A Preliminary Study on the Functional Benefits of Computerized Working Memory Training in Children With Pediatric Bipolar Disorder and Attention Deficit Hyperactivity Disorder.

Twenty-nine pediatric patients (age range, 10-16 years) with working memory (WM) deficits, including children with pediatric bipolar disorder (PBD) with and without attention-deficit hyperactivity disorder (ADHD) comorbidity and children with ADHD, underwent a Cogmed WM training program. For both patient groups, WM performance on Cogmed tasks and on the Digit Span test improved significantly after training. Moreover, the PBD group improved on Trails Making Test A and on the Inhibition Scale, the Behavior Regulation Index, and the Global Executive Composite of the Behavioral Rating Inventory of Executive Function. The ADHD group improved significantly on the Trails Making Test B, the Spatial Span Test, and the Reading Fluency Test of the Woodcock-Johnson III, as well as on depressive symptoms. The present findings suggest that working memory training is beneficial not only in youths with ADHD but also in youths with PBD. They also show evidence of near and far transfer of WM improvement in these patients, although in different ways for the two patient groups. Future studies examining the mechanisms of cognitive remediation in pediatric patients will aid in creating tailored illness-specific cognitive interventions.

Predictors of Attrition in Longitudinal Neuroimaging Research: Inhibitory Control, Head Movement, and Resting-State Functional Connectivity.

Attrition is a major problem in longitudinal neuroimaging studies, as it may lead to unreliable estimates of the stability of trait-like processes over time, of the identification of risk factors for clinical outcomes, and of the effects of treatment. Identification of characteristics associated with attrition has implications for participant recruitment and participant retention to achieve representative longitudinal samples. We investigated inhibitory control deficits, head motion, and resting-state functional connectivity within the cognitive control network (CCN) as predictors of attrition. Ninety-seven individuals with remitted major depressive disorder or healthy controls completed a functional magnetic resonance imaging scan, which included a go/no-go task and resting-state functional connectivity. Approximately 2 months later, participants were contacted and invited to return for a second scan. Seventeen individuals were lost to follow-up or declined to participate in the follow-up scan. Worse inhibitory control was correlated with greater movement within the scanner, and each predicted a greater likelihood of attrition, with movement mediating the effects of inhibitory control on attrition. Individuals who dropped out of the study exhibited greater movement than nondropouts across 9 of the 14 runs of the scan, with medium-to-large effect sizes. Finally, exploratory analyses suggested that attenuated resting-state connectivity with the CCN (particularly in bilateral dorsolateral prefrontal cortex) was associated with greater likelihood of attrition after accounting for head motion at several levels of analysis. Inhibitory control and movement within the scanner are associated with attrition, and should be considered for strategic oversampling and participant retention strategies to ensure generalizability of results in longitudinal studies.

Cognitive control neuroimaging measures differentiate between those with and without future recurrence of depression.

BACKGROUND: Major Depressive Disorder (MDD) is a prevalent, disruptive illness. A majority of those with MDD are at high risk for recurrence and increased risk for morbidity and mortality. This study examined whether multimodal baseline (and retest) Cognitive Control performance and neuroimaging markers (task activation and neural connectivity between key brain nodes) could differentiate between those with and without future recurrence of a major depressive (MD) episode within one year. We hypothesized that performance and neuroimaging measures of Cognitive Control would identify markers that differ between these two groups. METHODS: A prospective cohort study of young adults (ages 18-23) with history (h) of early-onset MDD (N = 60), now remitted, and healthy young adults (N = 49). Baseline Cognitive Control measures of performance, task fMRI and resting state connectivity (and reliability retest 4-12 weeks later) were used to compare those with future recurrence of MDD (N = 21) relative to those without future recurrence of MDD (N = 34 with resilience). The measures tested were (1) Parametric Go/No-Go (PGNG) performance, and task activation for (2) PGNG Correct Rejections, (3) PGNG Commission errors, and (4 & 5), resting state connectivity analyses of Cognitive Control Network to and from subgenual anterior cingulate. RESULTS: Relative to other groups at baseline, the group with MDD Recurrence had less bilateral middle frontal gyrus activation during commission errors. MDD Recurrence exhibited greater connectivity of right middle frontal gyrus to subgenual anterior cingulate (SGAC). SGAC connectivity was also elevated in this group to numerous regions in the Cognitive Control Network. Moderate to strong ICCs were present from test to retest, and highest for rs-fMRI markers. There were modest, significant correlations between task, connectivity and behavioral markers that distinguished between groups. CONCLUSION: Markers of Cognitive Control function could identify those with early course MD who are at risk for depression recurrence. Those at high risk for recurrence would benefit from maintenance or preventative treatments. Future studies could test and validate these markers as potential predictors, accounting for sample selection and bias in feature detection.

Differential engagement of cognitive control regions and subgenual cingulate based upon presence or absence of comorbid anxiety with depression.

BACKGROUND: Major depressive disorder (MDD) and anxiety disorders are highly comorbid, sharing many similar symptoms, including impairments in cognitive control. Deficits in cognitive control could be a potential mechanism underlying impaired emotion regulation in mood disorders. METHODS: Participants were 44 individuals with no history of mental illness (healthy controls, HC), 31 individuals in the remitted state of MDD (rMDD), and 18 individuals who met lifetime DSM-IV-TR criteria for rMDD and an anxiety disorder in remission (Comorbid). Participants completed a Parametric Go/No-Go (PGNG) test during fMRI. Event-related analyses modeled activity for cognitive control successes (Hits for Targets, Rejections for Lures) and failures (Commissions on Lures) on the PGNG task. RESULTS: The rMDD group showed significantly reduced activity within the cognitive control network (CCN) during Commission errors, including the middle frontal gyrus and inferior parietal lobule (IPL). The Comorbid group showed significantly reduced activity in several clusters within the CCN during correct Rejections, including the left IPL and right inferior frontal gyrus and greater subgenual cingulate. Notably, during correct Rejections, 60% of activation for the Comorbid group was within the Salience and Emotion Network (SEN), with 0% within the CCN. LIMITATIONS: The size of the Comorbid subgroup was modest, preventing subanalysis of the different AD subtypes. CONCLUSIONS: There is evidence that CCN activity declines in rMDD and that there may be compensatory SEN activity in individuals with Comorbid rMDD and anxiety. Our findings support the identification of comorbid anxiety as a meaningful subtype of MDD that may obscure group differences between rMDD and HCs.

Disrupted engagement of networks supporting hot and cold cognition in remitted major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is characterized by dysfunction in cognitive and emotional systems. However, the neural network correlates of cognitive control (cold cognition) and emotion processing (hot cognition) during the remitted state of MDD (rMDD) remain unclear and not fully probed, which has important implications for identifying intermediate phenotypes of depression risk. METHODS: 43 young adults with rMDD and 33 healthy controls (HCs) underwent fMRI while completing separate tasks of cold cognition (Parametric Go/No-Go test) and hot cognition (Facial Emotion Processing Test). Two 2 group (rMDD, HC) × 2 event (sad/fearful faces, correct rejections) factorial models of activation were calculated in SPM8. Functional activation was evaluated in the salience and emotional network (SEN) and the cognitive control network (CCN), including hypothesized interaction between group and task within the CCN. RESULTS: Individuals with rMDD demonstrated greater spatial extent of suprathreshold activation within the SEN during sad faces relative to HCs. There were several regions within the CCN in which HCs showed greater activation than rMDD during correct rejections of lures, whereas individuals with rMDD showed greater activation than HCs during sad or fearful faces. LIMITATIONS: Results were not directly compared with active MDD. CONCLUSIONS: These results provide evidence of deficient CCN engagement during cognitive control in rMDD (dysfunctional cold cognition). Elevated SEN activation during sad faces could represent heightened salience of negative emotional faces in rMDD; elevated CCN activation during emotional faces in rMDD could represent compensatory regulatory control. These group differences may represent vulnerability factors, scars of prior depressive episodes, or processes maintaining wellness.

Differences in Real World Executive Function between Children with Pediatric Bipolar Disorder and Children with ADHD.

BACKGROUND: Recent research evidence suggests that executive function (EF) is impaired in both pediatric bipolar disorder (PBD) and attention deficit-hyperactivity disorder (ADHD), although the underlying cognitive mechanisms are still unclear. In this study we examined EF, including cognitive and emotional control, in three pediatric groups with overlapping symptoms. METHODS: Sixteen children and adolescents with PBD, 17 children and adolescents with ADHD, Type Combined, and 13 children and adolescents with PBD and comorbid ADHD (PBD+ADHD) (mean age=12.70, SD=2.21) were assessed using the Behavioral Rating Inventory of Executive Function - Parental Report (BRIEF-PR), clinical scales and neuropsychological tests of attention, working memory and executive function. RESULTS: All groups showed impairment on the Trails A and B tests. However, there were no significant group differences. On the BRIEF-PR while all three groups were impaired in General Executive Functioning and Metacognition only the two PBD groups revealed more extensive EF dysfunction, in both cognitive and emotional control domains, relative to the ADHD group. Conversely, the ADHD group exhibited selective deficits in cognitive domains such as working memory, planning/organization, monitoring, and metacognition. The two PBD groups showed greater impairment than the ADHD group in the domains of Inhibition, Shifting, Monitoring and Emotional Control. Furthermore, results from regression analyses suggest cognitive predictors of EF impairment in ADHD and mood predictors for inhibition in PBD. CONCLUSIONS: The current results contribute new knowledge on domain-specific similarities and differences in executive dysfunction between PBD, ADHD, and the comorbid phenotype, which may inform the diagnostic process and cognitive intervention.

CONTEXTE: Des données probantes issues de recherches récentes suggèrent que la fonction exécutive (FE) est déficiente dans le trouble bipolaire pédiatrique (TBP) et dans le trouble de déficit de l'attention avec hyperactivité (TDAH), bien que les mécanismes cognitifs sous-jacents ne soient pas encore bien définis. Dans cette étude, nous avons examiné la FE, y compris le contrôle cognitif et émotionnel, dans trois groupes pédiatriques présentant des symptômes se chevauchant. MÉTHODES: Seize enfants et adolescents souffrant de TBP, 17 enfants et adolescents souffrant de TDAH, de type combiné, et 13 enfants et adolescents souffrant de TBP et de TDAH comorbide (TBP+TDAH) (âge moyen = 12,70, ET = 2,21) ont été évalués à l'aide de l'Inventaire de comportements reliés aux fonctions exécutives -- rapport des parents (BRIEF-PR), d'échelles cliniques et de tests neuropsychologiques de l'attention, de la mémoire de travail et de la fonction exécutive. RÉSULTATS: Tous les groupes ont indiqué une déficience aux Trail making tests A et B. Toutefois, il n'y avait pas de différences significatives entre les groupes. Dans le BRIEF-PR, même si les trois groupes étaient déficients dans le fonctionnement exécutif général et la métacognition, seulement les deux groupes de TBP révélaient une dysfonction importante de la FE, dans les deux domaines de contrôle cognitif et émotionnel, relativement au groupe de TDAH. À l'inverse, le groupe de TDAH a révélé des déficits sélectifs dans les domaines cognitifs comme la mémoire de travail, la planification/organisation, la surveillance et la métacognition. Les deux groupes de TBP ont montré une plus grande déficience que le groupe de TDAH dans les domaines de l'inhibition, la flexibilité, la surveillance et le contrôle émotionnel. En outre, les résultats des analyses de régression suggèrent des prédicteurs cognitifs de la déficience de la FE dans le TDAH et des prédicteurs de l'humeur pour l'inhibition dans le TBP. CONCLUSIONS: Les présents résultats contribuent aux nouvelles connaissances sur les similitudes et les différences propres aux domaines en matière de dysfonction exécutive entre le TBP, le TDAH et le phénotype comorbide, ce qui peut éclairer le processus diagnostique et l'intervention cognitive.

Deficient inhibitory control as an outcome of childhood trauma.

Childhood trauma has been linked to the development and severity of psychiatric disorders as well as deficits in cognitive functioning. This study aimed to investigate the performance of bipolar disorder (BD) patients and healthy controls (HC), with or without a history of childhood trauma, on a parametric Go/No-Go (PGNG) task measuring important aspects of executive functions, namely attention and inhibitory control. Two hundred and thirty-three individuals with BD and 90 HC completed diagnostic interview, childhood trauma questionnaire (CTQ), symptom severity scales, and a PGNG task. Four comparison groups were created using a 1.0 standard deviation cut-off of the mean of the HC total CTQ score: BD-trauma, BD-normative, HC-trauma and HC-normative. We assessed interactions between diagnosis and trauma on Go/No-Go levels of interest by using a two-way multivariate analysis of covariance. Results showed a significant main effect of trauma on inhibitory control accuracy, as the trauma group exhibited significantly poorer accuracy on inhibition trials compared to the normative group. There was also a main effect of diagnosis on response time. These findings suggest that early trauma might adversely impact the development of cognitive systems and brain circuits that support inhibitory aspects of executive functioning in individuals with a history of trauma.

Affective personality predictors of disrupted reward learning and pursuit in major depressive disorder.

Anhedonia, the diminished anticipation and pursuit of reward, is a core symptom of major depressive disorder (MDD). Trait behavioral activation (BA), as a proxy for anhedonia, and behavioral inhibition (BI) may moderate the relationship between MDD and reward-seeking. The present studies probed for reward learning deficits, potentially due to aberrant BA and/or BI, in active or remitted MDD individuals compared to healthy controls (HC). Active MDD (Study 1) and remitted MDD (Study 2) participants completed the modified monetary incentive delay task (mMIDT), a behavioral reward-seeking task whose response window parameters were individually titrated to theoretically elicit equivalent accuracy between groups. Participants completed the BI Scale and BA Reward-Responsiveness and Drive Scales. Despite individual titration, active MDD participants won significantly less money than HCs. Higher Reward-Responsiveness scores predicted more won; Drive and BI were not predictive. Remitted MDD participants' performance did not differ from controls', and trait BA and BI measures did not predict r-MDD performance. These results suggest that diminished reward-responsiveness may contribute to decreased motivation and reward pursuit during active MDD, but that reward learning is intact in remission. Understanding individual reward processing deficits in MDD may inform personalized intervention addressing anhedonia and motivation deficits in select MDD patients.

Current Neural and Behavioral Dimensional Constructs across Mood Disorders.

Our understanding of the underlying neurobiology for mood disorders is still limited. We present an integrated model for conceptualizing and understanding mood disorders drawing upon a broad literature pertinent to mood disorders. The integrated model of emotion processing and regulation incorporates the linguistic constructs of the Research Domain Criteria (RDoC) initiative. In particular, we focus on the Positive Valence domain/circuit (PVC), highlighting recent reward research and the Negative Valence domain/circuit (NVC), highlighting rumination. Furthermore, we also illustrate the Cognitive Control and Problem Solving (CCaPS) circuit, which is heavily involved in emotion regulation, as well as the default mode network (DMN) and interactions between circuits. We conclude by proposing methods for addressing challenges in the developmental study of mood disorders including using high-risk design that incorporates risk for many disorders.

Development of superficial white matter and its structural interplay with cortical gray matter in children and adolescents.

Healthy human brain undergoes significant changes during development. The developmental trajectory of superficial white matter (SWM) is less understood relative to cortical gray matter (GM) and deep white matter. In this study, a multimodal imaging strategy was applied to vertexwise map SWM microstructure and cortical thickness to characterize their developmental pattern and elucidate SWM-GM associations in children and adolescents. Microscopic changes in SWM were evaluated with water diffusion parameters including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in 133 healthy subjects aged 10-18 years. Results demonstrated distinct maturational patterns in SWM and GM. SWM showed increasing FA and decreasing MD and RD underneath bilateral motor sensory cortices and superior temporal auditory cortex, suggesting increasing myelination. A second developmental pattern in SWM was increasing FA and AD in bilateral orbitofrontal regions and insula, suggesting improved axonal coherence. These SWM patterns diverge from the more widespread GM maturation, suggesting that cortical thickness changes in adolescence are not explained by the encroachment of SWM myelin into the GM-WM boundary. Interestingly, age-independent intrinsic association between SWM and cortical GM seems to follow functional organization of polymodal and unimodal brain regions. Unimodal sensory areas showed positive correlation between GM thickness and FA whereas polymodal regions showed negative correlation. Axonal coherence and differences in interstitial neuron composition between unimodal and polymodal regions may account for these SWM-GM association patterns. Intrinsic SWM-GM relationships unveiled by neuroimaging in vivo can be useful for examining psychiatric disorders with known WM/GM disturbances.

Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania.

BACKGROUND: The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder. METHODS: Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks. RESULTS: We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls. LIMITATIONS: Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population. CONCLUSION: Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdala's engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest.

Negative emotion interference during a synonym matching task in pediatric bipolar disorder with and without attention deficit hyperactivity disorder.

This study examined whether processing of emotional words impairs cognitive performance in acutely ill patients with pediatric bipolar disorder (PBD), with or without comorbid attention-deficit hyperactivity disorder (ADHD), relative to healthy controls (HC). Forty youths with PBD without ADHD, 20 youths with PBD and ADHD, and 29 HC (mean age = 12.97 ± 3.13) performed a Synonym Matching task, where they decided which of two probe words was the synonym of a target word. The three words presented on each trial all had the same emotional valence, which could be negative, positive, or neutral. Relative to HC both PBD groups exhibited worse accuracy for emotional words relative to neutral ones. This effect was greater with negative words and observed regardless of whether PBD patients had comorbid ADHD. In the PBD group without ADHD, manic symptoms correlated negatively with accuracy for negative words, and positively with reaction time (RT) for all word types. Our findings suggest a greater disruptive effect of emotional valence in both PBD groups relative to HC, reflecting the adverse effect of altered emotion processing on cognitive function in PBD. Future studies including an ADHD group will help clarify how ADHD symptoms may affect emotional interference independently of PBD.

Deficits in emotion recognition in pediatric bipolar disorder: the mediating effects of irritability.

BACKGROUND: Pediatric Bipolar Disorder (PBD) is a debilitating condition associated with impairment in many domains. Social functioning is one of the disorder's most notable areas of impairment and this deficit may be in part due to difficulties recognizing affect in others. METHODS: In the present study, medication naïve youth with PBD were compared to age-matched healthy controls on their ability to (a) distinguish between categorical emotions, such as happiness, anger, and sadness on the Emotion Recognition Test (ER-40) and (b) differentiate between levels of emotional intensity on an adapted version of the Penn Emotional Acuity Task (Chicago-PEAT). RESULTS: Results indicated that PBD youth misidentified sad, fearful, and neutral faces more often than controls, and PBD girls mislabeled 'very angry' faces more often than healthy girls. A mediation analyses indicated that these diagnostic group differences on emotion recognition were significantly mediated by irritability. LIMITATIONS: The Chicago-PEAT only examined variations in emotional intensity for the emotions happy and anger. Additionally, all results are correlational; therefore causal inferences cannot be made. CONCLUSIONS: Supporting previous literature, the present findings highlight the importance of emotion recognition deficits in PBD individuals. Additionally, the irritability associated with PBD may be an important mechanism of this deficit and may thus represent an important target for treatment.

Where, when, how high, and how long? The hemodynamics of emotional response in psychotropic-naïve patients with adolescent bipolar disorder.

BACKGROUND: In response to emotional faces, patients with adolescent bipolar disorder (ABD) exhibit increased neural activity in subcortical emotional processing regions (e.g., amygdala, ventral striatum) and variable prefrontal activity. We extend previous research by identifying cortical and subcortical regions showing altered hemodynamic response shapes in ABD relative to healthy controls (HC). METHODS: ABD (N=65) and matched HC (N=79) completed a slow event-related affective hemodynamic probe task that required indicating the gender of fearful and neutral faces. An informed basis set in SPM8 evaluated shape variations of the hemodynamic responses to these faces. RESULTS: Patients with ABD showed higher activity for fearful relative to neutral faces in the amygdala and prefrontal cortex and a delayed hemodynamic response to fearful faces in dorsolateral and ventrolateral prefrontal cortices (PFC), as well as bilateral amygdala and caudate. Furthermore, the ABD group, relative to HC, showed a prolonged response to fearful faces in right dorsolateral PFC. Clinical measures of mania and depression severity correlated with increased processing delays in the amygdala and striatum. LIMITATIONS: By design, the task contained fewer, more widely-spaced stimuli, possibly reducing its power to detect group differences. The use of fearful faces makes comparisons with prior literature in ABD somewhat more difficult. CONCLUSIONS: The ABD group engaged in enhanced neural processing of the fearful faces which was associated with increasingly severe manic/mixed mood states. These exploratory findings could help elucidate a "biosignature" of emotion-attention interactions in ABD and present a potential target for reversal with medication treatment.

Reduced functional connectivity of prefrontal regions and amygdala within affect and working memory networks in pediatric bipolar disorder.

This study examined whether adolescents with pediatric bipolar disorder (PBD) have abnormal regional functional connectivity in distributed brain networks during an affective working memory task. Adolescents with PBD (n=41) and healthy controls (HC; n=16) performed a two-back functional magnetic resonance imaging working memory task with blocks of either angry or neutral faces. Independent component analysis methodology identified two temporally independent and functionally connected brain networks that showed differential functional connectivity in PBD and HC. Within a network for "affect evaluation and regulation," PBD showed decreased functional connectivity relative to HC in regions involved in emotion processing such as the right amygdala, and in emotion regulation regions such as the right ventrolateral prefrontal cortex (VLPFC), while functional connectivity was increased in emotion evaluation regions such as the bilateral medial PFC. Furthermore, in an "Affective Working Memory Network," PBD exhibited greater connectivity relative to HC in left dorsolateral PFC (DLPFC), caudate, and right VLPFC; and simultaneously reduced connectivity in emotion processing regions, such as the right amygdala, bilateral temporal regions, and the junction of DLPFC/VLPFC, which interfaces affective and cognitive processes. Dysfunction in network engagement in PBD patients illustrates that they are expending greater effort in face emotion evaluation, while being less able to engage affect regulation regions.

Microstructural abnormalities of white matter differentiate pediatric and adult-onset bipolar disorder.

OBJECTIVES: White-matter microstructure, known to undergo significant developmental transformation, is abnormal in bipolar disorder (BD). Available evidence suggests that white-matter deviation may be more pronounced in pediatric than adult-onset BD. The present study aimed to examine how white-matter microstructure deviates from a typical maturational trajectory in BD. METHODS: Fractional anisotropy (FA) was measured in 35 individuals presenting with first episode BD (type I) and 46 healthy controls (HC) (aged 9-42) using diffusion tensor imaging (DTI). Patients were medication free and close to illness onset at the time of the DTI scans. Tract-based spatial statistics were used to examine the center of white-matter tracts, and FA was extracted from nine tracts of interest. Axial, radial, and mean diffusivity were examined in post-hoc analyses. RESULTS: The left anterior limb of the internal capsule (ALIC) showed significantly lower FA in pediatric than adult-onset BD. The lower FA in BD was due primarily to greater radial, rather than decreased axial, diffusivity. CONCLUSIONS: The ALIC connects the frontal lobes with archistriatum, thalamus, and medial temporal regions, and alteration in these pathways may contribute to mood dysregulation in BD. Abnormalities in this pathway appear to be associated with an earlier onset of illness and thus may reflect a greater susceptibility to illness.