural responses to simple rewards. In addition, this paradigm further clarifies the functional specialization of the cingulate cortex in processes of decision-making.

Inhibitory control in anxious and healthy adolescents is modulated by incentive and incidental affective stimuli.

BACKGROUND: Anxiety disorders are characterized by elevated, sustained responses to threat, that manifest as threat attention biases. Recent evidence also suggests exaggerated responses to incentives. How these characteristics influence cognitive control is under debate and is the focus of the present study. METHODS: Twenty-five healthy adolescents and 25 adolescents meeting DSM-IV diagnostic criteria for an anxiety disorder were compared on a task of response inhibition. Inhibitory control was assayed with an antisaccade task that included both incentive (monetary reward) and incidental emotion (facial expression) cues presented prior to the execution of inhibitory behavior. RESULTS: Inhibitory control was enhanced following exposure to threat cues (fear faces) only in adolescent patients, and following exposure to positive cues (happy faces) only in healthy adolescents. Results also revealed a robust performance improvement associated with monetary incentives. This incentive effect did not differ by group. No interaction between incentives and emotional cues was detected. CONCLUSIONS: These findings suggest that biased processing of threat in anxious adolescents affects inhibitory control, perhaps by raising arousal prior to behavioral performance. The absence of normalization of performance in anxious adolescents following exposure to positive emotional cues is a novel finding and will require additional exploration. Future studies will need to more specifically examine how perturbations in positive emotion processes contribute to the symptomatology and the pathogenesis of anxiety disorders.

Striatal functional alteration in adolescents characterized by early childhood behavioral inhibition.

The temperamental style of behavioral inhibition has been characterized by exaggerated behavioral and neural responses to cues signaling threat. Virtually no work, however, has addressed whether behavioral inhibition may also confer heightened brain activation in response to positively valenced incentives. We used event-related functional MRI (fMRI) and a monetary incentive delay task to examine whether the neural response to incentives is also greater in adolescents characterized as behaviorally inhibited early in life compared with those characterized as non-inhibited. Whereas task performance did not differ between groups, fMRI revealed greater striatal activation to incentives in behaviorally inhibited adolescents than in non-inhibited adolescents. This was regardless of whether the incentive was an anticipated gain or loss. Alteration in neural systems underlying behavior modulated by both negative and positive contingencies may represent a correlate of behavioral inhibition that also underlies vulnerability to various forms of developmental psychopathology.

Reward and punishment sensitivity in shy and non-shy adults: Relations between social and motivated behavior.

Few studies have examined underlying mechanisms linking social behavior, motivated behavior, and reward and punishment systems. The current study was designed to investigate these mechanisms by examining responses to both rewarding and punishing non-social stimuli in shy and non-shy adults. Ninety-three participants, comprising three social behavior groups (Shy, Non-shy, Control) completed the Monetary Incentive Delay task. Consistent with previous research, all participants were sensitive to incentive manipulations. There were also significant individual differences in response. Non-shy participants demonstrated sensitivity to both reward and punishment stimuli, and behavior indicative of high levels of arousal in approach motivation. Shy individuals demonstrated a large discrepancy in sensitivity to reward compared to punishment, with this discrepancy being driven by enhanced sensitivity to reward. Their behavior suggested conflict generated by increased arousal in both approach and withdrawal motivation systems. Current findings contribute to theoretical accounts of relations between social behavior and behavior modulated by reward and punishment. These findings carry implications for the study of psychopathology and neuroimaging research designed to examine relationships between social behavior, motivated behavior, and underlying reward and punishment systems.

Cognitive control under contingencies in anxious and depressed adolescents: an antisaccade task.

BACKGROUND: Emotion-related perturbations in cognitive control characterize adult mood and anxiety disorders. Fewer data are available to confirm such deficits in youth. Studies of cognitive control and error processing can provide an ideal template to examine these perturbations. Antisaccade paradigms are particularly well suited for this endeavor because they provide exquisite behavioral measures of modulation of response errors. METHODS: A new monetary reward antisaccade task was used with 28 healthy, 11 anxious, and 12 depressed adolescents. Performance accuracy, saccade latency, and peak velocity of incorrect responses were analyzed. RESULTS: Performance accuracy across all groups was improved by incentives (obtain reward, avoid punishment). However, modulation of saccade errors by incentives differed by groups. In incentive trials relative to neutral trials, inhibitory efficiency (saccade latency) was enhanced in healthy, unaffected in depressed, and diminished in anxious adolescents. Modulation of errant actions (saccade peak velocity) was improved in the healthy group and unchanged in both the anxious and depressed groups. CONCLUSIONS: These findings provide grounds for testing hypotheses related to the impact of motivation deficits and emotional interference on directed action in adolescents with mood and anxiety disorders. Furthermore, neural mechanisms can now be examined by using this task paired with functional neuroimaging.

The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers.

RATIONALE: N-methyl-D: -aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience. OBJECTIVE: The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion. METHODS: Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation. RESULTS: At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels. CONCLUSION: This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.

Clozapine but not haloperidol Re-establishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex.

Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with (15)O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n=6) and normal volunteers (NVs) (n=12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1). Rest, (2). sensory motor control (SMC) task, and (3). decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n=5) and/or clozapine (n=5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol- and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidol-treated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

Fighting desires: Henry Miller's Queer Tropic.

"Fighting Desires: Henry Miller's Queer Tropic" is an investigation of Tropic of Cancer that investigates the deeply repressed homoerotic desire that periodically surfaces. This reading is dependent upon an interpretation of Eve Sedgwick that proposes male sexuality as a continuum. By looking at the nature of the male-male relationships, as well as the lack of emotion and presence in the male-female relationships, I will show that the most intimate relationships are between men, and that these relationships are expressed through the telling of stories about (heterosexual) sex; this is the function of women within the novel: one has sex with a woman, not for the pleasure that the act brings, but for the pleasure that the recounting of the story to other men brings. Furthermore, I will look at Miller's use of puns within the novel and how they also contribute to a homoerotic reading. None of this is to argue that Miller was not homophobic and sexist--Miller very clearly was--the purpose of this essay is to show the complex nature of sexuality, even within a protagonist who asserts a very defined heterosexuality.

Neurobiological markers of familial risk for depression.

Major depression is associated with a wide range of neurobiological disturbances, including anomalies in the structure and function of cortical and subcortical gray matter and dysregulation of the HPA axis. In this chapter, we review research demonstrating that many of these abnormalities are also present in never-depressed offspring of adults with recurrent depression and discuss how such findings might reflect dysfunctional neuroregulatory systems that precede the onset of this disorder. We also briefly discuss candidate genes and environmental factors that have been posited to be directly involved in the transmission of neural and HPA-axis abnormalities from depressed parents to their offspring, and we review how, by obtaining a better understanding of the neurobiological markers of depression risk, we can facilitate the development of targeted strategies for the prevention and treatment of major depression.

Validation of a child-friendly version of the monetary incentive delay task.

The monetary incentive delay (MID) task (Knutson, 2000) is an imaging paradigm used to measure neural activity of incentive receipt anticipation. The task reliably elicits striatal activation and is commonly used with both adult and adolescent populations, but is not designed for use with children. In the current article, we present data on the newly designed 'piñata task' a child-friendly analog of the MID task. We demonstrate the task can be used successfully in children to study the neural correlates of anticipatory incentive processing. Results from a behavioral study and a neuroimaging study are reported. In Study #1, a sample of 8- to 14-year-old children demonstrates expected behavioral effects: subjects responded most quickly and most accurately on trials with greater potential rewards; older children displayed faster reaction times than younger. In Study #2, 8- to 12-year-old children showed neural activation patterns consistent with those seen in adults in the MID task: activation was modulated by cue incentive value in reward-processing regions, including the striatum, thalamus, mesial prefrontal cortex and insula. Study results suggest that the piñata task is a valid analog of the MID task, and can be used to assess neural correlates of reward processing in children as young as 8-9 years of age.

Incentive processing in Congenital Adrenal Hyperplasia (CAH): a reward-based antisaccade study.

Little is known about how steroid hormones contribute to the beneficial effect of incentives on cognitive control during adolescent development. In this study, 27 adolescents with Congenital Adrenal Hyperplasia (CAH, mean age 15.6 years, 12 female), a disorder of cortisol deficiency and androgen excess, and 36 healthy participants (mean age 16.3 years, 18 female) completed a reward-based antisaccade task. In this mixed-saccade task, participants performed eye movements towards (prosaccades) or away (antisaccades) from a peripherally occuring stimulus. On incentive trials, monetary reward was provided for correct performance, while no such reward was provided on no-incentive trials. Consistent with the hypothesis, the results showed that healthy, but not CAH adolescents, significantly improved their inhibitory control (antisaccade accuracy) during incentive trials relative to no-incentive trials. These findings were not driven by severity of CAH (salt wasters vs. simple virilizers), individual hormone levels, sex, age-at-diagnosis, or medication type (dexamethasone vs. hydrocortisone). In addition, no significant differences between groups were found on orienting responses (prosaccades). Additional analyses revealed an impact of glucocorticoid (GC) dosage, such that higher GC dose predicted better antisaccade performance. However, this effect did not impact incentive processing. The data are discussed within the context of steroid hormone mediated effects on cognitive control and reward processing.

Incentive effect on inhibitory control in adolescents with early-life stress: an antisaccade study.

OBJECTIVE: Early-life stress (ES) such as adoption, change of caregiver, or experience of emotional neglect may influence the way in which affected individuals respond to emotional stimuli of positive or negative valence. These modified responses may stem from a direct alteration of how emotional stimuli are coded, and/or the cognitive function implicated in emotion modulation, such as self-regulation or inhibition. These ES effects have been probed on tasks either targeting reward and inhibitory function. Findings revealed deficits in both reward processing and inhibitory control in ES youths. However, no work has yet examined whether incentives can improve automatic response or inhibitory control in ES youths. METHOD: To determine whether incentives would only improve self-regulated voluntary actions or generalize to automated motoric responses, participants were tested on a mixed eye movement task that included reflex-like prosaccades and voluntary controlled antisaccade eye movements. Seventeen adopted children (10 females, mean age 11.3 years) with a documented history of neglect and 29 typical healthy youths (16 females, mean age 11.9 years) performed the mixed prosaccade/antisaccade task during monetary incentive conditions or during no-incentive conditions. RESULTS: Across both saccade types, ES adolescents responded more slowly than controls. As expected, control participants committed fewer errors on antisaccades during the monetary incentive condition relative to the no-incentive condition. By contrast, ES youths failed to show this incentive-related improvement on inhibitory control. No significant incentive effects were found with prepotent prosaccades trials in either group. Finally, co-morbid psychopathology did not modulate the findings. CONCLUSIONS: These data suggest that youths with experience of early stress exhibit deficient modulation of inhibitory control by reward processes, in tandem with a reward-independent deficit in preparation for both automatic and controlled responses. These data may be relevant to interventions in ES youths.

Effectiveness of Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) methods in Medicaid-supported prenatal care: Trial III.

This two-phase evaluation documented the delivery and effectiveness of evidence-based health education methods by regular staff to pregnant smokers. During Phase 1, a total of 436 Medicaid patients were screened and 416 (95%) gave consent: 334 nonsmokers and 102 smokers. This historical Comparison (C) group was assessed to document the "normal" pretrial smoking prevalence, patient nondisclosure (deception), and cessation rates at the first prenatal visit and during care. After this study, a formative evaluation of SCRIPT methods was conducted among 139 experimental group patients and 126 control group patients. During Phase 2, a total of 6,514 patients were screened over a 36-month period: 1,736 (27%) were smokers and 1,340 (77%) gave consent. After randomization, 247 became ineligible. The remaining 1,093 smokers received brief routine advice to quit. The experimental group (n = 544) also received a Commit to Quit video, A Pregnant Woman's Guide to Quit Smoking, and counseling. Self-reports and saliva were collected at baseline, ≥60 days, and ≤90 days postpartum for cotinine analyses to document cessation and significant reduction (SR) rates. The Phase 1 formative evaluation documented a 24% nondisclosure rate at the onset of care. It also confirmed a significantly higher experimental (17.3%) versus control group (8.8%) cessation rate and experimental versus control group SR rates of 22% and 16%. During Phase 2, unplanned policy changes, and delivery of experimental group counseling procedures to 15% to 20% of control group patients, resulted in a final experimental group cessation rate of 12% and a control group rate of 10%. The experimental group SR rate of 18%, however, was significantly higher than the control group SR rate of 13%. Effectiveness varied by the stability of clinic infrastructure, and degree of fidelity of staff performance of assessment and intervention procedures. The methods and results of this study will assist future health education programs for pregnant smokers to plan and conduct process and impact evaluations in prenatal care.

Perturbed reward processing in pediatric bipolar disorder: an antisaccade study.

Pediatric bipolar disorder is a severe and impairing illness. Characterizing the impact of pediatric bipolar disorder on cognitive function might aid in understanding the phenomenology of the disorder. While previous studies of pediatric bipolar disorder have reported deficits in cognitive control and reward behavior, little is understood about how affective processes influence behavioral control. Relative to prior studies using manual-response paradigms, eye movement tasks provide a more precise assessment of reward sensitivity and cognitive and motor control. The current study compares 20 youths with bipolar disorder (mean age = 13.9 years ± 2.22) and 23 healthy subjects (mean age = 13.8 years ± 2.49) on a mixed pro-antisaccade task with monetary incentives. On both types of saccades, participants were presented with three types of incentives: those where subjects can win money, lose money, or neither win nor lose money. Impaired reward processing was found in youths with bipolar disorder relative to controls, particularly on antisaccades. This difference was reflected in lower error rates during incentive trials in the control but not in the bipolar disorder group. By comparison, no group differences were found on prosaccade trials. The results provide further evidence for deficits in cognitive and reward processing in bipolar disorder.

Was killing the queer author necessary to liberate the queer text?: the case of Andy Warhol's A: a novel.

In the decades since Roland Barthes' "The Death of the Author" (1968), Michel Foucault's "What Is an Author?" (1969), and Andy Warhol's novel A (1968), we have become comfortable with the idea that the author is separate from the text. In many ways, however, killing the author was an unnecessary act since critics inherently read their own ideas into texts. Within the span of less than two years, all three texts proposed the removal of the author from the text, all three by prominent gay men in academia and art. The act of removing the author represented a kind of closet protection, separating artist from art, author from text. This aricle examines the convergence of ideas of Barthes and Foucault and how they relate to Warhol's A. In these writers and texts, we see a sexuality eager to burst forth from the page, but one that is hesitant, worried that the sexual politics of the late 1960s are not so liberated as to freely accept homosexuality among the artistic and academic elite. This is the real tragedy in the death of the author, when the identity and spirit of the artist/writer is so denied by the audience that not only is the sexuality lost, but the artist as well.

Functional brain imaging of development-related risk and vulnerability for substance use in adolescents.

The adolescent period is characterized by substantial behavioral changes, including increases in novelty-seeking and risk-taking, which may facilitate substance use and experimentation. These behavioral changes co-occur with widespread structural and functional neural developments. Ontogenic changes affecting the neural circuitry subserving inhibitory control and reward-related processes are particularly relevant to adolescent risk-taking behavior. Impairment or immaturity of these processes are shown to contribute to enhanced risk for substance abuse. Additionally, the direct neural action of drugs of abuse in adolescents may have more severe consequences than in adults because of the additional potential effects on development. Functional neuroimaging research is beginning to examine the neural correlates of reward and inhibitory processes in adolescents. However, the study of the consequences of exposure to drugs of abuse on brain function in adolescents is lagging. This review summarizes the functional neuroimaging literature that can inform conceptualizations of risk and consequences of substance use in adolescence.