White matter microstructure in youth with and at risk for bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto-limbic pathways. These abnormalities might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation. METHODS: To determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first-degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging. RESULTS: Individuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age-related in-creases in BD compared to REL and HV. Further, individuals with BD and REL showed in-creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation. DISCUSSION: Alterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation-a core characteristic of BD.

Applications of multivariate modeling to neuroimaging group analysis: a comprehensive alternative to univariate general linear model.

All neuroimaging packages can handle group analysis with t-tests or general linear modeling (GLM). However, they are quite hamstrung when there are multiple within-subject factors or when quantitative covariates are involved in the presence of a within-subject factor. In addition, sphericity is typically assumed for the variance-covariance structure when there are more than two levels in a within-subject factor. To overcome such limitations in the traditional AN(C)OVA and GLM, we adopt a multivariate modeling (MVM) approach to analyzing neuroimaging data at the group level with the following advantages: a) there is no limit on the number of factors as long as sample sizes are deemed appropriate; b) quantitative covariates can be analyzed together with within-subject factors; c) when a within-subject factor is involved, three testing methodologies are provided: traditional univariate testing (UVT) with sphericity assumption (UVT-UC) and with correction when the assumption is violated (UVT-SC), and within-subject multivariate testing (MVT-WS); d) to correct for sphericity violation at the voxel level, we propose a hybrid testing (HT) approach that achieves equal or higher power via combining traditional sphericity correction methods (Greenhouse-Geisser and Huynh-Feldt) with MVT-WS. To validate the MVM methodology, we performed simulations to assess the controllability for false positives and power achievement. A real FMRI dataset was analyzed to demonstrate the capability of the MVM approach. The methodology has been implemented into an open source program 3dMVM in AFNI, and all the statistical tests can be performed through symbolic coding with variable names instead of the tedious process of dummy coding. Our data indicates that the severity of sphericity violation varies substantially across brain regions. The differences among various modeling methodologies were addressed through direct comparisons between the MVM approach and some of the GLM implementations in the field, and the following two issues were raised: a) the improper formulation of test statistics in some univariate GLM implementations when a within-subject factor is involved in a data structure with two or more factors, and b) the unjustified presumption of uniform sphericity violation and the practice of estimating the variance-covariance structure through pooling across brain regions.

Cross-sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder.

BACKGROUND: There is debate as to whether chronic irritability (operationalized as severe mood dysregulation, SMD) is a developmental form of bipolar disorder (BD). Although structural brain abnormalities in BD have been demonstrated, no study compares neuroanatomy among SMD, BD, and healthy volunteers (HV) either cross-sectionally or over time. Furthermore, the developmental trajectories of structural abnormalities in BD or SMD are unknown. This study provides such data in BD, SMD, and HV. METHODS: An optimized, modulated voxel-based morphometry (VBM) analysis was conducted on structural MRI scans from 201 children (78 SMD, 55 BD, and 68 HV). In addition, 92 children (31 SMD, 34 BD, and 27 HV) were rescanned after 2 years (mean interval 1.99 ± 0.94 years), to compare time-related changes among the three groups. RESULTS: Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in HV compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with HV and SMD. Longitudinally, group-by-time interactions were evident in two clusters in the superior/inferior parietal lobule (R SPL/IPL) and in the precuneus. In both clusters, the interactions were driven by an abnormal increase in volume in BD. CONCLUSIONS: Cross-sectionally, both BD and SMD are associated with structural abnormalities in frontal cortex, insula, and basal ganglia. Although some of these deficits overlap (insula and DLPFC), others differentiate SMD and BD (pre-SMA and globus pallidus). Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Because of the high proportion of co-occurring ADHD in the SMD subjects, we could not separate effects of ADHD from those of SMD, and future research including a nonirritable ADHD group must address this issue.

Attention control ability, mood state, and emotional regulation ability partially affect executive control of attention on task-irrelevant emotional stimuli.

Executive control of attention is important for goal-directed behavior, and it is influenced by emotional information. This study examined the effect of stimulus valence on a color word flanker task and how individual differences within a general population may affect task performance. 119 participants completed a color word flanker task with task-irrelevant emotional information (positive, negative, neutral). This task was followed by several self-report scales that measured individual differences in attention control ability (ACS), current mood (PANAS), and emotion regulation ability (DERS). Faster reaction times and greater accuracy were associated with negative stimuli. The flanker effect was greater for negative trials than for neutral and positive trials. The greater flanker effect for negative trials was driven by decreased reaction time on negative congruent trials. A significant interaction was evident between stimulus valence and ACS score, such that reaction time was faster for negative trials than for neutral trials among those with low, average, and high ACS. However, this difference was largest for those with high ACS. Further, these relationships between attention control ability and executive control of attention were influenced by level of depressive symptoms (as measured by BDI-II). This study extends our knowledge about the relationship between executive control of attention to emotional stimuli and individual differences related to mood and attentional disorders in a general population. Study results may have important implications for theoretical models of cognitive control and task-irrelevant emotional information across individual differences.

White Matter Microstructure in Pediatric Bipolar Disorder and Disruptive Mood Dysregulation Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD) codifies severe, chronic irritability. Youths with bipolar disorder (BD) also present with irritability, but with an episodic course. To date, it is not clear whether aberrant white matter microstructure-a well-replicated finding in BD-can be observed in DMDD and relates to symptoms of irritability. METHOD: We acquired diffusion tensor imaging data from 118 participants (BD = 36, DMDD = 44, healthy volunteers (HV = 38). Images of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were processed with tract-based spatial statistics controlling for age and sex. The data were also used to train Gaussian process classifiers to predict diagnostic group. RESULTS: In BD vs DMDD, FA in the corticospinal tract was reduced. In DMDD vs HV, reductions in FA and AD were confined to the anterior corpus callosum. In BD vs HV, widespread reductions in FA and increased RD were observed. FA in the anterior corpus callosum and corticospinal tract was negatively associated with irritability. The Gaussian process classifier could not discriminate between BD and DMDD, but achieved 68% accuracy in predicting DMDD vs HV and 75% accuracy in predicting BD vs HV. CONCLUSION: Aberrant white matter microstructure was associated with both categorical diagnosis and the dimension of irritability. Alterations in DMDD were regionally discrete and related to reduced AD. In BD, we observed widespread increases in RD, supporting the hypothesis of altered myelination in BD. These findings will contribute to the pathophysiological understanding of DMDD and its differentiation from BD. CLINICAL TRIAL REGISTRATION INFORMATION: Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder; https://clinicaltrials.gov/; NCT00025935; Child & Adolescent Bipolar Disorder Brain Imaging and Treatment Study; https://clinicaltrials.gov/; NCT00006177.

Behavioral and Neural Sustained Attention Deficits in Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD), characterized by severe irritability, and attention-deficit/hyperactivity disorder (ADHD) are highly comorbid. This is the first study to characterize neural and behavioral similarities and differences in attentional functioning across these disorders. METHOD: Twenty-seven healthy volunteers, 31 patients with DMDD, and 25 patients with ADHD (8 to 18 years old) completed a functional magnetic resonance imaging attention task. Group differences in intra-subject variability in reaction time (RT) were examined. The present functional magnetic resonance imaging analytic approach precisely quantified trial-wise associations between RT and brain activity. RESULTS: Group differences manifested in the relation between RT and brain activity (all regions: p < .01, F > 2.54, partial eta-squared [ηp2] > 0.06). Patients with DMDD showed specific alterations in the right paracentral lobule, superior parietal lobule, fusiform gyrus, and cerebellar culmen. In contrast, patients with DMDD and those with ADHD exhibited blunted compensatory increases in activity on long RT trials. In addition, youth with DMDD exhibited increased activity in the postcentral gyrus, medial frontal gyrus, and cerebellar tonsil and declive (all regions: p < .05, F > 2.46, ηp2 > 0.06). Groups in the imaging sample did not differ significantly in intra-subject variability in RT (F2,79 = 2.664, p = .076, ηp2 = 0.063), although intra-subject variability in RT was significantly increased in youth with DMDD and ADHD when including those not meeting strict motion and accuracy criteria for imaging analysis (F2,96 = 4.283, p = .017, ηp2 = 0.083). CONCLUSION: Patients with DMDD exhibited specific alterations in the relation between pre-stimulus brain activity and RT. Patients with DMDD and those with ADHD exhibited similar blunting of compensatory neural activity in frontal, parietal, and other regions. In addition, patients with DMDD showed increased RT variability compared with healthy youth. This work is the first to identify common and unique behavioral and neural signatures of DMDD and ADHD.

Neural Markers in Pediatric Bipolar Disorder and Familial Risk for Bipolar Disorder.

OBJECTIVE: Bipolar disorder (BD) is highly heritable. Neuroimaging studies comparing unaffected youth at high familial risk for BD (i.e., those with a first-degree relative with the disorder; termed "high-risk" [HR]) to "low-risk" (LR) youth (i.e., those without a first-degree relative with BD) and to patients with BD may help identify potential brain-based markers associated with risk (i.e., regions where HR+BD≠LR), resilience (HR≠BD+LR), or illness (BD≠HR+LR). METHOD: During functional magnetic resonance imaging (fMRI), 99 youths (i.e., adolescents and young adults) aged 9.8 to 24.8 years (36 BD, 22 HR, 41 LR) performed a task probing face emotion labeling, previously shown to be impaired behaviorally in youth with BD and HR youth. RESULTS: We found three patterns of results. Candidate risk endophenotypes (i.e., where BD and HR shared deficits) included dysfunction in higher-order face processing regions (e.g., middle temporal gyrus, dorsolateral prefrontal cortex). Candidate resilience markers and disorder sequelae (where HR and BD, respectively, show unique alterations relative to the other two groups) included different patterns of neural responses across other regions mediating face processing (e.g., fusiform), executive function (e.g., inferior frontal gyrus), and social cognition (e.g., default network, superior temporal sulcus, temporo-parietal junction). CONCLUSION: If replicated in longitudinal studies and with additional populations, neural patterns suggesting risk endophenotypes could be used to identify individuals at risk for BD who may benefit from prevention measures. Moreover, information about risk and resilience markers could be used to develop novel treatments that recruit neural markers of resilience and attenuate neural patterns associated with risk. Clinical trial registration information-Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder and Child and Adolescent Bipolar Disorder Brain Imaging and Treatment Study; http://clinicaltrials.gov/; NCT00025935 and NCT00006177.

Behavioral and Neural Sustained Attention Deficits in Bipolar Disorder and Familial Risk of Bipolar Disorder.

BACKGROUND: Few neuroimaging studies compare individuals affected with bipolar disorder (BP), at high familial risk of BP, and at low risk to identify endophenotypes for BP. None have examined variability in attention, despite promising behavioral work in this area. We used functional magnetic resonance imaging (fMRI) methods uniquely powered to compare the neural correlates of attention variability in these three groups. METHODS: The present study examined 8- to 25-year-old individuals (n = 106) who completed an fMRI attention task: 24 with BP, 29 at risk based on a first-degree relative with BP, and 53 healthy, low-risk individuals. Group differences in intrasubject variability in reaction time were examined, and a sophisticated fMRI analytic approach was used to quantify precisely trialwise associations between reaction time and brain activity. The latter has not been examined previously in BP or risk of BP. RESULTS: Relative to healthy individuals, those with BP or at risk for BP exhibited increased reaction time variability (F2,102 = 4.26, p = .02, ηp2 = .08). Importantly, we identified blunted relationships between trialwise variation in reaction time and brain activity in the inferior and middle frontal gyri, precuneus, cingulate cortex, caudate, and postcentral gyrus (all regions: p < .001, ηp2 > .06) in both at-risk and BP individuals compared with healthy, low-risk individuals. This blunting partially mediated group differences in reaction time variability (ß = .010, 95% confidence interval 0.002 to 0.020, Sobel Z = 2.08, p = .038). CONCLUSIONS: Blunting in key frontal, cingulate, and striatal areas was evident in unaffected, at-risk individuals and in euthymic BP patients. Elucidating such novel neural endophenotypes can facilitate new approaches to BP prediction, diagnosis, and prevention.

Developmental differences in the neural mechanisms of facial emotion labeling.

Adolescence is a time of increased risk for the onset of psychological disorders associated with deficits in face emotion labeling. We used functional magnetic resonance imaging (fMRI) to examine age-related differences in brain activation while adolescents and adults labeled the emotion on fearful, happy and angry faces of varying intensities [0% (i.e. neutral), 50%, 75%, 100%]. Adolescents and adults did not differ on accuracy to label emotions. In the superior temporal sulcus, ventrolateral prefrontal cortex and middle temporal gyrus, adults show an inverted-U-shaped response to increasing intensities of fearful faces and a U-shaped response to increasing intensities of happy faces, whereas adolescents show the opposite patterns. In addition, adults, but not adolescents, show greater inferior occipital gyrus activation to negative (angry, fearful) vs positive (happy) emotions. In sum, when subjects classify subtly varying facial emotions, developmental differences manifest in several 'ventral stream' brain regions. Charting the typical developmental course of the brain mechanisms of socioemotional processes, such as facial emotion labeling, is an important focus for developmental psychopathology research.

Neural Correlates of Irritability in Disruptive Mood Dysregulation and Bipolar Disorders.

OBJECTIVE: Bipolar disorder and disruptive mood dysregulation disorder (DMDD) are clinically and pathophysiologically distinct, yet irritability can be a clinical feature of both illnesses. The authors examine whether the neural mechanisms mediating irritability differ between bipolar disorder and DMDD, using a face emotion labeling paradigm because such labeling is deficient in both patient groups. The authors hypothesized that during face emotion labeling, irritability would be associated with dysfunctional activation in the amygdala and other temporal and prefrontal regions in both disorders, but that the nature of these associations would differ between DMDD and bipolar disorder. METHOD: During functional MRI acquisition, 71 youths (25 with DMDD, 24 with bipolar disorder, and 22 healthy youths) performed a labeling task with happy, fearful, and angry faces of varying emotional intensity. RESULTS: Participants with DMDD and bipolar disorder showed similar levels of irritability and did not differ from each other or from healthy youths in face emotion labeling accuracy. Irritability correlated with amygdala activity across all intensities for all emotions in the DMDD group; such correlation was present in the bipolar disorder group only for fearful faces. In the ventral visual stream, associations between neural activity and irritability were found more consistently in the DMDD group than in the bipolar disorder group, especially in response to ambiguous angry faces. CONCLUSIONS: These results suggest diagnostic specificity in the neural correlates of irritability, a symptom of both DMDD and bipolar disorder. Such evidence of distinct neural correlates suggests the need to evaluate different approaches to treating irritability in the two disorders.

Age-related differences in the neural correlates of trial-to-trial variations of reaction time.

Intra-subject variation in reaction time (ISVRT) is a developmentally-important phenomenon that decreases from childhood through young adulthood in parallel with the development of executive functions and networks. Prior work has shown a significant association between trial-by-trial variations in reaction time (RT) and trial-by-trial variations in brain activity as measured by the blood-oxygenated level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI) studies. It remains unclear, however, whether such "RT-BOLD" relationships vary with age. Here, we determined whether such trial-by-trial relationships vary with age in a cross-sectional design. We observed an association between age and RT-BOLD relationships in 11 clusters located in visual/occipital regions, frontal and parietal association cortex, precentral/postcentral gyrus, and thalamus. Some of these relationships were negative, reflecting increased BOLD associated with decreased RT, manifesting around the time of stimulus presentation and positive several seconds later. Critically for present purposes, all RT-BOLD relationships increased with age. Thus, RT-BOLD relationships may reflect robust, measurable changes in the brain-behavior relationship across development.

Comparing Brain Morphometry Across Multiple Childhood Psychiatric Disorders.

OBJECTIVE: In both children and adults, psychiatric illness is associated with structural brain alterations, particularly in the prefrontal cortex (PFC). However, most studies compare gray matter volume (GMV) in healthy volunteers (HVs) to one psychiatric group. We compared GMV among youth with anxiety disorders, bipolar disorder (BD), disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), and HVs. METHOD: 3-Tesla T1-weighted magnetic resonance imaging scans were acquired in 184 youths (39 anxious, 20 BD, 52 DMDD, 20 ADHD, and 53 HV). Voxel-based morphometry analyses were conducted. One-way analysis of variance tested GMV differences with whole-brain familywise error (p < .05) correction; secondary, exploratory whole-brain analyses used a threshold of p < .001, ≥200 voxels. Given recent frameworks advocating dimensional approaches in psychopathology research, we also tested GMV associations with continuous anxiety, irritability, and inattention symptoms. RESULTS: Specificity emerged in the left dorsolateral PFC (dlPFC), which differed among youth with BD, anxiety, and HVs; GMV was increased in youth with anxiety, but decreased in BD, relative to HVs. Secondary analyses revealed BD-specific GMV decreases in the right lateral PFC, right dlPFC, and dorsomedial PFC, and also anxiety-specific GMV increases in the left dlPFC, right ventrolateral PFC, frontal pole, and right parahippocampal gyrus/lingual gyrus. Both BD and DMDD showed decreased GMV relative to HVs in the right dlPFC/superior frontal gyrus. GMV was not associated with dimensional measures of anxiety, irritability, or ADHD symptoms. CONCLUSION: Both disorder-specific and shared GMV differences manifest in pediatric psychopathology. Some differences were specific to anxiety disorders, others specific to BD, and others shared between BD and DMDD. Further developmental research might map commonalities and differences of structure and function in diverse pediatric psychopathologies.

Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation.

BACKGROUND: The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder. OBJECTIVES: To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD. DESIGN: We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures. SETTING: An academic referral setting, drawing from the Bay Area of San Francisco, Calif. RESULTS: Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation. CONCLUSIONS: Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed.

Detecting the subtle shape differences in hemodynamic responses at the group level.

The nature of the hemodynamic response (HDR) is still not fully understood due to the multifaceted processes involved. Aside from the overall amplitude, the response may vary across cognitive states, tasks, brain regions, and subjects with respect to characteristics such as rise and fall speed, peak duration, undershoot shape, and overall duration. Here we demonstrate that the fixed-shape (FSM) or adjusted-shape (ASM) methods may fail to detect some shape subtleties (e.g., speed of rise or recovery, or undershoot). In contrast, the estimated-shape method (ESM) through multiple basis functions can provide the opportunity to identify some subtle shape differences and achieve higher statistical power at both individual and group levels. Previously, some dimension reduction approaches focused on the peak magnitude, or made inferences based on the area under the curve (AUC) or interaction, which can lead to potential misidentifications. By adopting a generic framework of multivariate modeling (MVM), we showcase a hybrid approach that is validated by simulations and real data. With the whole HDR shape integrity maintained as input at the group level, the approach allows the investigator to substantiate these more nuanced effects through the unique HDR shape features. Unlike the few analyses that were limited to main effect, two- or three-way interactions, we extend the modeling approach to an inclusive platform that is more adaptable than the conventional GLM. With multiple effect estimates from ESM for each condition, linear mixed-effects (LME) modeling should be used at the group level when there is only one group of subjects without any other explanatory variables. Under other situations, an approximate approach through dimension reduction within the MVM framework can be adopted to achieve a practical equipoise among representation, false positive control, statistical power, and modeling flexibility. The associated program 3dMVM is publicly available as part of the AFNI suite.

Characterization of children of bipolar parents by parent report CBCL.

In past research the Child Behavior Checklist (CBCL) has differentiated among various diagnostic categories for children and adolescents. However, research has not been conducted on whether the CBCL differentiates among diagnostic categories for children at high risk for development of psychopathology. This study compares four diagnostic groups [bipolar disorder (BD), attention/deficit-hyperactivity disorder (ADHD), Depressed/Anxious and No Diagnosis] within a cohort of 58 children of bipolar parents to determine whether their CBCL scores will replicate the scores of children not at high risk for bipolar disorder. The cohort of children of bipolar parents received elevated scores on the CBCL scales in comparison with non-clinical populations. In addition, the CBCL distinguished between children of bipolar parents with and without clinical disorders. Finally the BD group differed from the ADHD group only on the Aggressive Behaviors, Withdrawn and Anxious/Depressed subscales of the CBCL. Therefore the CBCL did not discriminate between the BD and ADHD groups as it had in previous studies of children with BD and unspecified family history. It is possible that this discrepancy is due to a group of children of bipolar parents with ADHD who are currently prodromal for bipolar disorder and therefore received higher scores on the CBCL based on prodromal symptomatology. A longitudinal follow-up of this cohort is necessary to ascertain whether this is the case.

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.

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.

Prospective neurochemical characterization of child offspring of parents with bipolar disorder.

We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

Abnormal fusiform activation during emotional-face encoding assessed with functional magnetic resonance imaging.

This functional magnetic resonance imaging study shows that children and adults with bipolar disorder (BD), compared with healthy subjects, 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.

Elevated amygdala responses to emotional faces in youths with chronic irritability or bipolar disorder.

A major controversy in child psychiatry is whether bipolar disorder (BD) presents in children as severe, non-episodic irritability (operationalized here as severe mood dysregulation, SMD), rather than with manic episodes as in adults. Both classic, episodic BD and SMD are severe mood disorders characterized by deficits in processing emotional stimuli. Neuroimaging techniques can be used to test whether the pathophysiology mediating these deficits are similar across the two phenotypes. Amygdala dysfunction during face emotion processing is well-documented in BD, but little is known about amygdala dysfunction in chronically irritable youth. We compared neural activation in SMD (n=19), BD (n=19), and healthy volunteer (HV; n=15) youths during an implicit face-emotion processing task with angry, fearful and neutral expressions. In the right amygdala, both SMD and BD exhibited greater activity across all expressions than HV. However, SMD and BD differed from each other and HV in posterior cingulate cortex, posterior insula, and inferior parietal lobe. In these regions, only SMD showed deactivation in response to fearful expressions, whereas only BD showed deactivation in response to angry expressions. Thus, during implicit face emotion processing, youth with BD and those with SMD exhibit similar amygdala dysfunction but different abnormalities in regions involved in information monitoring and integration.