Understanding Irritability in Relation to Anger, Aggression, and Informant in a Pediatric Clinical Population.

OBJECTIVE: Despite its clinical relevance to pediatric mental health, the relationship of irritability with anger and aggression remains unclear. We aimed to quantify the relationships between well-validated, commonly used measurements of these constructs and informant effects in a clinically relevant population. METHOD: A total of 195 children with primary diagnoses of attention-deficit/hyperactivity disorder, disruptive mood dysregulation disorder, or no major disorder and their parents rate irritability, anger, and aggression on measures of each construct. Construct and informant relationships were mapped via multi-trait, multi-method factor analysis. RESULTS: Parent- and child-reported irritability and child-reported anger are highly associated (r = 0.89) but have some significant differences. Irritability overlaps with outward expression of anger but diverges from anger in anger suppression and control. Aggression has weaker associations with both irritability (r = 0.56) and anger (r = 0.49). Across measures, informant source explains a substantial portion of response variance. CONCLUSION: Irritability, albeit distinct from aggression, is highly associated with anger, with notable overlap in child-reported outward expression of anger, providing empirical support for formulations of clinical irritability as a proneness to express anger outwardly. Diagnostic and clinical intervention work on this facet of anger can likely translate to irritability. Further research on external validation of divergence of these constructs in anger suppression and control may guide future scale revisions. The proportion of response variance attributable to informant may be an under-recognized confound in clinical research and construct measurement.

A preliminary study on functional activation and connectivity during frustration in youths with bipolar disorder.

OBJECTIVES: Frustration is associated with impaired attention, heightened arousal, and greater unhappiness in youths with bipolar disorder (BD) vs healthy volunteers (HV). Little is known about functional activation and connectivity in the brain of BD youths in response to frustration. This exploratory study compared BD youths and HV on attentional abilities, self-reported affect, and functional activation and connectivity during a frustrating attention task. METHODS: Twenty BD (Mage  = 15.86) and 20 HV (Mage  = 15.55) youths completed an fMRI paradigm that differentiated neural responses during processing of frustrating feedback from neural responses during attention orienting following frustrating feedback. We examined group differences in (a) functional connectivity using amygdala, inferior frontal gyrus (IFG), and striatum as seeds and (b) whole-brain and regions of interest (amygdala, IFG, striatum) activation. We explored task performance (accuracy, reaction time), self-reported frustration and unhappiness, and correlations between these variables and irritability, depressive, and manic symptoms. RESULTS: Bipolar disorder youths, relative to HV, exhibited positive IFG-ventromedial prefrontal cortex (vmPFC) connectivity yet failed to show negative striatum-insula connectivity during feedback processing. Irritability symptoms were positively associated with striatum-insula connectivity during feedback processing. Moreover, BD vs HV youths showed positive IFG-parahippocampal gyrus (PHG)/periaqueductal gray (PAG) connectivity and negative amygdala-cerebellum connectivity during attention orienting following frustration. BD was not associated with atypical activation patterns. CONCLUSIONS: Positive IFG-vmPFC connectivity and striatum-insula decoupling in BD during feedback processing may mediate heightened sensitivity to reward-relevant stimuli. Elevated IFG-PAG/PHG connectivity in BD following frustration may suggest greater recruitment of attention network to regulate arousal and maintain goal-directed behavior.

Daily Vaginal Microbiota Fluctuations Associated with Natural Hormonal Cycle, Contraceptives, Diet, and Exercise.

The microorganisms of the vaginal tract are critical for vaginal and reproductive health. However, the regulation of these microorganisms is not well understood. Therefore, we investigated whether different factors regulate the vaginal microbiota of healthy college-aged women (n = 26) with high temporal resolution by collecting daily self-administered vaginal swabs and using 16S rRNA sequencing for bacterial identification. As expected, vaginal microbiota clustered into five predefined community state types. Vaginal microbial diversity, stability, and Lactobacillus abundances were associated with the menstrual cycle and hormonal contraceptive use. Vaginal microbial diversity, as measured using the Shannon index, increased during menses (P < 0.001), while Lactobacillus abundances decreased (P = 0.01). The covariance of these microbial measures with previously established estradiol levels suggests that estrogens can regulate vaginal microbiota. Moreover, the use of hormonal contraceptives may alter the temporal dynamics of the vaginal microbiota and decrease Lactobacillus abundances, depending on hormonal content and release method. Interestingly, intrasample diversity was greater in participants on a vegetarian diet (P = 0.004) and among participants who exercised more (P = 0.04). These findings indicate that ovarian hormones, diet, and exercise can regulate vaginal microbial composition and stability and may impact vaginal and reproductive health.IMPORTANCE The vaginal microbiome is a critical component of women's sexual and reproductive health, with variations in microbial composition, particularly the loss of Lactobacillus species, being implicated in gynecologic and obstetric diseases. Given that the vaginal microbiome is so crucial, why do vaginal microbial profiles vary strikingly from person to person and even change over time within the same person? In the present study, which tracked the daily vaginal microbiomes of young healthy women through different lifestyles, we found that use of a locally released progestin contraceptive, a vegetarian diet, and intense exercise appear to lead to vaginal microbiome alterations and loss of Lactobacillus species. The impact of these vaginal microbiome changes on immediate and long-term health remain to be investigated.

Multi-method assessment of irritability and differential linkages to neurophysiological indicators of attention allocation to emotional faces in young children.

Facilitated attention toward angry stimuli (attention bias) may contribute to anger proneness and temper outbursts exhibited by children with high irritability. However, most studies linking attention bias and irritability rely on behavioral measures with limited precision and no studies have explored these associations in young children. The present study explores irritability-related attention biases toward anger in young children (N = 128; ages 4-7 years) engaged in a dot-probe task with emotional faces, as assessed with event-related brain potential (ERP) indices of early selective attention and multi-method assessment of irritability. Irritability assessed via semi-structured clinical interview predicted larger anterior N1 amplitudes to all faces. In contrast, irritability assessed via a laboratory observation paradigm predicted reduced P1 amplitudes to angry relative to neutral faces. These findings suggest that altered early attentional processing occurs in young children with high irritability; however, the nature of these patterns may vary with methodological features of the irritability assessments. Future investigations using different assessment tools may provide greater clarity regarding the underlying neurocognitive correlates of irritability. Such studies may also contribute to the ongoing debates about how to best define and measure irritability across the developmental spectrum in a manner that is most informative for linkage to neural processes.

On Defining Irritability and its Relationship to Affective Traits and Social Interpretations.

Irritability has gained recognition as a clinically significant trait in youth and adults that when persistent and severe, predicts poor outcomes throughout life. However, its definition, measurement, and relationship to similar constructs remain poorly understood. In a community sample of adults (N=458; 19-74 years; M=40.5), we sought to identify a unitary irritability factor from independently constructed self-reported measures of irritability distinct from the related constructs of aggression, depression, and anxiety, and whether it was associated with face emotion identification deficits and hostile interpretation biases previously established in clinical pediatric samples. The three measures of irritability generated a common factor characterized by a rapid, angry response to provocation. This irritability factor had unique associations with tendencies to judge ambiguous stimuli as reflecting hostility, but not with face emotion identification performance. These findings clarify the nature of irritability and its associations with neurocognitive phenomenon.

Reward processing and irritability in young adults.

Despite increasing interest in the mechanisms of irritability, little research in this domain has been conducted with adults. The present study evaluates relationships among trait irritability, reward responsivity, and frustrative non-reward in a non-clinical sample of young adult females (n = 58) using a paradigm that has been used successfully in pediatric populations with clinically significant irritability. Similar to prior work in these pediatric populations, the frustration manipulation increased self-reported frustration and decreased task accuracy on trials requiring spatial attention shifts. Higher trait irritability was associated with smaller FRN amplitudes to loss feedback. Trait irritability was unrelated to the FRN to reward feedback and the reward positivity ERP. These findings provide preliminary evidence linking irritability with aberrant frustrative non-reward in a healthy young adult sample.

Temporally sensitive neural measures of inhibition in preschool children across a spectrum of irritability.

Irritability is a prominent feature of chronic mental disorders and a developmental marker of their early emergence. The most salient feature of irritability in early childhood is temper tantrums. While temper tantrums are normative in young children, they can be clinically concerning when they are dysregulated, very frequent, and/or occur in unexpected contexts. The present study uses behavioral and event-related brain potential (ERP) measures to characterize the relationship between irritability and neural markers of response inhibition in very young children. Forty-six children (ages 4-7 years) completed a go/no-go task under nonfrustrating and frustrating conditions. ERPs elicited by go and no-go stimuli were examined as a function of frustration condition and irritability, operationalized via the well-validated Temper Loss scale of the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB). Higher Temper Loss scores were associated with larger N2no-go amplitudes and reduced no-go accuracy during frustration. This suggests that higher levels of irritability corresponded with increased conflict monitoring and poorer task performance during frustration. These findings add to a developing literature identifying the neurocognitive markers of varying levels of irritability in young children.

Brain Mechanisms of Attention Orienting Following Frustration: Associations With Irritability and Age in Youths.

OBJECTIVE: Childhood irritability is a common, impairing problem with changing age-related manifestations that predict long-term adverse outcomes. However, more investigation of overall and age-specific neural correlates is needed. Because youths with irritability exhibit exaggerated responses to frustrating stimuli, the authors used a frustration functional MRI (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age. METHOD: The authors studied a transdiagnostic sample of 195 youths with varying levels of irritability (disruptive mood dysregulation disorder, N=52; anxiety disorder, N=42; attention deficit hyperactivity disorder, N=40; and healthy volunteers, N=61). Irritability was measured by parent and child reports on the Affective Reactivity Index. The fMRI paradigm was a cued-attention task differentiating neural activity in response to frustration (rigged feedback) from activity during attention orienting in the trial following frustration. RESULTS: Whole-brain activation analyses revealed associations with irritability during attention orienting following frustration. Irritability was positively associated with frontal-striatal activation, specifically in the dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate. Age moderated the association between irritability and activation in some frontal and posterior regions (the anterior cingulate cortex, medial frontal gyrus, cuneus, precuneus, and superior parietal lobule [F=19.04-28.51, df=1, 189, partial eta squared=0.09-0.13]). Specifically, higher irritability was more strongly related to increased activation in younger youths compared with older youths. CONCLUSIONS: Following frustration, levels of irritability correlated with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. Although most associations were independent of age, dysfunction in the anterior cingulate cortex and posterior regions was more pronounced in young children with irritability.

How generalizable is the inverse relationship between social class and emotion perception?

Compared to individuals in lower positions of power, higher-power individuals are theorized to be less motivated to attend to social cues. In support of this theory, previous research has consistently documented negative correlations between social class and emotion perception. Prior studies, however, were limited by the size and diversity of the participant samples as well as the systematicity with which social class and emotion perception were operationalized. Here, we examine the generalizability of prior research across 10,000+ total participants. In an initial modest sample, (n = 179), Study 1 partially replicated past results: emotion identification correlated negativity with subjective social class (ß = -0.15, 95% CI = [-0.28,-0.02]) and one of two objective social class measures (participant education ß = -0.15, 95% CI = [-0.03,-0.01]). Studies 2-4 followed up on Study 1's mixed results for objective social class in three much larger samples. These results diverged from past literature. In Study 2, complex emotion identification correlated non-significantly with participant education (ß = 0.02, p = 0.25; 95% CI = [-0.01, 0.05], n = 2,726), positively with childhood family income (ß = 0.03, 95% CI = [0.01,0.06], n = 4,312), and positively with parental education (ß = 0.06, 95% CI = [0.04,0.09], n = 4,225). In Study 3, basic emotion identification correlated positively with participant education (ß = 0.05, 95% CI = [0.02, 0.09]), n = 2,564). In Study 4, basic emotion discrimination correlated positively with participant education (ß = 0.09, 95% CI = [0.05,0.13], n = 2,079), positively with parental education (ß = 0.06, 95% CI = [0.02,0.09], n = 3,225), and non-significantly with childhood family income (ß = 0.2, 95% CI = [0.01,0.07], n = 3,272). Results remained similar when restricting analyses to U.S.-based participants. Taken together, these findings suggest that previously reported negative correlations between emotion perception and social class may generalize poorly past select samples and/or subjective measures of social class. Data from the three large web-based samples used in Studies 2-4 are available at osf.io/jf7r3 as normative datasets and to support future investigations of these and other research questions.

A prospective study of severe irritability in youths: 2- and 4-year follow-up.

BACKGROUND: Severe, chronic irritability is receiving increased research attention, and is the cardinal symptom of a new diagnostic category, disruptive mood dysregulation disorder (DMDD). Although data from epidemiological community samples suggest that childhood chronic irritability predicts unipolar depression and anxiety in adulthood, whether these symptoms are stable and cause ongoing clinical impairment is unknown. The present study presents 4-year prospective and longitudinal diagnostic and impairment data on a clinical sample of children selected for symptoms of severe irritability (operationalized as severe mood dysregulation [SMD]). METHODS: Youth meeting criteria for SMD (n = 200) were evaluated at baseline using standard diagnostic methods. Two-year (n = 78) and 4-year (n = 46) follow-up diagnostic and clinical impairment ratings collected at 6-month intervals were completed with those youths enrolled in the study for a sufficient time. RESULTS: Although the number of youth meeting strict categorical SMD criteria declined over time (49 and 40% at 2 and 4 years, respectively), many individuals not meeting full criteria continued to display clinically significant irritability symptoms (2 years: 42%; 4 years: 37%). Impairment due to these irritability symptoms remained consistently in the moderate range on the Clinical Global Impressions Scale. CONCLUSIONS: By the 4-year follow-up, only 40% of youths meet strict SMD criteria; however, most continue to display clinically impairing symptoms and significant impairment warranting psychiatric treatment. These findings provide evidence for the course of irritability, with implications for DMDD. Future research with populations meeting DMDD criteria and followed through the ages of high risk for psychiatric diagnoses is necessary.

Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder.

Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.

Parametric modulation of neural activity during face emotion processing in unaffected youth at familial risk for bipolar disorder.

OBJECTIVES: Both patients with pediatric bipolar disorder (BD) and unaffected youth at familial risk (AR) for the illness show impairments in face emotion labeling. Few studies, however, have examined brain regions engaged in AR youth when processing emotional faces. Moreover, studies have yet to explore neural responsiveness to subtle changes in face emotion in AR youth. METHODS: Sixty-four unrelated youth, including 20 patients with BD, 15 unaffected AR youth, and 29 healthy comparisons (HC), completed functional magnetic resonance imaging. Neutral faces were morphed with angry or happy faces in 25% intervals. In specific phases of the task, youth alternatively made explicit (hostility) or implicit (nose width) ratings of the faces. The slope of blood oxygenated level-dependent activity was calculated across neutral to angry and neutral to happy face stimuli. RESULTS: Behaviorally, both subjects with BD (p ≤ 0.001) and AR youth (p ≤ 0.05) rated faces as less hostile relative to HC. Consistent with this, in response to increasing anger on the face, patients with BD and AR youth showed decreased modulation in the amygdala and inferior frontal gyrus (IFG; BA 46) compared to HC (all p ≤ 0.05). Amygdala dysfunction was present across both implicit and explicit rating conditions, but IFG modulation deficits were specific to the explicit condition. With increasing happiness, AR youth showed aberrant modulation in the IFG, which was also sensitive to task demands (all p ≤ 0.05). CONCLUSIONS: Decreased amygdala and IFG modulation in patients with BD and AR youth may be pathophysiological risk markers for BD, and may underlie the social cognition and face emotion labeling deficits observed in BD and AR youth.

Neural response during explicit and implicit face processing varies developmentally in bipolar disorder.

Both children and adults with bipolar disorder (BD) exhibit face emotion labeling deficits and neural circuitry dysfunction in response to emotional faces. However, few studies have compared these groups directly to distinguish effects of age and diagnosis. Such studies are important to begin to elucidate the developmental trajectory of BD and facilitate its diagnosis, prevention and treatment. This functional magnetic resonance imaging study compares 41 individuals with BD (19 children; 22 adults) and 44 age-matched healthy individuals (25 children; 19 adults) when making explicit or implicit judgments about angry or happy face morphs across a range of emotion intensity. Linear trend analyses revealed that BD patients, irrespective of age, failed to recruit the amygdala in response to increasing angry face. This finding was no longer significant when the group was restricted to euthymic youth or those without comorbid attention deficit hyperactivity disorder although this may reflect low statistical power. Deficits in subgenual anterior cingulate modulation were observed in both patient groups but were related to implicit processing for child patients and explicit processing for adult patients. Abnormalities in face emotion labeling and the circuitry mediating it may be biomarkers of BD that are present across development.

A developmental study on the neural circuitry mediating response flexibility in bipolar disorder.

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, and 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.

Impaired fixation to eyes during facial emotion labelling in children with bipolar disorder or severe mood dysregulation.

BACKGROUND: Children with bipolar disorder (BD) or severe mood dysregulation (SMD) show behavioural and neural deficits during facial emotion processing. In those with other psychiatric disorders, such deficits have been associated with reduced attention to eye regions while looking at faces. METHODS: We examined gaze fixation patterns during a facial emotion labelling task among children with pediatric BD and SMD and among healthy controls. Participants viewed facial expressions with varying emotions (anger, fear, sadness, happiness, neutral) and emotional levels (60%, 80%, 100%) and labelled emotional expressions. RESULTS: Our study included 22 children with BD, 28 with SMD and 22 controls. Across all facial emotions, children with BD and SMD made more labelling errors than controls. Compared with controls, children with BD spent less time looking at eyes and made fewer eye fixations across emotional expressions. Gaze patterns in children with SMD tended to fall between those of children with BD and controls, although they did not differ significantly from either of these groups on most measures. Decreased fixations to eyes correlated with lower labelling accuracy in children with BD, but not in those with SMD or in controls. LIMITATIONS: Most children with BD were medicated, which precluded our ability to evaluate medication effects on gaze patterns. CONCLUSION: Facial emotion labelling deficits in children with BD are associated with impaired attention to eyes. Future research should examine whether impaired attention to eyes is associated with neural dysfunction. Eye gaze deficits in children with BD during facial emotion labelling may also have treatment implications. Finally, children with SMD exhibited decreased attention to eyes to a lesser extent than those with BD, and these equivocal findings are worthy of further study.

Neural mechanisms of frustration in chronically irritable children.

OBJECTIVE: Irritability is common in children and adolescents and is the cardinal symptom of disruptive mood dysregulation disorder, a new DSM-5 disorder, yet its neural correlates remain largely unexplored. The authors conducted a functional MRI study to examine neural responses to frustration in children with severe mood dysregulation. METHOD: The authors compared emotional responses, behavior, and neural activity between 19 severely irritable children (operationalized using criteria for severe mood dysregulation) and 23 healthy comparison children during a cued-attention task completed under nonfrustrating and frustrating conditions. RESULTS: Children in both the severe mood dysregulation and the healthy comparison groups reported increased frustration and exhibited decreased ability to shift spatial attention during the frustration condition relative to the nonfrustration condition. However, these effects of frustration were more marked in the severe mood dysregulation group than in the comparison group. During the frustration condition, participants in the severe mood dysregulation group exhibited deactivation of the left amygdala, the left and right striatum, the parietal cortex, and the posterior cingulate on negative feedback trials, relative to the comparison group (i.e., between-group effect) and to the severe mood dysregulation group's responses on positive feedback trials (i.e., within-group effect). In contrast, neural response to positive feedback during the frustration condition did not differ between groups. CONCLUSIONS: In response to negative feedback received in the context of frustration, children with severe, chronic irritability showed abnormally reduced activation in regions implicated in emotion, attention, and reward processing. Frustration appears to reduce attention flexibility, particularly in severely irritable children, which may contribute to emotion regulation deficits in this population. Further research is needed to relate these findings to irritability specifically, rather than to other clinical features of severe mood dysregulation.

Parametric modulation of neural activity by emotion in youth with bipolar disorder, youth with severe mood dysregulation, and healthy volunteers.

CONTEXT Youth with bipolar disorder (BD) and those with severe, nonepisodic irritability (severe mood dysregulation [SMD]) exhibit amygdala dysfunction during facial emotion processing. However, studies have not compared such patients with each other and with comparison individuals in neural responsiveness to subtle changes in facial emotion; the ability to process such changes is important for social cognition. To evaluate this, we used a novel, parametrically designed faces paradigm. OBJECTIVE To compare activation in the amygdala and across the brain in BD patients, SMD patients, and healthy volunteers (HVs). DESIGN Case-control study. SETTING Government research institute. PARTICIPANTS Fifty-seven youths (19 BD, 15 SMD, and 23 HVs). MAIN OUTCOME MEASURE Blood oxygenation level-dependent data. Neutral faces were morphed with angry and happy faces in 25% intervals; static facial stimuli appeared for 3000 milliseconds. Participants performed hostility or nonemotional facial feature (ie, nose width) ratings. The slope of blood oxygenation level-dependent activity was calculated across neutral-to-angry and neutral-to-happy facial stimuli. RESULTS In HVs, but not BD or SMD participants, there was a positive association between left amygdala activity and anger on the face. In the neutral-to-happy whole-brain analysis, BD and SMD participants modulated parietal, temporal, and medial-frontal areas differently from each other and from that in HVs; with increasing facial happiness, SMD patients demonstrated increased, and BD patients decreased, activity in the parietal, temporal, and frontal regions. CONCLUSIONS Youth with BD or SMD differ from HVs in modulation of amygdala activity in response to small changes in facial anger displays. In contrast, individuals with BD or SMD show distinct perturbations in regions mediating attention and face processing in association with changes in the emotional intensity of facial happiness displays. These findings demonstrate similarities and differences in the neural correlates of facial emotion processing in BD and SMD, suggesting that these distinct clinical presentations may reflect differing dysfunctions along a mood disorders spectrum.

A developmental study of the neural circuitry mediating motor inhibition in bipolar disorder.

OBJECTIVE: Despite increased interest in the developmental trajectory of the pathophysiology mediating bipolar disorder, few studies have compared adults and youths with bipolar disorder. Deficits in motor inhibition are thought to play an important role in the pathophysiology of the illness across the age spectrum. The authors compared the neural circuitry mediating this process in bipolar youths relative to bipolar adults and in healthy volunteers. METHOD: Participants were pediatric (N=16) and adult (N=23) patients with bipolar disorder and healthy child (N=21) and adult (N=29) volunteers. Functional MRI (fMRI) data were acquired while participants performed the stop-signal task. RESULTS: During failed inhibition, an age group-by-diagnosis interaction manifested in the anterior cingulate cortex, with bipolar youths exhibiting hypoactivation relative to both healthy youths and bipolar adults, and bipolar adults exhibiting hyperactivation relative to healthy adults. During successful inhibition, a main effect of diagnosis emerged in the right nucleus accumbens and the left ventral prefrontal cortex, with bipolar patients in both age groups showing less activation than healthy subjects. CONCLUSIONS: Anterior cingulate cortex dysfunction during failed motor inhibition was observed in both bipolar youths and adults, although the nature of this dysfunction differed between the two groups. Adults and youths with bipolar disorder exhibited similar deficits in activation of the nucleus accumbens and the ventral prefrontal cortex during successful inhibition. Therefore, while subcortical and ventral prefrontal cortex hypoactivation was present in bipolar patients across the lifespan, anterior cingulate cortex dysfunction varied developmentally, with reduced activation in youths and increased activation in adults during failed inhibition. Longitudinal fMRI studies of the developmental trajectory of the neural circuitry mediating motor inhibition in bipolar disorder are warranted.

Striatal dysfunction during failed motor inhibition in children at risk for bipolar disorder.

BACKGROUND: A better understanding of the neural underpinnings of bipolar disorder (BD) can be obtained by examining brain activity in symptom-free individuals at risk for BD. This study examined the neural correlates of motor inhibition in a sample of symptom-free youths at familial risk for BD. METHODS: 19 euthymic youths with BD, 13 asymptomatic youths with a first-degree relative with BD, and 21 healthy comparison children completed the stop signal task in a 3 T scanner. RESULTS: Children at familial risk for BD exhibited increased putamen activation during unsuccessful inhibition that distinguished them from both healthy and BD children. Youths with BD exhibited reduced activation of the right nucleus accumbens during unsuccessful inhibition as compared to the other participant groups. CONCLUSIONS: Striatal activation patterns differ between youths at risk for BD and healthy comparison children during a motor inhibition task.

Amygdala hyperactivation during face emotion processing in unaffected youth at risk for bipolar disorder.

OBJECTIVE: Youth at familial risk for bipolar disorder (BD) show deficits in face emotion processing, but the neural correlates of these deficits have not been examined. This preliminary study tests the hypothesis that, relative to healthy comparison (HC) subjects, both BD subjects and youth at risk for BD (i.e., those with a first-degree BD relative) will demonstrate amygdala hyperactivation when viewing fearful and happy faces. The at-risk youth were unaffected, in that they had no history of mood disorder. METHOD: Amygdala activity was examined in 101 unrelated participants, 8 to 18 years old. Age, gender, and IQ-matched groups included BD (N = 32), unaffected at-risk (N = 13), and HC (N = 56). During functional magnetic resonance imaging, participants attended to emotional and nonemotional aspects of fearful and happy faces. RESULTS: While rating their fear of fearful faces, both BD and unaffected at-risk subjects exhibited amygdala hyperactivity versus HC. There were no between-group differences in amygdala activity in response to happy faces. Post-hoc comparisons revealed that, in at-risk youth, familial risk status (offspring versus sibling), presence of Axis I diagnosis (n = 1 attention-deficit/hyperactivity disorder [ADHD], n = 1 social phobia), and history of medication exposure (n = 1) did not influence imaging findings. CONCLUSIONS: We found amygdala hyperactivation in both unaffected at-risk and BD youth while rating their fear of fearful faces. These pilot data suggest that both face emotion labeling deficits and amygdala hyperactivity during face processing should receive further study as potential BD endophenotypes. Longitudinal studies should test whether amygdala hyperactivity to fearful faces predicts conversion to BD in at-risk youth.