Ventrolateral Prefrontal Activation Research Articles

Neurobehavioral Reward and Sleep-Circadian Profiles Predict Present and Next-Year Mania/Hypomania Symptoms

BackgroundHeightened reward sensitivity/impulsivity, related neural activity, and sleep-circadian disruption are important risk factors for bipolar spectrum disorders, the defining feature of which is mania/hypomania. Our goal was to identify neurobehavioral profiles based on reward and sleep-circadian features and examine their specificity to mania/hypomania versus depression vulnerability. MethodsAt baseline, a transdiagnostic sample of 324 adults (18–25 years) completed trait measures of reward sensitivity (Behavioral Activation Scale), impulsivity (UPPS-P-Negative Urgency), and a functional magnetic resonance imaging card-guessing reward task (left ventrolateral prefrontal activity to reward expectancy, a neural correlate of reward motivation and impulsivity, was extracted). At baseline, 6-month follow-up, and 12-month follow-up, the Mood Spectrum Self-Report Measure – Lifetime Version assessed lifetime predisposition to subthreshold-syndromal mania/hypomania, depression, and sleep-circadian disturbances (insomnia, sleepiness, reduced sleep need, rhythm disruption). Mixture models derived profiles from baseline reward, impulsivity, and sleep-circadian variables. ResultsThree profiles were identified: 1) healthy (no reward or sleep-circadian disruption; n = 162); 2) moderate-risk (moderate reward and sleep-circadian disruption; n = 109); and 3) high-risk (high impulsivity and sleep-circadian disruption; n = 53). At baseline, the high-risk group had significantly higher mania/hypomania scores than the other groups but did not differ from the moderate-risk group in depression scores. Over the follow-up period, the high-risk and moderate-risk groups exhibited elevated mania/hypomania scores, whereas depression scores increased at a faster rate in the healthy group than in the other groups. ConclusionsCross-sectional and next-year predisposition to mania/hypomania is associated with a combination of heightened reward sensitivity and impulsivity, related reward circuitry activity, and sleep-circadian disturbances. These measures can be used to detect mania/hypomania risk and provide targets to guide and monitor interventions.

Left ventrolateral prefrontal cortical activity during reward expectancy predicts mania risk up to one year post scan

IntroductionIdentification of neural markers associated with risk for manic symptoms is an important challenge for neuropsychiatric research. Previous work has highlighted the association between predisposition for mania/hypomania and elevated reward sensitivity. Elevated activity in the left ventrolateral prefrontal cortex (L vlPFC) during reward expectancy (RE) is associated with measures predictive of risk for manic/hypomanic symptoms. However, no studies have examined this relationship longitudinally. The goal of this study was to identify a neural marker associated with longitudinal risk for manic/hypomanic symptoms. MethodsWe used a card guessing functional magnetic resonance imaging (fMRI) paradigm to examine RE-related L vlPFC activity. One hundred and three young adults who were either healthy or experiencing psychological distress completed a single baseline fMRI scan and self-report measures of manic/hypomanic symptoms. Self-report measures were repeated up to two follow up visits over one year. ResultsWe identified a significant positive relationship between baseline RE-related L vlPFC activity and MOODS Manic Domain scores up to one-year post scan. This relationship was specific to manic symptoms and was not present for MOODS depression-related domains. LimitationsThis study was not designed to predict conversion to bipolar disorder, but rather the more proximal construct of lifetime risk for mania/hypomania. ConclusionsRE-related L vlPFC activity may serve as an important marker of risk for future manic/hypomanic symptoms and may also be a potential target for intervention.

Neural Subtypes of Euthymic Bipolar I Disorder Characterized by Emotion Regulation Circuitry

BackgroundCurrent diagnostic strategy for bipolar disorders relies on symptomological classification. Yet, responses to both pharmacological and psychotherapeutic treatments vary widely, suggesting that underlying neuropathological differences are not well defined by current nosology. Classifying patients with bipolar disorder based on emotion regulation network (ERN) activation may account for some of the heterogeneity within the disorder. MethodsEuthymic participants diagnosed with bipolar I disorder (n = 86) and healthy subjects (n = 80) underwent functional magnetic resonance imaging scans while engaged in emotional reappraisal of negative stimuli. After determining average regional activations in key network regions, we applied agglomerative hierarchical clustering to identify subtypes of bipolar disorder. Next, we examined relations among neural subtypes, demographic variables, and mood symptoms. ResultsAnalyses revealed two primary neural subtypes of euthymic bipolar I disorder participants. The first subtype, ERN cluster 1, was characterized by increased amygdala activation and slightly increased ventrolateral prefrontal and subgenual cingulate activation, whereas ERN cluster 2 was defined by decreased amygdala activation with wider-spread prefrontal activation. Cluster 1 was associated with a higher number of hospitalizations for depression (odds ratio = 1.30, 95% confidence interval = 1.02–1.64) and later onset of manic episodes (odds ratio = 1.06, 95% confidence interval = 1.00–21.13) than cluster 2. ERN clusters of healthy subjects differed from bipolar disorder clusters and were defined by differential activation of the prefrontal cortex. ERN clusters of healthy subjects, which differed from bipolar disorder clusters, were defined by differential activation of the prefrontal cortex. ConclusionsEmotion regulation circuitry can distinguish neurobiological subtypes of bipolar disorder in the euthymic state. These subtypes, which are differentially associated with indices of illness severity and subsyndromal affective symptoms, may help to inform relapse risk and more personalized treatment approaches.

Practice-induced functional plasticity in inhibitory control interacts with aging

Inhibitory control deficits represent a key aspect of the cognitive declines associated with aging. Practicing inhibitory control has thus been advanced as a potential approach to compensate for age-induced neurocognitive impairments. Yet, the functional brain changes associated with practicing inhibitory control tasks in older adults and whether they differ from those observed in young populations remains unresolved.We compared electrical neuroimaging analyses of ERPs recorded during a Go/NoGo practice session with a Group (Young; Older adults) by Session (Beginning; End of the practice) design to identify whether the practice of an inhibition task in older adults reinforces already implemented compensatory activity or reduce it by enhancing the functioning of the brain networks primarily involved in the tasks.We observed an equivalent small effect of practice on performance in the two age-groups. The topographic ERP analyses and source estimations revealed qualitatively different effects of the practice over the N2 and P3 ERP components, respectively driven by a decrease in supplementary motor area activity and an increase in left ventrolateral prefrontal activity in the older but not in the young adults with practice.Our results thus indicate that inhibition task practice in older adults increases age-related divergences in the underlying functional processes.

Modulation of inhibitory control by prefrontal anodal tDCS: A crossover double-blind sham-controlled fMRI study.

Prefrontal anodal transcranial direct current stimulation (tDCS) has been proposed as a potential approach to improve inhibitory control performance. The functional consequences of tDCS during inhibition tasks remain, however, largely unresolved. We addressed this question by analyzing functional magnetic resonance imaging (fMRI) recorded while participants completed a Go/NoGo task after right-lateralized prefrontal anodal tDCS with a crossover, sham-controlled, double-blind experimental design. We replicated previous evidence for an absence of offline effect of anodal stimulation on Go/NoGo performance. The fMRI results revealed a larger increase in right ventrolateral prefrontal activity for Go than NoGo trials in the anodal than sham condition. This pattern suggests that tDCS-induced increases in cortical excitability have larger effects on fMRI activity in regions with a lower task-related engagement. This was the case for the right prefrontal cortex in the Go condition in our task because while reactive inhibition was not engaged during execution trials, the unpredictability of the demand for inhibitory control still incited an engagement of proactive inhibition. Exploratory analyses further revealed that right prefrontal stimulation interacted with task-related functional demands in the supplementary motor area and the thalamus. Our collective results emphasize the dependency of offline tDCS functional effects on the task-related engagement of the stimulated areas and suggest that this factor might partly account for the discrepancies in the functional effects of tDCS observed in previous studies.

Decreased Prefrontal Activation during Matrix Reasoning in Predementia Progranulin Mutation Carriers.

We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix-reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation.

Anger provocation in violent offenders leads to emotion dysregulation

Anger and anger regulation problems that result in aggressive behaviour pose a serious problem for society. In this study we investigated differences in brain responses during anger provocation or anger engagement, as well as anger regulation or distraction from anger, and compared 16 male violent offenders to 18 non-offender controls. During an fMRI adapted provocation and regulation task participants were presented with angry, happy and neutral scenarios. Prior research on violent offenders indicates that a combination of increased limbic activity (involved in emotion), along with decreased prefrontal activity (involved in emotion regulation), is associated with reactive aggression. We found increased ventrolateral prefrontal activity during anger engagement in violent offenders, while decreased dorsolateral and ventrolateral prefrontal activity was found during anger distraction. This activity pattern was specific for anger. We found no exclusive pattern for happiness. In violent offenders, this suggests an increased need to regulate specifically during anger engagement and regulation difficulties when explicitly instructed to distract. The constant effort required for violent offenders to regulate anger might exhaust the necessary cognitive resources, resulting in a risk for self-control failure. Consequently, continuous provocation might ultimately contribute to reactive aggression.

A pathway linking reward circuitry, impulsive sensation-seeking and risky decision-making in young adults: identifying neural markers for new interventions

High trait impulsive sensation seeking (ISS) is common in 18–25-year olds, and is associated with risky decision-making and deleterious outcomes. We examined relationships among: activity in reward regions previously associated with ISS during an ISS-relevant context, uncertain reward expectancy (RE), using fMRI; ISS impulsivity and sensation-seeking subcomponents; and risky decision-making in 100, transdiagnostically recruited 18–25-year olds. ISS, anhedonia, anxiety, depression and mania were measured using self-report scales; clinician-administered scales also assessed the latter four. A post-scan risky decision-making task measured ‘risky’ (possible win/loss/mixed/neutral) fMRI-task versus ‘sure thing’ stimuli. ‘Bias’ reflected risky over safe choices. Uncertain RE-related activity in left ventrolateral prefrontal cortex and bilateral ventral striatum was positively associated with an ISS composite score, comprising impulsivity and sensation-seeking–fun-seeking subcomponents (ISSc; P⩽0.001). Bias positively associated with sensation seeking–experience seeking (ES; P=0.003). This relationship was moderated by ISSc (P=0.009): it was evident only in high ISSc individuals. Whole-brain analyses showed a positive relationship between: uncertain RE-related left ventrolateral prefrontal cortical activity and ISSc; uncertain RE-related visual attention and motor preparation neural network activity and ES; and uncertain RE-related dorsal anterior cingulate cortical activity and bias, specifically in high ISSc participants (all ps<0.05, peak-level, family-wise error corrected). We identify an indirect pathway linking greater levels of uncertain RE-related activity in reward, visual attention and motor networks with greater risky decision-making, via positive relationships with impulsivity, fun seeking and ES. These objective neural markers of high ISS can guide new treatment developments for young adults with high levels of this debilitating personality trait.

Longitudinal Relationships Among Activity in Attention Redirection Neural Circuitry and Symptom Severity in Youth

BackgroundChanges in neural circuitry function may be associated with longitudinal changes in psychiatric symptom severity. Identification of these relationships may aid in elucidating the neural basis of psychiatric symptom evolution over time. We aimed to distinguish these relationships using data from the Longitudinal Assessment of Manic Symptoms cohort. MethodsForty-one youth completed two study visits (interscan mean = 21.3 months). Elastic net regression (multiple-response Gaussian family) identified emotional regulation neural circuitry that changed in association with changes in depression, mania, anxiety, affect lability, and positive mood and energy dysregulation, accounting for clinical and demographic variables. ResultsNonzero coefficients between change in the previously mentioned symptom measures and change in activity over the interscan interval were identified in right amygdala and left ventrolateral prefrontal cortex. Differing patterns of neural activity change were associated with changes in each of the previously mentioned symptoms over time. Specifically, from scan 1 to scan 2, worsening affective lability and depression severity were associated with increased right amygdala and left ventrolateral prefrontal cortical activity. Worsening anxiety and positive mood and energy dysregulation were associated with decreased right amygdala and increased left ventrolateral prefrontal cortical activity. Worsening mania was associated with increased right amygdala and decreased left ventrolateral prefrontal cortical activity. These changes in neural activity between scans accounted for 13.6% of the variance; that is, 25% of the total explained variance (39.6%) in these measures. ConclusionsDistinct neural mechanisms underlie changes in different mood and anxiety symptoms over time.

Distinct frontal and amygdala correlates of change detection for facial identity and expression.

Recruitment of ‘top-down’ frontal attentional mechanisms is held to support detection of changes in task-relevant stimuli. Fluctuations in intrinsic frontal activity have been shown to impact task performance more generally. Meanwhile, the amygdala has been implicated in ‘bottom-up’ attentional capture by threat. Here, 22 adult human participants took part in a functional magnetic resonance change detection study aimed at investigating the correlates of successful (vs failed) detection of changes in facial identity vs expression. For identity changes, we expected prefrontal recruitment to differentiate ‘hit’ from ‘miss’ trials, in line with previous reports. Meanwhile, we postulated that a different mechanism would support detection of emotionally salient changes. Specifically, elevated amygdala activation was predicted to be associated with successful detection of threat-related changes in expression, over-riding the influence of fluctuations in top-down attention. Our findings revealed that fusiform activity tracked change detection across conditions. Ventrolateral prefrontal cortical activity was uniquely linked to detection of changes in identity not expression, and amygdala activity to detection of changes from neutral to fearful expressions. These results are consistent with distinct mechanisms supporting detection of changes in face identity vs expression, the former potentially reflecting top-down attention, the latter bottom-up attentional capture by stimulus emotional salience.

Cognitive vulnerability and implicit emotional processing: imbalance in frontolimbic brain areas?

It has been proposed that the neural basis for cognitive vulnerability to depression involves an imbalance in frontolimbic activity during the processing of cues with a negative affective value. Although the question is central to cognitive theory, whether this association is amplified by diagnosis of an affective disorder or recent life stress has not been investigated. A composite cognitive vulnerability score based on questionnaire assessment was used to predict neural responses to negative emotional stimuli in N = 112 participants. Potential moderating effects of psychiatric diagnosis and negative life events were examined. Main and interaction effects were tested against a threshold of p < .05, family-wise error (FWE) corrected at the cluster level, and the results were small-volume corrected in regions of interest. Cognitive vulnerability predicted higher activation of superior parietal areas (p(FWE) < .01) for negative than for positive faces. The association was significantly stronger in healthy participants. For negative versus control stimuli, cognitive vulnerability predicted higher ventrolateral prefrontal and subgenual anterior cingulate activation (p(FWE) < .05) to equal extents in both groups. We found no evidence for an association with amygdala activation. Life events did not moderate the findings. We concluded that cognitive vulnerability was associated with higher activation of frontoparietal areas during an implicit emotional task. These higher levels of activation may potentially reflect increased effort being required to ignore irrelevant negative emotional information in vulnerable populations.

Prefrontal activation during inhibitory control measured by near-infrared spectroscopy for differentiating between autism spectrum disorders and attention deficit hyperactivity disorder in adults

The differential diagnosis of autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) based solely on symptomatic and behavioral assessments can be difficult, even for experts. Thus, the development of a neuroimaging marker that differentiates ASDs from ADHD would be an important contribution to this field. We assessed the differences in prefrontal activation between adults with ASDs and ADHD using an entirely non-invasive and portable neuroimaging tool, near-infrared spectroscopy. This study included 21 drug-naïve adults with ASDs, 19 drug-naïve adults with ADHD, and 21 healthy subjects matched for age, sex, and IQ. Oxygenated hemoglobin concentration changes in the prefrontal cortex were assessed during a stop signal task and a verbal fluency task. During the stop signal task, compared to the control group, the ASDs group exhibited lower activation in a broad prefrontal area, whereas the ADHD group showed underactivation of the right premotor area, right presupplementary motor area, and bilateral dorsolateral prefrontal cortices. Significant differences were observed in the left ventrolateral prefrontal cortex between the ASDs and ADHD groups during the stop signal task. The leave-one-out cross-validation method using mean oxygenated hemoglobin changes yielded a classification accuracy of 81.4% during inhibitory control. These results were task specific, as the brain activation pattern observed during the verbal fluency task did not differentiate the ASDs and ADHD groups significantly. This study therefore provides evidence of a difference in left ventrolateral prefrontal activation during inhibitory control between adults with ASDs and ADHD. Thus, near-infrared spectroscopy may be useful as an auxiliary tool for the differential diagnosis of such developmental disorders.

Emotion-related brain activity to conflicting socio-emotional cues in unmedicated depression

BackgroundAbnormalities in amygdala function have been implicated in major depression. However, results are inconsistent, and little is known about how the depressed brain encodes conflicting social signals. We sought to determine how the task relevance of socio-emotional cues impacts neural encoding of emotion in depression. MethodsEighteen medication-free depressed patients and 18 matched controls participated in an FMRI experiment. Whole-brain analyses and a region-of-interest approach was used to measure amygdala activity during the presentation of fearful, happy, or neutral target faces with congruent, incongruent, or neutral distracters. ResultsGreater amygdala activity to target fearful faces was associated with depression, as was attenuated amygdala activity to target and peripheral happy faces. Although no group differences emerged in the amygdala to unattended fearful faces, we observed reduced ventrolateral and dorsomedial prefrontal activity in depressed individuals during this condition. LimitationsNine patients had a history of anti-depressant use, though they were unmedicated for at least three months at testing. ConclusionsDepression was associated with reduced amygdala reactivity to positive social stimuli. However, enhanced amygdala responsiveness to negative emotional cues was only observed to target (attended) expressions. The results highlight the need to further determine factors that affect emotional reactivity in depression.

Neural Basis of Impaired Cognitive Flexibility in Patients with Anorexia Nervosa

BackgroundImpaired cognitive flexibility in anorexia nervosa (AN) causes clinical problems and makes the disease hard to treat, but its neural basis has yet to be fully elucidated. The purpose of this study was to evaluate the brain activity of individuals with AN while performing a task requiring cognitive flexibility on the Wisconsin Card Sorting Test (WCST), which is one of the most frequently used neurocognitive measures of cognitive flexibility and problem-solving ability.MethodsParticipants were 15 female AN patients and 15 age- and intelligence quotient-matched healthy control women. Participants completed the WCST while their brain activity was measured by functional magnetic resonance imaging during the task. Brain activation in response to set shifting error feedback and the correlation between such brain activity and set shifting performance were analyzed.ResultsThe correct rate on the WCST was significantly poorer for AN patients than for controls. Patients showed poorer activity in the right ventrolateral prefrontal cortex and bilateral parahippocampal cortex on set shifting than controls. Controls showed a positive correlation between correct rate and ventrolateral prefrontal activity in response to set shifting whereas patients did not.ConclusionThese findings suggest dysfunction of the ventrolateral prefrontal cortex and parahippocampal cortex as a cause of impaired cognitive flexibility in AN patients.

Anticipatory Regulation of Action Control in a Simon Task: Behavioral, Electrophysiological, and fMRI Correlates

With the present study we investigated cue-induced preparation in a Simon task and measured electroencephalogram and functional magnetic resonance imaging (fMRI) data in two within-subjects sessions. Cues informed either about the upcoming (1) spatial stimulus-response compatibility (rule cues), or (2) the stimulus location (position cues), or (3) were non-informative. Only rule cues allowed anticipating the upcoming compatibility condition. Position cues allowed anticipation of the upcoming location of the Simon stimulus but not its compatibility condition. Rule cues elicited fastest and most accurate performance for both compatible and incompatible trials. The contingent negative variation (CNV) in the event-related potential (ERP) of the cue-target interval is an index of anticipatory preparation and was magnified after rule cues. The N2 in the post-target ERP as a measure of online action control was reduced in Simon trials after rule cues. Although compatible trials were faster than incompatible trials in all cue conditions only non-informative cues revealed a compatibility effect in additional indicators of Simon task conflict like accuracy and the N2. We thus conclude that rule cues induced anticipatory re-coding of the Simon task that did not involve cognitive conflict anymore. fMRI revealed that rule cues yielded more activation of the left rostral, dorsal, and ventral prefrontal cortex as well as the pre-SMA as compared to POS and NON-cues. Pre-SMA and ventrolateral prefrontal activation after rule cues correlated with the effective use of rule cues in behavioral performance. Position cues induced a smaller CNV effect and exhibited less prefrontal and pre-SMA contributions in fMRI. Our data point to the importance to disentangle different anticipatory adjustments that might also include the prevention of upcoming conflict via task re-coding.

Shared and Drug-Specific Effects of Atomoxetine and Methylphenidate on Inhibitory Brain Dysfunction in Medication-Naive ADHD Boys

The stimulant methylphenidate (MPX) and the nonstimulant atomoxetine (ATX) are the most commonly prescribed medications for attention deficit hyperactivity disorder (ADHD). However, no functional magnetic resonance imaging (fMRI) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX. A randomized, double-blind, placebo-controlled, crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX, ATX, and placebo during a stop task, combined with fMRI within 19 medication-naive ADHD boys, and their potential normalization effects relative to 29 age-matched healthy boys. Compared with controls, ADHD boys under placebo showed bilateral ventrolateral prefrontal, middle temporal, and cerebellar underactivation. Within patients, MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation, which correlated with enhanced inhibitory capacity. Relative to controls, both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo, while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX. The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX.

Neural responses to advantageous and disadvantageous inequity

In this paper we study neural responses to inequitable distributions of rewards despite equal performance. We specifically focus on differences between advantageous inequity (AI) and disadvantageous inequity (DI). AI and DI were realized in a hyperscanning functional magnetic resonance imaging (fMRI) experiment with pairs of subjects simultaneously performing a task in adjacent scanners and observing both subjects' rewards. Results showed (1) hypoactivation of the ventral striatum (VS) under DI but not under AI; (2) inequity induced activation of the right dorsolateral prefrontal cortex (DLPFC) that was stronger under DI than under AI; (3) correlations between subjective evaluations of AI evaluation and bilateral ventrolateral prefrontal and left insular activity. Our study provides neurophysiological evidence for different cognitive processes that occur when exposed to DI and AI, respectively. One possible interpretation is that any form of inequity represents a norm violation, but that important differences between AI and DI emerge from an asymmetric involvement of status concerns.

Reduced Specificity of Hippocampal and Posterior Ventrolateral Prefrontal Activity during Relational Retrieval in Normal Aging

Neuroimaging studies of episodic memory in young adults demonstrate greater functional neural activity in ventrolateral pFC and hippocampus during retrieval of relational information as compared with item information. We tested the hypothesis that healthy older adults--individuals who exhibit behavioral declines in relational memory--would show reduced specificity of ventrolateral prefrontal and hippocampal regions during relational retrieval. At study, participants viewed two nouns and were instructed to covertly generate a sentence that related the words. At retrieval, fMRIs were acquired during item and relational memory tasks. In the relational task, participants indicated whether the two words were previously seen together. In the item task, participants indicated whether both items of a pair were previously seen. In young adults, left posterior ventrolateral pFC and bilateral hippocampal activity was modulated by the extent to which the retrieval task elicited relational processing. In older adults, activity in these regions was equivalent for item and relational memory conditions, suggesting a reduction in ventrolateral pFC and hippocampal specificity with normal aging.

Reduced Specificity of Hippocampal and Posterior Ventrolateral Prefrontal Activity during Relational Retrieval in Normal Aging

Reduced Specificity of Hippocampal and Posterior Ventrolateral Prefrontal Activity during Relational Retrieval in Normal Aging

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

BackgroundYouth 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. MethodsThe current fMRI study examined the neural basis of cognitive flexibility in BD youth (n = 28), unaffected youth at risk for BD (AR; n = 13), and healthy volunteer youth (HV; n = 21) 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. ResultsDuring 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. ConclusionsAbnormal 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.