Biomedical subjects

Daniel S Pine

Publications and source records attributed to Daniel S Pine.

At least 19 recordsLinked to original sources

PubMed2007

Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder.

CONTEXT: Considerable work implicates abnormal neural activation and disrupted attention to facial-threat cues in adult anxiety disorders. However, in pediatric anxiety, no research has examined attention modulation of neural response to threat cues. OBJECTIVE: To determine whether attention modulates amygdala and cortical responses to facial-threat cues differentially in adolescents with generalized anxiety disorder and in healthy adolescents. DESIGN: Case-control study. SETTING: Government clinical research institute. PARTICIPANTS: Fifteen adolescents with generalized anxiety disorder and 20 controls. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging. During imaging, participants completed a face-emotion rating task that systematically manipulated attention. RESULTS: While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful faces than to happy faces in a distributed network including the amygdala, ventral prefrontal cortex, and anterior cingulate cortex (P<.05, small-volume corrected, for all). Right amygdala findings appeared particularly strong. Functional connectivity analyses demonstrated positive correlations among the amygdala, ventral prefrontal cortex, and anterior cingulate cortex. CONCLUSIONS: This is the first evidence in juveniles that generalized anxiety disorder-associated patterns of pathologic fear circuit activation are particularly evident during certain attention states. Specifically, fear circuit hyperactivation occurred in an attention state involving focus on subjectively experienced fear. These findings underscore the importance of attention and its interaction with emotion in shaping the function of the adolescent human fear circuit.

Adolescent↗

PubMed2007

Memory deficits in children with and at risk for anxiety disorders.

There are limited data on the neurocognitive correlates of childhood anxiety disorders. The objective of this study was to examine whether visual and verbal memory deficits of nonemotional stimuli are (1) a shared feature of three common childhood anxiety disorders (social phobia, separation anxiety disorder, and generalized anxiety disorder) or whether these deficits are restricted to specific anxiety disorders, and (2) present in offspring who possess at least one of the following established risk factors for anxiety disorders, parental history of panic disorder (PD), or major depressive disorder (MDD). One hundred and sixty offspring, ages 9-20 years, were recruited from parents with lifetime diagnoses of PD, MDD, PD plus MDD, or neither illness. Different clinicians blindly administered semistructured diagnostic interviews to offspring and parents. Verbal and visual memory subtests of the Wide Range Assessment of Memory and Learning were administered to offspring. The results showed that offspring with ongoing social phobia demonstrated reduced visual but not verbal memory scores compared to those without social phobia when controlling for offspring IQ, separation anxiety disorder, and generalized anxiety disorder. No other offspring anxiety disorder predicted memory performance. Neither parental PD nor parental MDD was associated with offspring memory performance. These findings are relevant to understanding the phenomenology of childhood anxiety disorders and may provide insights into the neural circuits underlying these disorders.

Adolescent↗

PubMed2007

Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder.

OBJECTIVE: Deficits in motor inhibition may contribute to impulsivity and irritability in children with bipolar disorder. Studies of the neural circuitry engaged during failed motor inhibition in pediatric bipolar disorder may increase our understanding of the pathophysiology of the illness. The authors tested the hypothesis that children with bipolar disorder and comparison subjects would differ in ventral prefrontal cortex, striatal, and anterior cingulate activation during unsuccessful motor inhibition. They also compared activation in medicated versus unmedicated children with bipolar disorder and in children with bipolar disorder and attention deficit hyperactivity disorder (ADHD) versus those with bipolar disorder without ADHD. METHOD: The authors conducted an event-related functional magnetic resonance imaging study comparing neural activation in children with bipolar disorder and healthy comparison subjects while they performed a motor inhibition task. The study group included 26 children with bipolar disorder (13 unmedicated and 15 with ADHD) and 17 comparison subjects matched by age, gender, and IQ. RESULTS: On failed inhibitory trials, comparison subjects showed greater bilateral striatal and right ventral prefrontal cortex activation than did patients. These deficits were present in unmedicated patients, but the role of ADHD in mediating them was unclear. CONCLUSIONS: In relation to comparison subjects, children with bipolar disorder may have deficits in their ability to engage striatal structures and the right ventral prefrontal cortex during unsuccessful inhibition. Further research should ascertain the contribution of ADHD to these deficits and the role that such deficits may play in the emotional and behavioral dysregulation characteristic of bipolar disorder.

Adolescent↗

PubMed2006

Association between lung function and mental health problems among adults in the United States: findings from the First National Health and Nutrition Examination Survey.

The objective of this study was to determine the association between lung function and mental health problems among adults in the United States. Data were drawn from the First National Health and Nutrition Examination Survey (1971-1975), with available information on a representative sample of US adults aged 25-74 years. Lung function was assessed by spirometry, and provisional diagnoses of restrictive and obstructive airway disease were assigned based on percentage of expected forced expiratory volume. Mental health problems were assessed with the General Well-Being scales. Restrictive lung function and obstructive lung function, compared with normal lung function, were each associated with a significantly increased likelihood of mental health problems. After adjustment for differences in demographic characteristics, obstructive lung function was associated with significantly lower overall well-being (p = 0.025), and restrictive lung function was associated with significantly lower overall well-being (p < 0.001), general health (p < 0.0001), vitality (p < 0.0001), and self-control (p = 0.001) and with higher depression (p = 0.002) subscale scores compared with no lung function problems. Consistent with previous findings from clinical and community-based studies, these results extend available data by providing evidence of a link between objectively measured lung function and self-reported mental health problems in a representative sample of community adults. Future studies are needed to determine the mechanisms of these associations.

Adult↗

PubMed2006

Neural substrates of choice selection in adults and adolescents: development of the ventrolateral prefrontal and anterior cingulate cortices.

A heightened propensity for risk-taking and poor decision-making underlies the peak morbidity and mortality rates reported during adolescence. Delayed maturation of cortical structures during the adolescent years has been proposed as a possible explanation for this observation. Here, we test the hypothesis of adolescent delayed maturation by using fMRI during a monetary decision-making task that directly examines risk-taking behavior during choice selection. Orbitofrontal/ventrolateral prefrontal cortex (OFC/VLPFC) and dorsal anterior cingulate cortex (ACC) were examined selectively since both have been implicated in reward-related processes, cognitive control, and resolution of conflicting decisions. Group comparisons revealed greater activation in the OFC/VLPFC (BA 47) and dorsal ACC (BA 32) in adults than adolescents when making risky selections. Furthermore, reduced activity in these areas correlated with greater risk-taking performance in adolescents and in the combined group. Consistent with predictions, these results suggest that adolescents engage prefrontal regulatory structures to a lesser extent than adults when making risky economic choices.

Adolescent↗

PubMed2006

Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children.

BACKGROUND: Controversy concerning the diagnosis of pediatric bipolar disorder (BD) has focused attention on children with chronic irritability and hyperarousal. This syndrome has been called the "broad BD phenotype" or severe mood dysregulation (SMD). This study examines prevalence, concurrent Axis I diagnoses, and longitudinal outcome of SMD in an epidemiologic sample. METHODS: Data were drawn from the Great Smoky Mountains Study, a longitudinal epidemiological study. Items from the Child and Adolescent Psychiatric Assessment were used to generate SMD criteria. RESULTS: Among 1420 children, the lifetime prevalence of SMD in children ages 9-19 was 3.3%. Most (67.7%) SMD youth had an Axis I diagnosis, most commonly attention-deficit/hyperactivity disorder (26.9%), conduct disorder (25.9%), and/or oppositional defiant disorder (24.5%). In young adulthood (mean age 18.3 +/- 2.1 years), youth who met criteria for SMD in the first wave (mean age 10.6 +/- 1.4 years) were significantly more likely to be diagnosed with a depressive disorder (odds ratio 7.2, confidence interval 1.3-38.8, p = .02) than youth who never met criteria for SMD. CONCLUSIONS: Severe mood dysregulation is relatively common in childhood and predicts risk for early adulthood depressive disorders. Research should continue to explore the course of illness in children with SMD.

Adolescent↗

PubMed2006

Impaired recognition of fear facial expressions in 5-HTTLPR S-polymorphism carriers following tryptophan depletion.

RATIONALE: Genotype at the 5' promoter region (5-HTTLPR) of the serotonin transporter has been implicated in moderating the effects of acute tryptophan depletion on neurocognitive functioning. Acute tryptophan depletion has been associated with the processing of fear-relevant cues, such as emotional expressions, but the effect of genotype at the 5-HTTLPR has not been assessed. OBJECTIVE: The present study investigated the effects of acute tryptophan depletion on the recognition of standardized facial expressions of emotions in healthy volunteers classified as ll homozygotes or s carriers. MATERIALS AND METHODS: A double-blind between-groups design was used with volunteers randomly selected to ingest capsules containing an amino acid mixture specifically lacking tryptophan, or placebo capsules containing lactose. 5 h after capsule ingestion, subjects were required to identify anger, disgust, fear, happiness, sadness, and surprise expressions that progressed from neutral to each full emotional expression in 5% steps. RESULTS: Tryptophan depletion significantly impaired the recognition of fearful facial expressions in s carriers but not ll homozygotes. This impairment was specific to fear expressions. No significant differences in the recognition of other expressions were found. Free tryptophan levels were correlated with fear recognition in s carriers but not ll homozygotes. CONCLUSIONS: The effects of acute tryptophan depletion on the processing of emotional expressions varies as a function of genotype at the 5-HTTLPR. Depletion impairs the recognition of fear in s carriers but not ll homozygotes. This finding reinforces the importance of considering genotype when assessing the behavioral effects of pharmacologic modulation.

Adult↗

PubMed2006

fMRI predictors of treatment outcome in pediatric anxiety disorders.

INTRODUCTION: A growing number of studies have found evidence that anxiety and depressive disorders are associated with atypical amygdala hyperactivation, which decreases with effective treatment. Interest has emerged in this phenomenon as a possible biological marker for individuals who are likely to benefit from tailored treatment approaches. OBJECTIVE: The present study was designed to examine relationships between pretreatment amygdala activity and treatment response in a sample of anxious children and adolescents. MATERIALS AND METHODS: Participants, who were diagnosed predominantly with generalized anxiety disorder (GAD), underwent functional magnetic resonance imaging (fMRI) scanning before treatment with fluoxetine or cognitive behavioral therapy (CBT). RESULTS: Results indicated significant negative associations between degree of left amygdala activation and measures of posttreatment symptom improvement in the group, as a whole. DISCUSSION: Taken together with research on associations between adult amygdala activation and treatment response, these findings suggest that patients whose pretreatment amygdala activity is the strongest may be particularly likely to respond well to such widely used treatments as selective serotonin reuptake inhibitor (SSRI) medications and CBT.

Adolescent↗

PubMed2006

A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fear-potentiated startle study.

Serotonin reuptake inhibitors may increase symptoms of anxiety immediately following treatment initiation. The present study examined whether acute citalopram increased fear-potentiated startle to predictable and/or unpredictable shocks in healthy subjects. Eighteen healthy subjects each received two treatments, placebo and 20 mg citalopram in a crossover design. Participants were exposed to three conditions including one in which predictable aversive shocks were signaled by a cue, a second in which unpredictable shocks were anticipated, and a third in which no shocks were administered. Changes in aversive states were investigated using acoustic startle stimuli. Citalopram did not affect baseline startle. However, the phasic startle potentiation to the threat cue in the predictable condition was robustly increased by acute citalopram. The sustained startle potentiation in the unpredictable conditions was also increased by citalopram, but only when the drug was given during the first session. These results indicate that a single dose of citalopram is not anxiogenic in itself, but can exacerbate the expression of fear and anxiety.

Adolescent↗

PubMed2006

The impact of tryptophan depletion and 5-HTTLPR genotype on passive avoidance and response reversal instrumental learning tasks.

Transient reductions in serotonin levels during tryptophan depletion (TD) are thought to impair reward processing in healthy volunteers, while another facet of the serotonergic system, the serotonin transporter (5-HTTLPR) short allele polymorphism, is implicated in augmented processing of aversive stimuli. We examined the impact and interactions of TD and the serotonin promoter polymorphism genotype on reward and punishment via two forms of instrumental learning: passive avoidance and response reversal. In this study, healthy volunteers (n=35) underwent rapid TD or control procedures and genotyping (n=26) of the 5-HTTLPR for long and short allele variants. In the passive avoidance task, tryptophan-depleted volunteers failed to respond sufficiently to rewarded stimuli compared to the control group. Additionally, long allele homozygous individuals (n=11) were slower to learn to avoid punished stimuli compared to short allele carriers (n=15). TD alone did not produce measurable deficits in probabilistic response reversal errors. However, a significant drug group by genotype interaction was found indicating that in comparison to short allele carriers, tryptophan-depleted individuals homozygous for the long allele failed to appropriately use punishment information to guide responding. These findings extend prior reports of impaired reward processing in TD to include instrumental learning. Furthermore, they demonstrate behavioral differences in responses to punishing stimuli between long allele homozygotes and short allele carriers when serotonin levels are acutely reduced.

Adult↗

PubMed2006

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.

Adolescent↗

PubMed2006

Age-related influence of contingencies on a saccade task.

Adolescence is characterized by increased risk-taking and sensation-seeking, presumably brought about by developmental changes within reward-mediating brain circuits. A better understanding of the neural mechanisms underlying reward-seeking during adolescence can have critical implications for the development of strategies to enhance adolescent performance in potentially dangerous situations. Yet little research has investigated the influence of age on the modulation of behavior by incentives with neuroscience-based methods. A monetary reward antisaccade task (the RST) was used with 23 healthy adolescents and 30 healthy adults. Performance accuracy, latency and peak velocity of saccade responses (prosaccades and antisaccades) were analyzed. Performance accuracy across all groups was improved by incentives (obtain reward, avoid punishment) for both, prosaccades and antisaccades. However, modulation of antisaccade errors (direction errors) by incentives differed between groups: adolescents modulated saccade latency and peak velocity depending on contingencies, with incentives aligning their performance to that of adults; adults did not show a modulation by incentives. These findings suggest that incentives modulate a global measure of performance (percent direction errors) in adults and adolescents, and exert a more powerful influence on the control of incorrect motor responses in adolescents than in adults. These findings suggest that this task can be used in neuroimaging studies as a probe of the influence of incentives on cognitive control from a developmental perspective as well as in health and disease.

Adolescent↗

PubMed2006

Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder.

Reflecting a paradigm shift in clinical neuroscience, many chronic psychiatric illnesses are now hypothesized to result from perturbed neural development. However, most work in this area focuses on schizophrenia. Here, we extend this paradigm to pediatric bipolar disorder (BD), thus demonstrating traction in the developmental psychobiology perspective. To study amygdala dysfunction, we examined neural mechanisms mediating face processing in 22 youths (mean age 14.21 +/- 3.11 yr) with BD and 21 controls of comparable age, gender, and IQ. Event-related functional MRI compared neural activation when attention was directed to emotional aspects of faces (hostility, subjects' fearfulness) vs. nonemotional aspects (nose width). Compared with controls, patients perceived greater hostility in neutral faces and reported more fear when viewing them. Also, compared with controls, patients had greater activation in the left amygdala, accumbens, putamen, and ventral prefrontal cortex when rating face hostility, and greater activation in the left amygdala and bilateral accumbens when rating their fear of the face. There were no between-group behavioral or neural differences in the nonemotional conditions. Results implicate deficient emotion-attention interactions in the pathophysiology of BD in youth and suggest that developmental psychobiology approaches to chronic mental illness have broad applicability.

Adolescent↗

PubMed2006

The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle.

BACKGROUND: The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue. METHODS: Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions. RESULTS: Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam. CONCLUSIONS: Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states.

Acoustic Stimulation↗

PubMed2006

Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An FMRI study.

BACKGROUND: Although major depressive disorder (MDD) represents one of the most serious psychiatric problems afflicting adolescents, efforts to understand the neural circuitry of adolescent MDD have lagged behind those of adult MDD. This study tests the hypothesis that adolescent MDD is associated with abnormal amygdala activity during evocative-face viewing. METHODS: Using functional magnetic resonance imaging (fMRI), between-group differences among MDD (n = 10), anxious (n = 11), and non-psychiatric comparisons (n = 23) were examined during successful vs. unsuccessful face encoding, with encoding success measured post-scan. RESULTS: Compared to healthy adolescents, MDD patients exhibited poorer memory for faces. fMRI analyses accounted for this performance difference through event-related methods. In an analysis comparing successful vs. unsuccessful face encoding, MDD patients exhibited greater left amygdala activation relative to healthy and anxious youth. CONCLUSIONS: Given prior findings among adults, this study suggests that adolescent and adult MDD may involve similar underlying abnormalities in amygdala functioning.

Adolescent↗

PubMed2006

Pharmacotherapy of depressed children and adolescents: current issues and potential directions.

The recent deliberations by the U.S. Food and Drug Administration (FDA) regarding the relationship between antidepressants and suicidality in children have incited debates about the safety of these medications for the treatment of pediatric depression. In light of these events, this review discusses four issues pertaining to pharmacotherapy for pediatric depression. First, we summarize pertinent data from randomized controlled trials of antidepressants for pediatric depression. These data provide strong support for fluoxetine and modest support for the other antidepressants. Second, we examine the outcome of the FDA meta-analysis of the data on antidepressant-induced suicidality, with specific emphasis on the methodological limitations of this analysis. Third, we consider the collective implications of the antidepressant efficacy and suicidality data on clinical practice. Specifically, we present several compelling arguments that justify the continued use of antidepressants for pediatric depression, despite the inherent limitations of these medications. Finally, we review several pathophysiological factors that might provide insights into treatment response and impact the design of future pharmacotherapy studies of depression. These factors relate to diagnostic heterogeneity, developmental consistency, and psychobiology. Potentially novel pharmacotherapies are also discussed.

Adolescent↗

PubMed2006

Triadic model of the neurobiology of motivated behavior in adolescence.

BACKGROUND: Risk-taking behavior is a major cause of morbidity and mortality in adolescence. In the context of decision theory and motivated (goal-directed) behavior, risk-taking reflects a pattern of decision-making that favors the selection of courses of action with uncertain and possibly harmful consequences. We present a triadic, neuroscience systems-based model of adolescent decision-making. METHOD: We review the functional role and neurodevelopmental findings of three key structures in the control of motivated behavior, i.e. amygdala, nucleus accumbens, and medial/ventral prefrontal cortex. We adopt a cognitive neuroscience approach to motivated behavior that uses a temporal fragmentation of a generic motivated action. Predictions about the relative contributions of the triadic nodes to the three stages of a motivated action during adolescence are proposed. RESULTS: The propensity during adolescence for reward/novelty seeking in the face of uncertainty or potential harm might be explained by a strong reward system (nucleus accumbens), a weak harm-avoidant system (amygdala), and/or an inefficient supervisory system (medial/ventral prefrontal cortex). Perturbations in these systems may contribute to the expression of psychopathology, illustrated here with depression and anxiety. CONCLUSIONS: A triadic model, integrated in a temporally organized map of motivated behavior, can provide a helpful framework that suggests specific hypotheses of neural bases of typical and atypical adolescent behavior.

Adolescent↗

PubMed2006

Chronic versus episodic irritability in youth: a community-based, longitudinal study of clinical and diagnostic associations.

OBJECTIVE: Irritability is both a normal developmental phenomenon and a common psychiatric symptom in children. In psychiatric nosology, a distinction is made between chronic and episodic irritability. This study examines the validity of this distinction. METHODS: A sample of 776 youths received Diagnostic and Statistical Manual of Mental Disorders (DSM)-based structured interviews at three time points. Questions regarding episodic and chronic irritability were used to create scales measuring these constructs; associations with age, gender, and diagnosis were examined. RESULTS: Episodic and chronic irritability differed in their associations with age. The longitudinal stability within irritability type was stronger than between types. In longitudinal analyses, chronic irritability at time 1 (mean age 13.8 +/- 2.6 years) predicted attention deficit/ hyperactivity disorder at time 2 (mean age 16.2 +/- 2.8 years) and major depression at time 3 (mean age 22.1 +/- 2.7 years). Episodic irritability at time 1 predicted simple phobia and mania at time 2. CONCLUSIONS: Episodic and chronic irritability in adolescents appear to be stable, distinct constructs. Further research is needed to elucidate the longitudinal associations of each with specific psychiatric diagnoses.

Adolescent↗