Ellen Leibenluft

Amygdala Hyperactivation During Face Emotion Processing in Unaffected Youth at Risk for Bipolar Disorder

OBJECTIVEnYouth 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.nnnMETHODnAmygdala 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.nnnRESULTSnWhile 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.nnnCONCLUSIONSnWe 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.

Experience-dependent plasticity for attention to threat: Behavioral and neurophysiological evidence in humans

Biased attention to threat represents a key feature of anxiety disorders. This bias is altered by therapeutic or stressful experiences, suggesting that the bias is plastic. Charting on-line behavioral and neurophysiological changes in attention bias may generate insights on the nature of such plasticity. We used an attention-orientation task with threat cues to examine how healthy individuals alter their response over time to such cues. In Experiments 1 through 3, we established that healthy individuals demonstrate an increased attention bias away from threat over time. For Experiment 3, we used functional magnetic resonance imaging to determine the neural bases for this phenomenon. Gradually increasing attention bias away from threat is associated with increased activation in the occipitotemporal cortex. Examination of plasticity of attention bias with individuals at risk for anxiety disorders may reveal how threatening stimuli come to be categorized differently in this population over time.

Neural correlates of cognitive flexibility in children at risk for bipolar disorder

BACKGROUNDnYouth with bipolar disorder (BD) show behavioral and neural deficits in cognitive flexibility; however, whether such deficits exist among youths at risk for BD has not been explored.nnnMETHODSnThe current fMRI study examined the neural basis of cognitive flexibility in BD youth (nxa0=xa028), unaffected youth at risk for BD (AR; nxa0=xa013), and healthy volunteer youth (HV; nxa0=xa021) by comparing brain activation patterns while participants performed the change task. On change trials, subjects must inhibit a prepotent response and execute an alternate one.nnnRESULTSnDuring successful change trials, both BD and AR youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to HV youth. During failed change trials, both BD and AR youth exhibited increased caudate activation relative to HV youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex (ACC) relative to the other two groups.nnnCONCLUSIONSnAbnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself.

Neural recruitment during failed motor inhibition differentiates youths with bipolar disorder and severe mood dysregulation.

Controversy exists about whether non-episodic irritability (operationalized as severe mood dysregulation, SMD) should be considered a developmental presentation of pediatric bipolar disorder (BD). While assessments of brain function may address this controversy, only one fMRI study has compared BD versus SMD. We compared neural activation in BD, SMD, and controls during a motor inhibition task, since motor disinhibition is an important clinical feature in both BD and SMD. During failed inhibition, BD youths exhibited less activation in the right anterior cingulate cortex (ACC) and right nucleus accumbens relative to both SMD and healthy youths. Exploratory analyses indicate that, in BD youths, reduced activation in the right ACC may be independent of comorbid ADHD. These findings highlight neural distinctions between the phenotypically related BD and SMD populations.

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

BACKGROUNDnA 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.nnnMETHODSn19 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.nnnRESULTSnChildren 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.nnnCONCLUSIONSnStriatal activation patterns differ between youths at risk for BD and healthy comparison children during a motor inhibition task.

Neuroimaging studies of pediatric social anxiety: paradigms, pitfalls and a new direction for investigating the neural mechanisms

Social Anxiety Disorder (SAD) is a common and debilitating condition that typically manifests in adolescence. Here we describe cognitive factors engaged by brain-imaging tasks, which model the peer-based social interactions that evoke symptoms of SAD. We then present preliminary results from the Virtual School paradigm, a novel peer-based social interaction task. This paradigm is designed to investigate the neural mechanisms mediating individual differences in social response flexibility and in participants’ responses to uncertainty in social contexts. We discuss the utility of this new paradigm for research on brain function and developmental psychopathology.

Affective Prosody Labeling in Youths with Bipolar Disorder or Severe Mood Dysregulation.

BACKGROUNDnAccurate identification of nonverbal emotional cues is essential to successful social interactions, yet most research is limited to emotional face expression labeling. Little research focuses on the processing of emotional prosody, or tone of verbal speech, in clinical populations.nnnMETHODSnUsing the Diagnostic Analysis of Nonverbal Accuracy, the current study examined whether youths with pediatric-onset bipolar disorder (BD) and/or those with chronic and severe irritability (i.e. the severe mood dysregulation phenotype) are impaired in their ability to identify the emotional prosody of a spoken sentence with neutral content.nnnRESULTSnYouths with severe mood dysregulation (n = 67) performed more poorly than healthy comparison children (n = 57), even when the sample was limited to unmedicated patients. Medicated BD youths (n = 52) exhibited impairment relative to healthy comparison children. No interactions between group and emotion were observed, suggesting that emotional prosody labeling problems may represent a general deficit in chronically irritable youths and in medicated youths with BD.nnnCONCLUSIONnIn concert with previously documented facial emotion labeling deficits, difficulties ascertaining the correct emotional tone of a spoken sentence may contribute to emotion dysregulation in chronically irritable children, and possibly also in youths with BD.

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.