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1.  Cognitive control moderates early childhood temperament in predicting social behavior in seven year old children: An ERP study 
Developmental science  2014;17(5):667-681.
Behavioral inhibition (BI) is a temperament associated with heightened vigilance and fear of novelty in early childhood, and social reticence and increased risk for anxiety problems later in development. However, not all behaviorally inhibited children develop signs of anxiety. One mechanism that might contribute to the variability in developmental trajectories is the recruitment of cognitive-control resources. The current study measured N2 activation, an ERP (event-related potential) associated with cognitive control, and modeled source-space activation (LORETA; Low Resolution Brain Electromagnetic Tomography) at seven years of age while children performed a go/no-go task. Activation was estimated for the entire cortex and then exported for four regions of interest: ventromedial prefrontal cortex (VMPFC), ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dorsal ACC), and dorsal lateral prefrontal cortex (DLPFC). BI was measured in early childhood (ages two and three years). Anxiety problems and social reticence were measured at seven years of age to ascertain stability of temperamental style. Results revealed that BI was associated with increased performance accuracy, longer reaction times, greater (more negative) N2 activation, and higher estimated dorsal ACC and DLPFC activation. Furthermore, early BI was only associated with social reticence at age 7 at higher (more negative) levels of N2 activation or higher estimated dorsal ACC or DLPFC activation. Results are discussed in the context of overcontrolled behavior contributing to social reticence and signs of anxiety in middle childhood.
PMCID: PMC4334573  PMID: 24754610
Behavioral inhibition; cognitive control; no-go N2; social reticence; dorsal anterior cingulate cortex; dorsolateral prefrontal cortex; children
2.  Antidepressant effects on serotonin 1A/1B receptors in the rat brain using a Gene × Environment model 
Neuroscience letters  2013;559:163-168.
A gene--environment (G×E) interaction is implicated in both the pathophysiology and treatment of major depressive disorder (MDD). This study modeled the effects of genetic vulnerability by using the Flinders Sensitive Line (FSL), a rat model of depression and its control counterpart—the Flinders Resistant Line (FRL). The effects of environmental vulnerability (e.g. early-life stress) were modeled by using maternal separation. Rats (n=105) were drawn from four groups reflecting experimental crossing of strain (FSL vs. FRL) and early-life stress (high vs. low) to assess the effects of two antidepressants (escitalopram or nortriptyline) compared to vehicle. Quantitative in vitro autoradiography was performed using [125I]MPPI (5-HT1a) and [125I]CYP (5-HT1B) in prefrontal cortex (PFC) and hippocampus. Stringent, Bonferroni-corrected statistical analyses showed significant strain-by-rearing-by-treatment (three-way) interactions in PFC 5-HT1a and hippocampal 5-HT1B receptors. Either vulnerability reduced serotonergic binding; no additive effects were associated with the two vulnerabilities. Both antidepressants increased hippocampal 5-HT1B receptor binding; however, only nortriptyline selectively increased PFC 5-HT1a receptor binding. Taken together, our findings demonstrate that antidepressant effects on the serotonergic system are shaped by a G×E interaction that is dependent on antidepressant class and brain region.
PMCID: PMC4204401  PMID: 24287374
FSL/FRL (Flinders Sensitive / Resistant Line); serotonin 1A/1B (5-HT1A/1B) receptors; escitalopram; nortriptyline; PFC (prefrontal cortex); hippocampus, gene- environment (G×E)
3.  Screening electrocardiograms in psychiatric research: Implications for physicians and healthy volunteers 
International journal of clinical practice  2014;68(1):10.1111/ijcp.12218.
While there is controversy regarding utility of screening electrocardiograms (ECGs) in competitive athletes and children exposed to psychostimulants, there is no data on the use of screening ECGs in psychiatric research. We aimed to examine the prevalence and clinical significance of ECG abnormalities and their impact on eligibility for studies.
We analyzed 500 consecutive ECG reports from physically healthy volunteers who had a negative cardiac history, normal cardiovascular examination and no other significant medical illnesses. For the purpose of this report, all ECGs were over-read by one cardiologist.
The mean age of our cohort was 28.3+/−8.0 years. A total of 112 (22.4%) ECGs were reported as abnormal (14.2%) or borderline (8.2%). These abnormalities were considered clinically insignificant in all but eight subjects (1.6%) who underwent evaluation with an echocardiogram. All echocardiograms were normal. No subject was excluded from studies. After the over-reading, no abnormalities or isolated bradycardia were present in 37 of 112 (33%) ECGs that were initially reported as abnormal or borderline, while minor abnormalities were found in 7 of 204 (3.4%) ECGs that were reported as normal.
Although screening ECGs did not detect significant cardiac pathology or affect eligibility for our studies, over 20 % of subjects were labeled as having an abnormal or borderline ECG which was incorrect in one third of cases. Strategies to minimize unintended consequences of screening are discussed.
PMCID: PMC3869037  PMID: 24341305
4.  Preliminary Evidence for the Interaction of the Oxytocin Receptor Gene (OXTR) and Face Processing in Differentiating Prenatal Smoking Patterns 
Neuroscience letters  2014;0:259-264.
Prenatal smoking cessation has been described as an empathic action “for the baby,” but this has not been empirically demonstrated. We capitalized on a genetically-characterized extant dataset with outstanding measurement of prenatal smoking patterns and maternal face processing data (as an indicator of empathy) to test this hypothesis, and explore how empathy and smoking patterns may be moderated by a genetic substrate of empathy, the oxytocin receptor gene (OXTR). Participants were 143 Caucasian women from the East Boston Family Study with repeated prospective reports of smoking level, adjusted based on repeated cotinine bioassays. Salivary DNA and face processing (Diagnostic Analysis of Nonverbal Accuracy-2) were assessed 14 years later at an adolescent follow-up of offspring. Two-thirds of participants reported smoking prior to pregnancy recognition. Of these, 21% quit during pregnancy; 56% reduced smoking, and 22% smoked persistently at the same level. A significant interaction between face processing and OXTR variants previously associated with increased sensitivity to social context, rs53576GG and rs2254298A, was found (β = -.181; p = .015); greater ability to identify distress in others was associated with lower levels of smoking during pregnancy for rs53576(GG)/rs2254298(A) individuals (p = .013), but not for other genotypes (p = .892). Testing this “empathy hypothesis of prenatal smoking cessation” in larger studies designed to examine this question can elucidate whether interventions to enhance empathy can improve prenatal smoking cessation rates.
PMCID: PMC4267911  PMID: 25450139
Pregnancy smoking; oxytocin receptor gene; social cognition; nonverbal accuracy; cognitive empathy; differential susceptibility
Depression and Anxiety  2013;31(7):566-573.
Our objective was to compare self- and parent-reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability.
We compared parent- and self-report forms of the Affective Reactivity Index (ARI), a validated measure of irritability, in youths ages 8–17 years with no psychopathology (healthy comparison, HC; n = 38), anxiety disorders (ANX; n = 42), bipolar disorder (BD; n = 35), or severe mood dysregulation (SMD; n = 61; a phenotype characterized by chronic, severely impairing irritability).
Irritability was significantly higher in ANX than HC youths by both parent and self-report (partial η2 = 0.24 and 0.22, respectively, P’s < 0.001). Informant effects differed among ANX, BD, and SMD. Overall, parent-reported irritability was higher in BD with comorbid anxiety disorders and SMD with or without comorbid anxiety disorders than ANX (P’s < 0.007), but self-reported irritability was not significantly different among the three patient groups.
By both parent and self-report, youths with anxiety disorders exhibit significantly more irritability and associated impairment than healthy subjects. Self-reported irritability in youths with anxiety disorders is comparable to that observed in youths with severe mood disorders, although parental reports of irritability differ among the disorders. Future research should examine the pathophysiology of anxiety-associated irritability, as well as its prognostic and treatment implications.
PMCID: PMC3937265  PMID: 23818321
irritable mood; anxiety disorders; trait anger
6.  A developmental study on the neural circuitry mediating response flexibility in bipolar disorder 
Psychiatry research  2013;214(1):56-65.
Cross-sectional neuroimaging studies are an important first step in examining developmental differences in brain function between adults and youth with bipolar disorder (BD). Impaired response flexibility may contribute to reduced ability to modify goal-directed behavior in BD appropriately. We compared neural circuitry mediating this process in child (CBD) vs. adult BD (ABD) and age-matched healthy subjects. fMRI data from 15 CBD, 23 ABD, 20 healthy children, 27 healthy adults were acquired during a response flexibility paradigm, a task where subjects inhibit a prepotent response and execute an alternative response. When successfully executing an alternate response, CBD showed frontal, parietal, and temporal hyperactivation relative to healthy children and ABD, while ABD hypoactivated these regions relative to healthy adults. Previous studies of response flexibility in healthy volunteers revealed frontal, temporal, and parietal cortex hyperactivation in children and hypoactivation in adults. Relative to age-matched healthy subjects, we found hyperactivation in these regions in CBD and hypoactivation in ABD. This suggests that our findings in patients may represent the extreme extension of the age-related response flexibility activation differences found in healthy subjects. Future studies should use longitudinal fMRI to examine the developmental trajectory of the neural circuitry mediating response flexibility in BD.
PMCID: PMC3759594  PMID: 23958598
bipolar disorder; neuroimaging; response flexibility; cross-sectional; stop-change task
7.  Cognitive Inflexibility and Frontal-Cortical Activation in Pediatric Obsessive-Compulsive Disorder 
Deficits in cognitive flexibility and response inhibition have been linked to perturbations in cortico-striatal-thalamic circuitry in adult obsessive-compulsive disorder (OCD). Although similar cognitive deficits have been identified in pediatric OCD, few neuroimaging studies have been conducted to examine its neural correlates in the developing brain. In this study, we tested hypotheses regarding group differences in the behavioral and neural correlates of cognitive flexibility in a pediatric OCD and a healthy comparison (HC) sample.
In this functional magnetic resonance imaging (fMRI) study, a pediatric sample of 10- to 17-year-old subjects, 15 with OCD and 20 HC, completed a set-shifting task. The task, requiring an extradimensional shift to identify a target, examines cognitive flexibility. Within each block, the dimension (color or shape) that identified the target either alternated (i.e., mixed) or remained unchanged (i.e., repeated).
Compared with the HC group, the OCD group tended to be slower to respond to trials within mixed blocks. Compared with the HC group, the OCD group exhibited less left inferior frontal gyrus/BA47 activation in the set-shifting contrast (i.e., HC > OCD, mixed versus repeated); only the HC group exhibited significant activation in this region. The correlation between set shifting-induced right caudate activation and shift cost (i.e., reaction time differential in response to mixed versus repeated trials) was significantly different between HC and OCD groups, in that we found a positive correlation in HC and a negative correlation in OCD.
In pediatric OCD, less fronto-striatal activation may explain previously identified deficits in shifting cognitive sets.
PMCID: PMC4196669  PMID: 20732630
anxiety; set-shifting; fMRI; inferior frontal gyrus; striatum
8.  Response to learned threat: an fMRI study in adolescent and adult anxiety 
The American journal of psychiatry  2013;170(10):1195-1204.
Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, no prior study examines neural correlates of threat-safety discrimination in this group. The current study compares prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning.
Anxious and healthy adolescents and adults (n=114) completed fear conditioning and extinction in the clinic. Conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Several weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in a magnetic resonance imaging (MRI) scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+.
During conditioning and extinction, anxious groups reported more fear than healthy groups, but patient groups did not differ on physiology. During imaging, both anxious adolescents and adults exhibited lower sub-genual anterior cingulate (sgACC) activation than healthy peers, specifically when appraising threat. In ventromedial prefrontal cortex (vmPFC), relative to their age-matched peer groups, anxious adults exhibited reduced activation when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation to the most extreme CS and CS−.
Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced sgACC engagement is a shared feature in adult and adolescent anxiety disorders, but vmPFC dysfunction is age-specific. The unique U-shaped pattern of vmPFC activation in many anxious adolescents could reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.
PMCID: PMC3790858  PMID: 23929092
9.  Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior 
The American journal of psychiatry  2014;171(3):323-331.
This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth—an animal model of human childhood stress—were also studied.
At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N = 8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration.
Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures.
Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.
PMCID: PMC4181537  PMID: 24480874
10.  The role of serotonin in the neurocircuitry of negative affective bias: serotonergic modulation of the dorsal medial prefrontal-amygdala ‘aversive amplification’ circuit 
NeuroImage  2013;78:217-223.
Serotonergic medications can mitigate the negative affective biases in disorders such as depression or anxiety, but the neural mechanism by which this occurs is largely unknown. In line with recent advances demonstrating that negative affective biases may be driven by specific medial prefrontal-amygdala circuitry, we asked whether serotonin manipulation can alter affective processing within a key dorsal medial prefrontal-amygdala circuit: the putative human homologue of the rodent prelimbic-amygdala circuit or ‘aversive amplification’ circuit. In a double-blind, placebo-controlled crossover pharmaco-fMRI design, subjects (N=19) performed a forced-choice face identification task with word distractors in an fMRI scanner over two separate sessions. On one session subjects received dietary depletion of the serotonin precursor tryptophan while on the other session they received a balanced placebo control diet. Results showed that dorsal medial prefrontal responding was elevated in response to fearful relative to happy faces under depletion but not placebo. This negative bias under depletion was accompanied by a corresponding increase in positive dorsal medial prefrontal-amygdala functional connectivity. We therefore conclude that serotonin depletion engages a prefrontal-amygdala circuit during the processing of fearful relative to happy face stimuli. This same ‘aversive amplification’ circuit is also engaged during anxiety induced by shock anticipation. As such, serotonergic projections may inhibit engagement of the ‘aversive amplification’ circuit and dysfunction in this projection may contribute to the negative affective bias in mood and anxiety disorders. These findings thus provide a promising explanation for the role of serotonin and serotonergic medications in the neurocircuitry of negative affective bias.
PMCID: PMC3677215  PMID: 23583742
Serotonin; ATD; amygdala; dMPFC; negative bias; aversive amplification
11.  Dissociable Roles of Ventromedial Prefrontal Cortex (vmPFC) and Rostral Anterior Cingulate Cortex (rACC) in Value Representation and Optimistic Bias 
NeuroImage  2013;78:103-110.
Optimistic bias (OB) is seen when individuals underestimate their probability of experiencing negative life events and overestimate their probability of experiencing positive life events. A reduced OB has been linked with increased depression symptoms . However, given the relevance of this information to mood and anxiety disorders, little is currently known regarding the neurobiology of OB. In the current study, we examine the neural basis of OB in healthy individuals (n=33) during probability estimation of future positive and negative events occurring to themselves relative to other, comparable individuals. In line with previous work, subjects showed significant OB; they considered themselves significantly more likely to experience future positive and significantly less likely to experience future negative events relative to comparable others. Positive, relative to negative events, un-modulated by subjects’ probability estimates, were associated with significantly greater activity within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Moreover, responses within both regions to positive events negatively related to the healthy subjects’ self reports of depression symptoms. However, there was no significant modulation of activity in either region by the subject’s OB, objectified as the level to which they thought the event was more likely [positive events] or less likely [negative events] to occur to them relative to comparable others. In contrast, activity within rostral anterior cingulate cortex (rACC) was positively modulated by OB for positive events and activity within anterior insula and dorsomedial prefrontal cortex (dmPFC) was negatively modulated by OB for negative events. However, there was no significant relationship between responsiveness within these regions and self reports of depression symptoms. The data are discussed with reference to current models of vmPFC, rACC and anterior insula functioning.
PMCID: PMC3686504  PMID: 23567883
fMRI; ventromedial prefrontal prefrontal cortex; rostral anterior cingulate cortex; optimistic bias
12.  Patterns of Neural Connectivity during an Attention Bias Task Moderate Associations between Early Childhood Temperament and Internalizing Symptoms in Young Adulthood 
Biological psychiatry  2013;74(4):273-279.
Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area may clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood.
Children were assessed for BI at multiple age points from infancy through age seven. Based on a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (N=44). Participants completed an event-related fMRI attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews.
The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms.
BI during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology.
PMCID: PMC3725217  PMID: 23489415
Attention Bias; Temperament; Internalizing Problems; Functional Connectivity; Granger Causality; Imaging
14.  Empathic responsiveness in amygdala and anterior cingulate cortex in youths with psychopathic traits 
Psychopathic traits are associated with increases in antisocial behaviors such as aggression and are characterized by reduced empathy for others’ distress. This suggests that psychopathic traits may also impair empathic pain sensitivity. However, whether psychopathic traits affect responses to the pain of others versus the self has not been previously assessed.
We used whole-brain functional magnetic resonance imaging (fMRI) scanning to measure neural activation in 14 adolescents with Oppositional Defiant Disorder or Conduct Disorder and psychopathic traits, as well as 21 healthy controls matched on age, sex, and intelligence. Activation in structures associated with empathic pain perception was assessed as adolescents viewed photographs of pain-inducing injuries. Adolescents imagined either that the body in each photograph was their own or that it belonged to another person. Behavioral and neuroimaging data were analyzed using random-effects analysis of variance.
Youths with psychopathic traits showed reduced activity within regions associated with empathic pain as the depicted pain increased. These regions included rostral anterior cingulate cortex, ventral striatum (putamen), and amygdala. Reductions in amygdala activity particularly occurred when the injury was perceived as occurring to another. Empathic pain responses within both amygdala and rostral anterior cingulate cortex were negatively correlated with the severity of psychopathic traits as indexed by PCL:YV scores.
Youths with psychopathic traits show less responsiveness in regions implicated in the affective response to another’s pain as the perceived intensity of this pain increases. Moreover, this reduced responsiveness appears to predict symptom severity.
PMCID: PMC3716835  PMID: 23488588
Psychopathy; adolescents; empathy; pain; amygdala; Conduct Disorder
15.  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.
PMCID: PMC3739918  PMID: 22569186
Reward; childhood; fMRI
Depression and anxiety  2013;31(1):53-62.
Behavioral inhibition, a temperament identified in early childhood, is often associated with dysregulated attention and affective processing, particularly in response to threat. Longitudinal studies find that the manifestation of perturbed attention and affective processing often dissipates with age. Yet, childhood behavioral inhibition continues to predict perturbed brain function into adulthood. This suggests that adults with childhood behavioral inhibition may engage compensatory processes to effectively regulate emotion-related attention. However, it is unknown whether perturbations in brain function reflect compensation for attention bias to emotional stimuli generally, or to threatening contexts more specifically. The present study tests these possibilities.
Adults with and without a history of stable childhood behavioral inhibition completed an attention-control task in the context of threatening and nonthreatening stimuli while undergoing functional magnetic resonance imaging. Participants were asked to identify the gender of fearful (threatening) and happy (nonthreatening) faces, while ignoring both the face emotion and overlaid congruent (low attention control, LAC) or incongruent (high attention control, HAC) gender words.
When fearful faces were present, adults with stable childhood behavioral inhibition exhibited more activity in striatum, cingulate, and dorsolateral prefrontal cortex for HAC trials compared with LAC trials, relative to those without behavioral inhibition. When happy faces were present, the opposite activation pattern emerged. No group differences in behavior were observed.
Among adults, stable childhood behavioral inhibition predicts neural, but not behavioral, responding when attention control is engaged in discrete emotional contexts. This suggests a mechanism by which adults may compensate for the behavioral manifestation of threat-based attention biases.
PMCID: PMC4118474  PMID: 23861165
personality; magnetic resonance imaging; emotions; attention; risk factor; anxiety
17.  Lasting associations between early-childhood temperament and late-adolescent reward-circuitry response to peer feedback 
Development and psychopathology  2014;26(1):229-243.
Behavioral inhibition, a temperament identifiable in infancy, is associated with heightened withdrawal from social encounters. Prior studies raise particular interest in the striatum, which responds uniquely to monetary gains in behaviorally inhibited children followed into adolescence. Although behavioral manifestations of inhibition are expressed primarily in the social domain, it remains unclear whether observed striatal alterations to monetary incentives also extend to social contexts. In the current study, imaging data were acquired from 39 participants (17 males, 22 females; ages 16–18 years) characterized since infancy on measures of behavioral inhibition. A social evaluation task was used to assess neural response to anticipation and receipt of positive and negative feedback from novel peers, classified by participants as being of high or low interest. As with monetary rewards, striatal response patterns differed during both anticipation and receipt of social reward between behaviorally inhibited and noninhibited adolescents. The current results, when combined with prior findings, suggest that early-life temperament predicts altered striatal response in both social and nonsocial contexts and provide support for continuity between temperament measured in early childhood and neural response to social signals measured in late adolescence and early adulthood.
PMCID: PMC4096565  PMID: 24444176
19.  Linear mixed-effects modeling approach to FMRI group analysis 
NeuroImage  2013;73:176-190.
Conventional group analysis is usually performed with Student-type t-test, regression, or standard AN(C)OVA in which the variance–covariance matrix is presumed to have a simple structure. Some correction approaches are adopted when assumptions about the covariance structure is violated. However, as experiments are designed with different degrees of sophistication, these traditional methods can become cumbersome, or even be unable to handle the situation at hand. For example, most current FMRI software packages have difficulty analyzing the following scenarios at group level: (1) taking within-subject variability into account when there are effect estimates from multiple runs or sessions; (2) continuous explanatory variables (covariates) modeling in the presence of a within-subject (repeated measures) factor, multiple subject-grouping (between-subjects) factors, or the mixture of both; (3) subject-specific adjustments in covariate modeling; (4) group analysis with estimation of hemodynamic response (HDR) function by multiple basis functions; (5) various cases of missing data in longitudinal studies; and (6) group studies involving family members or twins.
Here we present a linear mixed-effects modeling (LME) methodology that extends the conventional group analysis approach to analyze many complicated cases, including the six prototypes delineated above, whose analyses would be otherwise either difficult or unfeasible under traditional frameworks such as AN(C)OVA and general linear model (GLM). In addition, the strength of the LME framework lies in its flexibility to model and estimate the variance–covariance structures for both random effects and residuals. The intraclass correlation (ICC) values can be easily obtained with an LME model with crossed random effects, even at the presence of confounding fixed effects. The simulations of one prototypical scenario indicate that the LME modeling keeps a balance between the control for false positives and the sensitivity for activation detection. The importance of hypothesis formulation is also illustrated in the simulations. Comparisons with alternative group analysis approaches and the limitations of LME are discussed in details.
PMCID: PMC3638840  PMID: 23376789
FMRI group analysis; GLM; AN(C)OVA; LME; ICC; AFNI; R
20.  Empirical Examination of the Potential Adverse Psychological Effects Associated with Pediatric fMRI Scanning 
Over the past decade, the number of functional magnetic resonance imaging (fMRI) studies has increased dramatically. As MRI scans may be anxiety provoking, performing them in a research setting, particularly with children already prone to anxiety, raises questions about ethics as well as methodological feasibility. It is essential to address these questions before expanding the use of this technique to clinical settings, or more widely in the context of pediatric psychopharmacology and biological psychiatry research. The current study investigates the psychological reactions of anxious and non-anxious children and non-anxious adults to an fMRI scan.
Eighty-seven anxious children, 140 non-anxious children, and 98 non-anxious adults rated their emotional reactions to an fMRI scan.
Results indicated that anxious and non-anxious children reported no greater anxiety after fMRI scanning than did adults. In addition, no age-related differences in distress were observed. These data demonstrate that anxious children, healthy children, and healthy adults have similar emotional reactions to fMRI scanning.
The observed findings suggest that the potential for fMRI to produce anxiety should not impede its widespread use in clinical research, psychopharmacology, and biological psychiatry.
PMCID: PMC3689936  PMID: 23738869
21.  Abnormal fusiform activation during emotional-face encoding in children and adults with bipolar disorder 
Psychiatry research  2013;212(2):161-163.
This fMRI study shows that, compared to healthy subjects, children and adults with bipolar disorder (BD) exhibit impaired memory for emotional faces and abnormal fusiform activation during encoding. Fusiform activation abnormalities in BD were correlated with mania severity and may therefore represent a trait and state BD biomarker.
PMCID: PMC3717571  PMID: 23541333
22.  Nucleus accumbens, thalamus and insula connectivity during incentive anticipation in typical adults and adolescents☆,☆☆ 
NeuroImage  2012;0:508-521.
Reward neurocircuitry links motivation with complex behavioral responses. Studies of incentive processing have repeatedly demonstrated activation of nucleus accumbens (NAc), thalamus, and anterior insula, three key components of reward neurocircuitry. The contribution of the thalamus to this circuitry in humans has been relatively ignored, a gap that needs to be filled, given the central role of this structure in processing and filtering information. This study aimed to understand how these three regions function as a network during gain or loss anticipation in adults and youth. Towards this goal, functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) were used to examine effective connectivity among these three nodes in healthy adults and adolescents who performed the monetary incentive delay (MID) task. Seven connectivity models, based on anatomic connections, were tested. They were estimated for incentive anticipation and underwent Bayesian Model Selection (BMS) to determine the best-fit model for each adult and adolescent group. Connection strengths were extracted from the best-fit model and examined for significance in each group. These variables were then entered into a linear mixed model to test between-group effects on effective connectivity in reward neurocircuitry. The best-fit model for both groups included all possible anatomic connections. Three main findings emerged: (1) Across the task, thalamus and insula significantly influenced NAc; (2) A broader set of significant connections was found for the loss-cue condition than the gain-cue condition in both groups; (3) Finally, between-group comparisons of connectivity strength failed to detect statistical differences, suggesting that adults and adolescents use this incentive-processing network in a similar manner. This study demonstrates the way in which the thalamus and insula influence the NAc during incentive processing in humans. Specifically, this is the first study to demonstrate in humans the key role of thalamus projections onto the NAc in support of reward processing. Our results suggest that anticipation of gain/loss involves an ‘alerting’ signal (thalamus) that converges with interoceptive information (insula) to shape action selection programs in the ventral striatum.
PMCID: PMC3949208  PMID: 23069809
23.  Training-associated changes and stability of attention bias in youth: Implications for Attention Bias Modification Treatment for pediatric anxiety 
Attention Bias Modification Treatment (ABMT), an emerging treatment for anxiety disorders, is thought to modify underlying, stable patterns of attention. Therefore, ABMT research should take into account the impact of attention bias stability on attention training response, especially in pediatric populations. ABMT research typically relies on the dot-probe task, where individuals detect a probe following an emotional-neutral stimulus pair. The current research presents two dot-probe experiments relevant to ABMT and attention-bias stability. In Experiment 1, anxious youth receiving 8-weeks of cognitive-behavioral therapy (CBT) were randomly assigned to ABMT that trains attention towards happy faces (n=18) or placebo (n=18). Two additional comparison groups, anxious youth receiving only CBT (n=17) and healthy comparison youth (n=16), were studied. Active attention training towards happy faces did not augment clinician-rated response to CBT; however, individuals receiving training exhibited reductions on self-report measures of anxiety earlier than individuals receiving CBT only. In Experiment 2, healthy youth (n=12) completed a dot-probe task twice while undergoing functional magnetic resonance imaging. Intra class-correlation demonstrated stability of neural activation in response to attention bias in the ventrolateral prefrontal cortex and amygdala. Together, these two studies investigate the ways in which attention-bias stability may impact future work on ABMT.
PMCID: PMC3606014  PMID: 23200784
dot-probe; attention training; test-retest reliability; fMRI
25.  Attention training towards positive stimuli in clinically anxious children 
Attention bias modification training (ABMT) is a promising treatment. Nevertheless, few studies examine its effectiveness in anxious children. This study examined the efficacy of such an ABMT protocol in pediatric anxiety.
37 anxious children were randomly assigned to one of two ABMT conditions. In the attention-towards-positive (ATP) condition, children searched 3 × 3 matrices for a happy face amongst angry faces. In the attention-training-control (ATC) condition, they searched for a bird amongst flowers. Children completed 160 trials in each of four training sessions per week for three weeks at home (1920 total trials). Clinical and attention bias measures were assessed before and after ABMT.
Children randomized to ATP showed greater post-training attention bias towards happy faces than children randomized to ATC. ATP also produced significantly greater reductions in clinician-rated diagnostic severity and number of diagnoses, compared to ATC. In the ATP group, 50% of children who completed training did not meet criteria for their principal diagnosis, compared to 8% in the ATC group.
Training anxious children to focus attention on positive features of their environment may be a promising treatment.
PMCID: PMC3947762  PMID: 23063461
Attention bias; Anxiety; Attention bias modification training; Cognitive behavioural therapy

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